Bio

Bio


Robert W. Haile, M.D., PhD, is a Professor in the Division of Oncology at Stanford University School of Medicine and the Associate Director for Population Sciences at the Stanford Cancer Institute. He has 30 years of experience conducting genetic epidemiology studies of cancer, including several large, international, multi-institutional studies of breast and colorectal cancer. He served as Chair of the Steering Committee of the Colon Cancer Family Registry (Colon CFR) for four years and then co-chair of the Colon CFR SC for another four years and directed two successful renewals of the Colon CFR. He is the Principle Investigator of the USC Consortium within the Colon CFR, which includes seven institutions nationally. He also served on the external Advisory Committee for the Breast Cancer Family Registry. Robert founded and directs the Latin American Cancer Epidemiology (LACE) consortium, which includes members from Spain, Puerto Rico, Brazil, Argentina, Chile, Uruguay, Colombia, El Salvador, and Mexico. The long-term goal of LACE is to establish centers in each of the member countries to support etiological, prevention, and clinical research in cancer. He was also Principal Investigator of an international study of families with ataxia telangiectasia (AT) and risk of cancer that involved centers in seven countries. He has also been a member of the Polyps Prevention Studies Group (PPSG), directed by Dr. John Baron, for 20 years. The PPSG has conducted numerous randomized, double-blind, placebo-controlled prevention trials of colorectal adenomas.

Academic Appointments


Administrative Appointments


  • Associate Director, Population Sciences, Stanford Cancer Institute (2012 - Present)
  • Founder and Director, Latin American Cancer Epidemiology (2008 - Present)
  • Associate Director, Norris Comprehensive Cancer Center, USC (2007 - 2012)
  • Chair, Steering Committee, Collaborative Family Registries for Colorectal Cancer Reaserch (1998 - 2002)
  • Director of Genetic Epidemiology Program, Department of Preventative Medicine, USC School of Medicine (1994 - 2012)

Honors & Awards


  • Lifetime Achievement Award, Collaborative Group of the Americas (2014)

Professional Education


  • Dr.P.H, University of California, Los Angeles, Epidemiology (1979)
  • MPH, University of California, Los Angeles, Population, Family, International Health (1974)
  • B.A., University of California, Riverside, Psychology (1973)

Research & Scholarship

Current Research and Scholarly Interests


Robert Haile's main areas of research interest include genetics, cancer epidemiology and cancer health disparities with a focus on genetic and epidemiologic studies of colon and breast cancer.

Robert's early studies were some of the first to bring formal statistical genetics techniques to the study of non-Mendelian disease with variable age-of-onset and variable penetrance. Robert was among the first to apply for formal, lod score-based analysis to multiple sclerosis pedigrees; the first to develop and incorporate an age-of-onset correction into these analyses; and the first to use haplotypes to infer presence/absence of the “MS gene variant” to investigate gene-environment interactions with selected immune parameters, such as measles antibody titers.

Robert subsequently led efforts to extend segregation and linkage analyses to breast cancer, with a focus on population-based studies of bilateral breast cancer. He was the Principal Investigator of funded grants that enabled this research and, often, the first or last author of the resulting publications.

Another major focus of Robert’s research has been to help understand the etiology of colorectal adenomas and colorectal cancer, with a focus of lifestyle related factors that are potentially modifiable and gene-environment interactions.

From mid-career onwards, Robert has helped to provide senior leadership to a number of collaborative groups, including the Polyps Prevention Studies Group (PPSG) that is led by Dr. John Baron (Dartmouth and then University of North Carolina). In addition to serving as the PI of a clinical center at USC that included Kaiser Permanente, his role was to provide expertise in genetic epidemiology to the PPSG. The PPSG has contributed major articles on the preventive effects (or lack thereof) of beta carotene and vitamins C and E, calcium and vitamin D, folic acid, and aspirin. Robert plays a similar role in the WECARE study that is the largest single study in the world on bilateral breast cancer, which is led by Dr. Jonine Bernstein at Memorial Sloan Kettering Cancer Center.

In the latter half of his career, Robert has provided consistent, sustained leadership to the Colon Cancer Family Registry (CCFR) as Chair or Co-Chair of the Steering Committee, leading the CCFR through two successful renewals and, most recently, Contact PI of the CCFR Cohort grant. The Colon CFR has facilitated over 250 publications, many of which are seminal or important contributions to the field of colorectal cancer research.

Teaching

Publications

Journal Articles


  • Role of tumour molecular and pathology features to estimate colorectal cancer risk for first-degree relatives GUT Win, A. K., Buchanan, D. D., Rosty, C., MacInnis, R. J., Dowty, J. G., Dite, G. S., Giles, G. G., Southey, M. C., Young, J. P., Clendenning, M., Walsh, M. D., Walters, R. J., Boussioutas, A., Smyrk, T. C., Thibodeau, S. N., Baron, J. A., Potter, J. D., Newcomb, P. A., Le Marchand, L., Haile, R. W., Gallinger, S., Lindor, N. M., Hopper, J. L., Ahnen, D. J., Jenkins, M. A. 2015; 64 (1): 101-110

    Abstract

    To estimate risk of colorectal cancer (CRC) for first-degree relatives of CRC cases based on CRC molecular subtypes and tumour pathology features.We studied a cohort of 33,496 first-degree relatives of 4853 incident invasive CRC cases (probands) who were recruited to the Colon Cancer Family Registry through population cancer registries in the USA, Canada and Australia. We categorised the first-degree relatives into four groups: 28,156 of 4095 mismatch repair (MMR)-proficient probands, 2302 of 301 MMR-deficient non-Lynch syndrome probands, 1799 of 271 suspected Lynch syndrome probands and 1239 of 186 Lynch syndrome probands. We compared CRC risk for first-degree relatives stratified by the absence or presence of specific tumour molecular pathology features in probands across each of these four groups and for all groups combined.Compared with first-degree relatives of MMR-proficient CRC cases, a higher risk of CRC was estimated for first-degree relatives of CRC cases with suspected Lynch syndrome (HR 2.06, 95% CI 1.59 to 2.67) and with Lynch syndrome (HR 5.37, 95% CI 4.16 to 6.94), but not with MMR-deficient non-Lynch syndrome (HR 1.04, 95% CI 0.82 to 1.31). A greater risk of CRC was estimated for first-degree relatives if CRC cases were diagnosed before age 50 years, had proximal colon cancer or if their tumours had any of the following: expanding tumour margin, peritumoral lymphocytes, tumour-infiltrating lymphocytes or synchronous CRC.Molecular pathology features are potentially useful to refine screening recommendations for first-degree relatives of CRC cases and to identify which cases are more likely to be caused by genetic or other familial factors.

    View details for DOI 10.1136/gutjnl-2013-306567

    View details for Web of Science ID 000346167700015

    View details for PubMedID 24615377

  • Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Tillmans, L. S., Vierkant, R. A., Wang, A. H., Samadder, N. J., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2015

    Abstract

    Background: Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer (CRC) risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor beta (ESR2) has been associated with CRC stage and survival. Methods: In this prospective cohort study, we examined smoking, MHT, and folate -associated CRC risks by ESR2protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded CRC tissue specimens were collected and evaluated for ESR2protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between smoking, MHT, or folate and ESR2-defined CRC subtypes. Results: Informative environmental exposure and protein expression data were available for 491 incident CRC cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR = 4.24; 95% CI = 1.81-9.91 for ESR2-low and RR=2.15; 95%CI=1.05-4.41 for ESR2-high for >40 cigarettes compared to non-smokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR = 0.54; 95% CI = 0.26-1.13 for > 5 years compared to never use). No associations were found for folate. Conclusions: In this study, smoking and MHT were associated with ESR2expression patterns. Impact: These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women.

    View details for DOI 10.1158/1055-9965.EPI-14-0756

    View details for PubMedID 25650184

  • Association of the Colorectal CpG Island Methylator Phenotype with Molecular Features, Risk Factors, and Family History. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Weisenberger, D. J., Levine, A. J., Long, T. I., Buchanan, D. D., Walters, R., Clendenning, M., Rosty, C., Joshi, A. D., Stern, M. C., Le Marchand, L., Lindor, N. M., Daftary, D., Gallinger, S., Selander, T., Bapat, B., Newcomb, P. A., Campbell, P. T., Casey, G., Ahnen, D. J., Baron, J. A., Haile, R. W., Hopper, J. L., Young, J. P., Laird, P. W., Siegmund, K. D. 2015

    Abstract

    The CpG island methylator phenotype (CIMP) represents a subset of colorectal cancers characterized by widespread aberrant DNA hypermethylation at select CpG islands. The risk factors and environmental exposures contributing to etiologic heterogeneity between CIMP and non-CIMP tumors are not known.We measured the CIMP status of 3,119 primary population-based colorectal cancer tumors from the multinational Colon Cancer Family Registry. Etiologic heterogeneity was assessed by a case-case study comparing risk factor frequency of colorectal cancer cases with CIMP and non-CIMP tumors using logistic regression to estimate the case-case odds ratio (ccOR).We found associations between tumor CIMP status and MSI-H (ccOR = 7.6), BRAF V600E mutation (ccOR = 59.8), proximal tumor site (ccOR = 9; all P < 0.0001), female sex [ccOR = 1.8; 95% confidence interval (CI), 1.5-2.1], older age (ccOR = 4.0 comparing over 70 years vs. under 50; 95% CI, 3.0-5.5), and family history of CRC (ccOR = 0.6; 95% CI, 0.5-0.7). While use of NSAIDs varied by tumor CIMP status for both males and females (P = 0.0001 and P = 0.02, respectively), use of multivitamin or calcium supplements did not. Only for female colorectal cancer was CIMP status associated with increased pack-years of smoking (Ptrend < 0.001) and body mass index (BMI; Ptrend = 0.03).The frequency of several colorectal cancer risk factors varied by CIMP status, and the associations of smoking and obesity with tumor subtype were evident only for females.Differences in the associations of a unique DNA methylation-based subgroup of colorectal cancer with important lifestyle and environmental exposures increase understanding of the molecular pathologic epidemiology of this heavily methylated subset of colorectal cancer. Cancer Epidemiol Biomarkers Prev; 24(3); 1-8. ©2015 AACR.

    View details for DOI 10.1158/1055-9965.EPI-14-1161

    View details for PubMedID 25587051

  • Association of Aspirin and NSAID Use With Risk of Colorectal Cancer According to Genetic Variants. JAMA Nan, H., Hutter, C. M., Lin, Y., Jacobs, E. J., Ulrich, C. M., White, E., Baron, J. A., Berndt, S. I., Brenner, H., Butterbach, K., Caan, B. J., Campbell, P. T., Carlson, C. S., Casey, G., Chang-Claude, J., Chanock, S. J., Cotterchio, M., Duggan, D., Figueiredo, J. C., Fuchs, C. S., Giovannucci, E. L., Gong, J., Haile, R. W., Harrison, T. A., Hayes, R. B., Hoffmeister, M., Hopper, J. L., Hudson, T. J., Jenkins, M. A., Jiao, S., Lindor, N. M., Lemire, M., Le Marchand, L., Newcomb, P. A., Ogino, S., Pflugeisen, B. M., Potter, J. D., Qu, C., Rosse, S. A., Rudolph, A., Schoen, R. E., Schumacher, F. R., Seminara, D., Slattery, M. L., Thibodeau, S. N., Thomas, F., Thornquist, M., Warnick, G. S., Zanke, B. W., Gauderman, W. J., Peters, U., Hsu, L., Chan, A. T. 2015; 313 (11): 1133-1142

    Abstract

    Use of aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs) is associated with lower risk of colorectal cancer.To identify common genetic markers that may confer differential benefit from aspirin or NSAID chemoprevention, we tested gene × environment interactions between regular use of aspirin and/or NSAIDs and single-nucleotide polymorphisms (SNPs) in relation to risk of colorectal cancer.Case-control study using data from 5 case-control and 5 cohort studies initiated between 1976 and 2003 across the United States, Canada, Australia, and Germany and including colorectal cancer cases (n=8634) and matched controls (n=8553) ascertained between 1976 and 2011. Participants were all of European descent.Genome-wide SNP data and information on regular use of aspirin and/or NSAIDs and other risk factors.Colorectal cancer.Regular use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer (prevalence, 28% vs 38%; odds ratio [OR], 0.69 [95% CI, 0.64-0.74]; P = 6.2 × 10-28) compared with nonregular use. In the conventional logistic regression analysis, the SNP rs2965667 at chromosome 12p12.3 near the MGST1 gene showed a genome-wide significant interaction with aspirin and/or NSAID use (P = 4.6 × 10-9 for interaction). Aspirin and/or NSAID use was associated with a lower risk of colorectal cancer among individuals with rs2965667-TT genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.61-0.70]; P = 7.7 × 10-33) but with a higher risk among those with rare (4%) TA or AA genotypes (prevalence, 35% vs 29%; OR, 1.89 [95% CI, 1.27-2.81]; P = .002). In case-only interaction analysis, the SNP rs16973225 at chromosome 15q25.2 near the IL16 gene showed a genome-wide significant interaction with use of aspirin and/or NSAIDs (P = 8.2 × 10-9 for interaction). Regular use was associated with a lower risk of colorectal cancer among individuals with rs16973225-AA genotype (prevalence, 28% vs 38%; OR, 0.66 [95% CI, 0.62-0.71]; P = 1.9 × 10-30) but was not associated with risk of colorectal cancer among those with less common (9%) AC or CC genotypes (prevalence, 36% vs 39%; OR, 0.97 [95% CI, 0.78-1.20]; P = .76).In this genome-wide investigation of gene × environment interactions, use of aspirin and/or NSAIDs was associated with lower risk of colorectal cancer, and this association differed according to genetic variation at 2 SNPs at chromosomes 12 and 15. Validation of these findings in additional populations may facilitate targeted colorectal cancer prevention strategies.

    View details for DOI 10.1001/jama.2015.1815

    View details for PubMedID 25781442

  • Lung Cancer Incidence Trends by Histology Type among Asian American, Native Hawaiian, and Pacific Islander Populations in the United States, 1990-2010 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cheng, I., Le, G. M., Noone, A., Gali, K., Patel, M., Haile, R. W., Wakelee, H. A., Gomez, S. L. 2014; 23 (11): 2250-2265
  • A novel colorectal cancer risk locus at 4q32.2 identified from an international genome-wide association study CARCINOGENESIS Schmit, S. L., Schumacher, F. R., Edlund, C. K., Conti, D. V., Raskin, L., Lejbkowicz, F., Pinchev, M., Rennert, H. S., Jenkins, M. A., Hopper, J. L., Buchanan, D. D., Lindor, N. M., Le Marchand, L., Gallinger, S., Haile, R. W., Newcomb, P. A., Huang, S., Rennert, G., Casey, G., Gruber, S. B. 2014; 35 (11): 2512-2519

    Abstract

    Only a fraction of colorectal cancer heritability is explained by known risk-conferring genetic variation. This study was designed to identify novel risk alleles in Europeans. We conducted a genome-wide association study (GWAS) meta-analysis of colorectal cancer in participants from a population-based case-control study in Israel (n = 1616 cases, 1329 controls) and a consortium study from the Colon Cancer Family Registry (n = 1977 cases, 999 controls). We used a two-stage (discovery-replication) GWAS design, followed by a joint meta-analysis. A combined analysis identified a novel susceptibility locus that reached genome-wide significance on chromosome 4q32.2 [rs35509282, risk allele = A (minor allele frequency = 0.09); odds ratio (OR) per risk allele = 1.53; P value = 8.2 × 10(-9); nearest gene = FSTL5]. The direction of the association was consistent across studies. In addition, we confirmed that 14 of 29 previously identified susceptibility variants were significantly associated with risk of colorectal cancer in this study. Genetic variation on chromosome 4q32.2 is significantly associated with risk of colorectal cancer in Ashkenazi Jews and Europeans in this study.

    View details for DOI 10.1093/carcin/bgu148

    View details for Web of Science ID 000345835800014

    View details for PubMedID 25023989

  • Trans-ethnic genome-wide association study of colorectal cancer identifies a new susceptibility locus in VTI1A NATURE COMMUNICATIONS Wang, H., Burnett, T., Kono, S., Haiman, C. A., Iwasaki, M., Wilkens, L. R., Loo, L. W., Van Den Berg, D., Kolonel, L. N., Henderson, B. E., Keku, T. O., Sandler, R. S., Signorello, L. B., Blot, W. J., Newcomb, P. A., Pande, M., Amos, C. I., West, D. W., Bezieau, S., Berndt, S. I., Zanke, B. W., Hsu, L., Lindor, N. M., Haile, R. W., Hopper, J. L., Jenkins, M. A., Gallinger, S., Casey, G., Stenzel, S. L., Schumacher, F. R., Peters, U., Gruber, S. B., Tsugane, S., Stram, D. O., Le Marchand, L. 2014; 5

    Abstract

    The genetic basis of sporadic colorectal cancer (CRC) is not well explained by known risk polymorphisms. Here we perform a meta-analysis of two genome-wide association studies in 2,627 cases and 3,797 controls of Japanese ancestry and 1,894 cases and 4,703 controls of African ancestry, to identify genetic variants that contribute to CRC susceptibility. We replicate genome-wide statistically significant associations (P<5 × 10(-8)) in 16,823 cases and 18,211 controls of European ancestry. This study reveals a new pan-ethnic CRC risk locus at 10q25 (rs12241008, intronic to VTI1A; P=1.4 × 10(-9)), providing additional insight into the aetiology of CRC and highlighting the value of association mapping in diverse populations.

    View details for DOI 10.1038/ncomms5613

    View details for Web of Science ID 000341057000004

    View details for PubMedID 25105248

  • Family History of Colorectal Cancer Is Not Associated with Colorectal Cancer Survival Regardless of Microsatellite Instability Status CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Phipps, A. I., Ahnen, D. J., Campbell, P. T., Win, A. K., Jenkins, M. A., Lindor, N. M., Gryfe, R., Potter, J. D., Newcomb, P. A. 2014; 23 (8): 1700-1704

    Abstract

    Individuals with a family history of colorectal cancer in first-degree relatives have an elevated risk of developing colorectal cancer themselves, particularly colorectal cancer exhibiting high microsatellite instability (MSI-high). Given that MSI-high colorectal cancer is associated with a favorable prognosis, it is plausible that having a family history of colorectal cancer could, in turn, be favorably associated with colorectal cancer survival.This study comprised N = 4,284 incident colorectal cancer cases enrolled in the Colon Cancer Family Registry via population-based cancer registries. Using Cox proportional hazards regression, we evaluated the association between family history and both overall and disease-specific survival, accounting for MSI status and tumor site via stratified analyses and statistical adjustment.There was no evidence of association between family history and overall [hazard ratio (HR), 0.92; 95% confidence interval (CI), 0.79-1.08] or disease-specific survival (HR, 1.03; 95% CI, 0.85-1.24) for all cases combined, after adjustment for MSI status or tumor site. Only for rectal cancer cases was colorectal cancer family history modestly associated with more favorable overall survival (HR, 0.75; 95% CI, 0.56-0.99).Although individuals with a family history of colorectal cancer were more likely to have MSI-high tumors than those with nonfamilial disease, this did not translate to a survival benefit.Overall, there is no evidence that family history of colorectal cancer is associated with colorectal cancer survival; however, specific mechanisms underlying family history may have prognostic impact and merit further study.

    View details for DOI 10.1158/1055-9965.EPI-14-0533

    View details for Web of Science ID 000345274200029

    View details for PubMedID 24891550

  • Characterisation of Familial Colorectal Cancer Type X, Lynch syndrome, and non-familial colorectal cancer. British journal of cancer Shiovitz, S., Copeland, W. K., Passarelli, M. N., Burnett-Hartman, A. N., Grady, W. M., Potter, J. D., Gallinger, S., Buchanan, D. D., Rosty, C., Win, A. K., Jenkins, M., Thibodeau, S. N., Haile, R., Baron, J. A., Marchand, L. L., Newcomb, P. A., Lindor, N. M. 2014; 111 (3): 598-602

    Abstract

    Familial Colorectal Cancer Type X (FCCTX) is defined as individuals with colorectal cancer (CRC) who families meet Amsterdam Criteria-1 (AC1), but whose tumours are DNA-mismatch-repair-proficient, unlike Lynch syndrome (LS). FCCTX does not have an increased risk of extra-colonic cancers. This analysis compares epidemiologic and clinicopathologic features among FCCTX, LS, and 'non-familial' (non-AC1) CRC cases.From the Colon Cancer Family Registry, FCCTX (n=173), LS (n=303), and non-AC1 (n=9603) CRC cases were identified. Questionnaire-based epidemiologic information and CRC pathologic features were compared across case groups using polytomous logistic regression.Compared with LS, FCCTX cases were less likely to be current (vs never) smokers; have a proximal subsite (vs rectal) tumour; or have mucinous histology, poor differentiation, or tumour-infiltrating lymphocytes. There were no observed differences in co-morbidities or medication usage.FCCTX were less likely to be current tobacco users; other exposures were similar between these groups. Histopathologic differences highly suggestive of LS CRCs do not appear to be shared by FCCTX.

    View details for DOI 10.1038/bjc.2014.309

    View details for PubMedID 24918813

  • Does risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair gene depend on family history of endometrial cancer or colorectal cancer? GYNECOLOGIC ONCOLOGY Bharati, R., Jenkins, M. A., Lindor, N. M., Le Marchand, L., Gallinger, S., Haile, R. W., Newcomb, P. A., Hopper, J. L., Win, A. K. 2014; 133 (2): 287-292

    Abstract

    To determine whether risk of endometrial cancer for women without a germline mutation in a DNA mismatch repair (MMR) gene depends on family history of endometrial or colorectal cancer.We retrospectively followed a cohort of 79,166 women who were recruited to the Colon Cancer Family Registry, after exclusion of women who were relatives of a carrier of a MMR gene mutation. The Kaplan-Meier failure method was used to estimate the cumulative risk of endometrial cancer. Cox regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for association between family history of endometrial or colorectal cancer and risk of endometrial cancer.A total of 628 endometrial cancer cases were observed, with mean age at diagnosis of 54.4 (standard deviation: 15.7) years. The cumulative risk of endometrial cancer to age 70 years was estimated to be 0.94% (95% CI 0.83-1.05) for women with no family history of endometrial cancer, and 3.80% (95% CI 2.75-4.98) for women with at least one first- or second-degree relative with endometrial cancer. Compared with women without family history, we found an increased risk of endometrial cancer for women with at least one first- or second-degree relative with endometrial cancer (HR 3.66, 95% CI 2.63-5.08), and for women with one first-degree relative with colorectal cancer diagnosed at age <50 years (HR 1.48, 95% CI 1.15-1.91).An increased risk of endometrial cancer is associated with a family history of endometrial cancer or early-onset colorectal cancer for women without a MMR gene mutation, indicating for potential underlying genetic and environmental factors shared by colorectal and endometrial cancers other than caused by MMR gene mutations.

    View details for DOI 10.1016/j.ygyno.2014.03.011

    View details for Web of Science ID 000335540700027

    View details for PubMedID 24631449

  • Pleiotropic effects of genetic risk variants for other cancers on colorectal cancer risk: PAGE, GECCO and CCFR consortia GUT Cheng, I., Kocarnik, J. M., Dumitrescu, L., Lindor, N. M., Chang-Claude, J., Avery, C. L., Caberto, C. P., Love, S., Slattery, M. L., Chan, A. T., Baron, J. A., Hindorff, L. A., Park, S. L., Schumacher, F. R., Hoffmeister, M., Kraft, P., Butler, A. M., Duggan, D. J., Hou, L., Carlson, C. S., Monroe, K. R., Lin, Y., Carty, C. L., Mann, S., Ma, J., Giovannucci, E. L., Fuchs, C. S., Newcomb, P. A., Jenkins, M. A., Hopper, J. L., Haile, R. W., Conti, D. V., Campbell, P. T., Potter, J. D., Caan, B. J., Schoen, R. E., Hayes, R. B., Chanock, S. J., Berndt, S. I., Kuery, S., Bezieau, S., Ambite, J. L., Kumaraguruparan, G., Richardson, D. M., Goodloe, R. J., Dilks, H. H., Baker, P., Zanke, B. W., Lemire, M., Gallinger, S., Hsu, L., Jiao, S., Harrison, T. A., Seminara, D., Haiman, C. A., Kooperberg, C., Wilkens, L. R., Hutter, C. M., White, E., Crawford, D. C., Heiss, G., Hudson, T. J., Brenner, H., Bush, W. S., Casey, G., Le Marchand, L., Peters, U. 2014; 63 (5): 800-807

    Abstract

    Genome-wide association studies have identified a large number of single nucleotide polymorphisms (SNPs) associated with a wide array of cancer sites. Several of these variants demonstrate associations with multiple cancers, suggesting pleiotropic effects and shared biological mechanisms across some cancers. We hypothesised that SNPs previously associated with other cancers may additionally be associated with colorectal cancer. In a large-scale study, we examined 171 SNPs previously associated with 18 different cancers for their associations with colorectal cancer.We examined 13 338 colorectal cancer cases and 40 967 controls from three consortia: Population Architecture using Genomics and Epidemiology (PAGE), Genetic Epidemiology of Colorectal Cancer (GECCO), and the Colon Cancer Family Registry (CCFR). Study-specific logistic regression results, adjusted for age, sex, principal components of genetic ancestry, and/or study specific factors (as relevant) were combined using fixed-effect meta-analyses to evaluate the association between each SNP and colorectal cancer risk. A Bonferroni-corrected p value of 2.92×10(-4) was used to determine statistical significance of the associations.Two correlated SNPs--rs10090154 and rs4242382--in Region 1 of chromosome 8q24, a prostate cancer susceptibility region, demonstrated statistically significant associations with colorectal cancer risk. The most significant association was observed with rs4242382 (meta-analysis OR=1.12; 95% CI 1.07 to 1.18; p=1.74×10(-5)), which also demonstrated similar associations across racial/ethnic populations and anatomical sub-sites.This is the first study to clearly demonstrate Region 1 of chromosome 8q24 as a susceptibility locus for colorectal cancer; thus, adding colorectal cancer to the list of cancer sites linked to this particular multicancer risk region at 8q24.

    View details for DOI 10.1136/gutjnl-2013-305189

    View details for Web of Science ID 000334393400016

    View details for PubMedID 23935004

  • Risk of Colorectal Cancer for Carriers of Mutations in MUTYH, With and Without a Family History of Cancer GASTROENTEROLOGY Win, A. K., Dowty, J. G., Cleary, S. P., Kim, H., Buchanan, D. D., Young, J. P., Clendenning, M., Rosty, C., MacInnis, R. J., Giles, G. G., Boussioutas, A., Macrae, F. A., Parry, S., Goldblatt, J., Baron, J. A., Burnett, T., Le Marchand, L., Newcomb, P. A., Haile, R. W., Hopper, J. L., Cotterchio, M., Gallinger, S., Lindor, N. M., Tucker, K. M., Winship, I. M., Jenkins, M. A. 2014; 146 (5): 1208-?

    Abstract

    We studied 2332 individuals with monoallelic mutations in MUTYH among 9504 relatives of 264 colorectal cancer (CRC) cases with a MUTYH mutation. We estimated CRC risks through 70 years of age of 7.2% for male carriers of monoallelic mutations (95% confidence interval [CI], 4.6%-11.3%) and 5.6% for female carriers of monoallelic mutations (95% CI, 3.6%-8.8%), irrespective of family history. For monoallelic MUTYH mutation carriers with a first-degree relative with CRC diagnosed by 50 years of age who does not have the MUTYH mutation, risks of CRC were 12.5% for men (95% CI, 8.6%-17.7%) and 10% for women (95% CI, 6.7%-14.4%). Risks of CRC for carriers of monoallelic mutations in MUTYH with a first-degree relative with CRC are sufficiently high to warrant more intensive screening than for the general population.

    View details for DOI 10.1053/j.gastro.2014.01.022

    View details for Web of Science ID 000334507600021

    View details for PubMedID 24444654

  • Genome-wide diet-gene interaction analyses for risk of colorectal cancer. PLoS genetics Figueiredo, J. C., Hsu, L., Hutter, C. M., Lin, Y., Campbell, P. T., Baron, J. A., Berndt, S. I., Jiao, S., Casey, G., Fortini, B., Chan, A. T., Cotterchio, M., Lemire, M., Gallinger, S., Harrison, T. A., Le Marchand, L., Newcomb, P. A., Slattery, M. L., Caan, B. J., Carlson, C. S., Zanke, B. W., Rosse, S. A., Brenner, H., Giovannucci, E. L., Wu, K., Chang-Claude, J., Chanock, S. J., Curtis, K. R., Duggan, D., Gong, J., Haile, R. W., Hayes, R. B., Hoffmeister, M., Hopper, J. L., Jenkins, M. A., Kolonel, L. N., Qu, C., Rudolph, A., Schoen, R. E., Schumacher, F. R., Seminara, D., Stelling, D. L., Thibodeau, S. N., Thornquist, M., Warnick, G. S., Henderson, B. E., Ulrich, C. M., Gauderman, W. J., Potter, J. D., White, E., Peters, U. 2014; 10 (4)

    Abstract

    Dietary factors, including meat, fruits, vegetables and fiber, are associated with colorectal cancer; however, there is limited information as to whether these dietary factors interact with genetic variants to modify risk of colorectal cancer. We tested interactions between these dietary factors and approximately 2.7 million genetic variants for colorectal cancer risk among 9,287 cases and 9,117 controls from ten studies. We used logistic regression to investigate multiplicative gene-diet interactions, as well as our recently developed Cocktail method that involves a screening step based on marginal associations and gene-diet correlations and a testing step for multiplicative interactions, while correcting for multiple testing using weighted hypothesis testing. Per quartile increment in the intake of red and processed meat were associated with statistically significant increased risks of colorectal cancer and vegetable, fruit and fiber intake with lower risks. From the case-control analysis, we detected a significant interaction between rs4143094 (10p14/near GATA3) and processed meat consumption (OR = 1.17; p = 8.7E-09), which was consistently observed across studies (p heterogeneity = 0.78). The risk of colorectal cancer associated with processed meat was increased among individuals with the rs4143094-TG and -TT genotypes (OR = 1.20 and OR = 1.39, respectively) and null among those with the GG genotype (OR = 1.03). Our results identify a novel gene-diet interaction with processed meat for colorectal cancer, highlighting that diet may modify the effect of genetic variants on disease risk, which may have important implications for prevention.

    View details for DOI 10.1371/journal.pgen.1004228

    View details for PubMedID 24743840

  • A Randomized Trial to Increase Colonoscopy Screening in Members of High-Risk Families in the Colorectal Cancer Family Registry and Cancer Genetics Network CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lowery, J. T., Horick, N., Kinney, A. Y., Finkelstein, D. M., Garrett, K., Haile, R. W., Lindor, N. M., Newcomb, P. A., Sandler, R. S., Burke, C., Hill, D. A., Ahnen, D. J. 2014; 23 (4): 601-610

    Abstract

    Individuals with a strong family history of colorectal cancer have significant risk for colorectal cancer, although adherence to colonoscopy screening in these groups remains low. This study assessed whether a tailored telephone counseling intervention can increase adherence to colonoscopy in members of high-risk families in a randomized, controlled trial.Eligible participants were recruited from two national cancer registries if they had a first-degree relative with colorectal cancer under age 60 or multiple affected family members, which included families that met the Amsterdam criteria for hereditary non-polyposis colon cancer (HNPCC), and if they were due for colonoscopy within 24 months. Participants were randomized to receive a tailored telephone intervention grounded in behavioral theory or a mailed packet with general information about screening. Colonoscopy status was assessed through follow-up surveys and endoscopy reports. Cox proportional hazards models were used to assess intervention effect.Of the 632 participants (ages 25-80), 60% were female, the majority were White, non-Hispanic, educated, and had health insurance. Colonoscopy adherence increased 11 percentage points in the tailored telephone intervention group, compared with no significant change in the mailed group. The telephone intervention was associated with a 32% increase in screening adherence compared with the mailed intervention (HR, 1.32; P = 0.01).A tailored telephone intervention can effectively increase colonoscopy adherence in high-risk persons. This intervention has the potential for broad dissemination to healthcare organizations or other high-risk populations.Increasing adherence to colonoscopy among persons with increased colorectal cancer risk could effectively reduce incidence and mortality from this disease. Cancer Epidemiol Biomarkers Prev; 23(4); 601-10. ©2014 AACR.

    View details for DOI 10.1158/1055-9965.EPI-13-1085

    View details for Web of Science ID 000335145000005

  • A Genome-wide Association Study of Early-Onset Breast Cancer Identifies PFKM as a Novel Breast Cancer Gene and Supports a Common Genetic Spectrum for Breast Cancer at Any Age CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ahsan, H., Halpern, J., Kibriya, M. G., Pierce, B. L., Tong, L., Gamazon, E., McGuire, V., Felberg, A., Shi, J., Jasmine, F., Roy, S., Brutus, R., Argos, M., Melkonian, S., Chang-Claude, J., Andrulis, I., Hopper, J. L., John, E. M., Malone, K., Ursin, G., Gammon, M. D., Thomas, D. C., Seminara, D., Casey, G., Knight, J. A., Southey, M. C., Giles, G. G., Santella, R. M., Lee, E., Conti, D., Duggan, D., Gallinger, S., Haile, R., Jenkins, M., Lindor, N. M., Newcomb, P., Michailidou, K., Apicella, C., Park, D. J., Peto, J., Fletcher, O., Silva, I. d., Lathrop, M., Hunter, D. J., Chanock, S. J., Meindl, A., Schmutzler, R. K., Mueller-Myhsok, B., Lochmann, M., Beckmann, L., Hein, R., Makalic, E., Schmidt, D. F., Quang Minh Bui, Q. M., Stone, J., Flesch-Janys, D., Dahmen, N., Nevanlinna, H., Aittomaki, K., Blomqvist, C., Hall, P., Czene, K., Irwanto, A., Liu, J., Rahman, N., Turnbull, C., Dunning, A. M., Pharoah, P., Waisfisz, Q., Meijers-Heijboer, H., Uitterlinden, A. G., Rivadeneira, F., Nicolae, D., Easton, D. F., Cox, N. J., Whittemore, A. S. 2014; 23 (4): 658-669

    Abstract

    Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages ≤ 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 × 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 × 10(-4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome-wide gene-based threshold of 2.5 × 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. Cancer Epidemiol Biomarkers Prev; 23(4); 658-69. ©2014 AACR.

    View details for DOI 10.1158/1055-9965.EPI-13-0340

    View details for Web of Science ID 000335145000011

    View details for PubMedID 24493630

  • Associations between Cigarette Smoking, Hormone Therapy, and Folate Intake with Incident Colorectal Cancer by TP53 Protein Expression Level in a Population-Based Cohort of Older Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Tillmans, L. S., Vierkant, R. A., Wang, A. H., Samadder, N. J., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2014; 23 (2): 350-355
  • Associations between cigarette smoking, hormone therapy, and folate intake with incident colorectal cancer by TP53 protein expression level in a population-based cohort of older women. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology Tillmans, L. S., Vierkant, R. A., Wang, A. H., Jewel Samadder, N., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2014; 23 (2): 350-355

    Abstract

    Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (>5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27-0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53-related pathways of colorectal carcinogenesis in older women.

    View details for DOI 10.1158/1055-9965.EPI-13-0780

    View details for PubMedID 24343843

  • The association of telomere length with colorectal cancer differs by the age of cancer onset. Clinical and translational gastroenterology Boardman, L. A., Litzelman, K., Seo, S., Johnson, R. A., Vanderboom, R. J., Kimmel, G. W., Cunningham, J. M., Gangnon, R. E., Engelman, C. D., Riegert-Johnson, D. L., Potter, J., Haile, R., Buchanan, D., Jenkins, M. A., Rider, D. N., Thibodeau, S. N., Petersen, G. M., Skinner, H. G. 2014; 5

    Abstract

    Telomeres are nucleoprotein structures that cap the end of chromosomes and shorten with sequential cell divisions in normal aging. Short telomeres are also implicated in the incidence of many cancers, but the evidence is not conclusive for colorectal cancer (CRC). Therefore, the aim of this study was to assess the association of CRC and telomere length.In this case-control study, we measured relative telomere length from peripheral blood leukocytes (PBLs) DNA with quantitative PCR in 598 CRC patients and 2,212 healthy controls.Multivariate analysis indicated that telomere length was associated with risk for CRC, and this association varied in an age-related manner; younger individuals (≤50 years of age) with longer telomeres (80-99 percentiles) had a 2-6 times higher risk of CRC, while older individuals (>50 years of age) with shortened telomeres (1-10 percentiles) had 2-12 times the risk for CRC. The risk for CRC varies with extremes in telomere length in an age-associated manner.Younger individuals with longer telomeres or older individuals with shorter telomeres are at higher risk for CRC. These findings indicate that the association of PBL telomere length varies according to the age of cancer onset and that CRC is likely associated with at minimum two different mechanisms of telomere dynamics.

    View details for DOI 10.1038/ctg.2014.3

    View details for PubMedID 24598784

  • Fine-mapping of genome-wide association study-identified risk loci for colorectal cancer in African Americans HUMAN MOLECULAR GENETICS Wang, H., Haiman, C. A., Burnett, T., Fortini, B. K., Kolonel, L. N., Henderson, B. E., Signorello, L. B., Blot, W. J., Keku, T. O., Berndt, S. I., Newcomb, P. A., Pande, M., Amos, C. I., West, D. W., Casey, G., Sandler, R. S., Haile, R., Stram, D. O., Le Marchand, L. 2013; 22 (24): 5048-5055

    Abstract

    Genome-wide association studies of colorectal cancer (CRC) in Europeans and Asians have identified 21 risk susceptibility regions [29 index single-nucleotide polymorphisms (SNPs)]. Characterizing these risk regions in diverse racial groups with different linkage disequilibrium (LD) structure can help localize causal variants. We examined associations between CRC and all 29 index SNPs in 6597 African Americans (1894 cases and 4703 controls). Nine SNPs in eight regions (5q31.1, 6q26-q27, 8q23.3, 8q24.21, 11q13.4, 15q13.3, 18q21.1 and 20p12.3) formally replicated in our data with one-sided P-values <0.05 and the same risk directions as reported previously. We performed fine-mapping of the 21 risk regions (including 250 kb on both sides of the index SNPs) using genotyped and imputed markers at the density of the 1000 Genomes Project to search for additional or more predictive risk markers. Among the SNPs correlated with the index variants, two markers, rs12759486 (or rs7547751, a putative functional variant in perfect LD with it) in 1q41 and rs7252505 in 19q13.1, were more strongly and statistically significantly associated with CRC (P < 0.0006). The average per allele risk was improved using the replicated index variants and the two new markers (odds ratio = 1.14, P = 6.5 × 10(-16)) in African Americans, compared with using all index SNPs (odds ratio = 1.07, P = 3.4 × 10(-10)). The contribution of the two new risk SNPs to CRC heritability was estimated to be 1.5% in African Americans. This study highlights the importance of fine-mapping in diverse populations.

    View details for DOI 10.1093/hmg/ddt337

    View details for Web of Science ID 000327542600015

    View details for PubMedID 23851122

  • Genetic Variation in the Inflammation and Innate Immunity Pathways and Colorectal Cancer Risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wang, H., Taverna, D., Stram, D. O., Fortini, B. K., Cheng, I., Wilkens, L. R., Burnett, T., Makar, K. W., Lindor, N. M., Hopper, J. L., Gallinger, S., Baron, J. A., Haile, R., Kolonel, L. N., Henderson, B. E., Newcomb, P. A., Casey, G., Duggan, D., Ulrich, C. M., Le Marchand, L. 2013; 22 (11): 2094-2101

    Abstract

    It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the "effective" number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency < 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Further replication in independent samples is warranted.

    View details for DOI 10.1158/1055-9965.EPI-13-0694

    View details for Web of Science ID 000327726800019

    View details for PubMedID 24045924

  • Telomere Length Varies By DNA Extraction Method: Implications for Epidemiologic Research CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Cunningham, J. M., Johnson, R. A., Litzelman, K., Skinner, H. G., Seo, S., Engelman, C. D., Vanderboom, R. J., Kimmel, G. W., Gangnon, R. E., Riegert-Johnson, D. L., Baron, J. A., Potter, J. D., Haile, R., Buchanan, D. D., Jenkins, M. A., Rider, D. N., Thibodeau, S. N., Petersen, G. M., Boardman, L. A. 2013; 22 (11): 2047-2054

    Abstract

    Both shorter and longer telomeres in peripheral blood leukocyte (PBL) DNA have been associated with cancer risk. However, associations remain inconsistent across studies of the same cancer type. This study compares DNA preparation methods to determine telomere length from patients with colorectal cancer.We examined PBL relative telomere length (RTL) measured by quantitative PCR (qPCR) in 1,033 patients with colorectal cancer and 2,952 healthy controls. DNA was extracted with phenol/chloroform, PureGene, or QIAamp.We observed differences in RTL depending on DNA extraction method (P < 0.001). Phenol/chloroform-extracted DNA had a mean RTL (T/S ratio) of 0.78 (range 0.01-6.54) compared with PureGene-extracted DNA (mean RTL of 0.75; range 0.00-12.33). DNA extracted by QIAamp yielded a mean RTL of 0.38 (range 0.02-3.69). We subsequently compared RTL measured by qPCR from an independent set of 20 colorectal cancer cases and 24 normal controls in PBL DNA extracted by each of the three extraction methods. The range of RTL measured by qPCR from QIAamp-extracted DNA (0.17-0.58) was less than from either PureGene or phenol/chloroform (ranges, 0.04-2.67 and 0.32-2.81, respectively).RTL measured by qPCR from QIAamp-extracted DNA was less than from either PureGene or phenol/chloroform (P < 0.001).Differences in DNA extraction method may contribute to the discrepancies between studies seeking to find an association between the risk of cancer or other diseases and RTL.

    View details for DOI 10.1158/1055-9965.EPI-13-0409

    View details for Web of Science ID 000327726800014

    View details for PubMedID 24019396

  • Diagnostic Chest X-Rays and Breast Cancer Risk before Age 50 Years for BRCA1 and BRCA2 Mutation Carriers CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION John, E. M., McGuire, V., Thomas, D., Haile, R., Ozcelik, H., Milne, R. L., Felberg, A., West, D. W., Miron, A., Knight, J. A., Terry, M. B., Daly, M., Buys, S. S., Andrulis, I. L., Hopper, J. L., Southey, M. C., Giles, G. G., Apicella, C., Thorne, H., Whittemore, A. S. 2013; 22 (9): 1547-1556

    Abstract

    Background: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. Methods: We studied 454 BRCA1 and 273 BRCA2 mutation carriers aged <50 years from three breast cancer family registries in the USA, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest x-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest x-rays was self-reported. Mammograms were not considered in the analysis. Results: After adjusting for known risk factors for breast cancer, the odds ratio (OR) for a history of diagnostic chest x-rays, excluding those for tuberculosis or pneumonia, was 1.16 (95% confidence interval (CI) = 0.64-2.11) for BRCA1 mutations carriers and 1.22 (95% CI=0.62-2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with 3-5 diagnostic chest x-rays (p = 0.01), but not for those with 6 or more chest x-rays. Few women reported chest fluoroscopy for tuberculosis or chest x-rays for pneumonia; the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. Conclusions: Our findings do not support a positive association between diagnostic chest x-rays and breast cancer risk before age 50 years for BRCA1 or BRCA2 mutation carriers. Impact: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted.

    View details for DOI 10.1158/1055-9965.EPI-13-0189

    View details for Web of Science ID 000324674500008

    View details for PubMedID 23853209

  • Contralateral breast cancer after radiotherapy among BRCA1 and BRCA2 mutation carriers: A WECARE Study Report EUROPEAN JOURNAL OF CANCER Bernstein, J. L., Thomas, D. C., Shore, R. E., Robson, M., Boice, J. D., Stovall, M., Andersson, M., Bernstein, L., Malone, K. E., Reiner, A. S., Lynch, C. F., Capanu, M., Smith, S. A., Tellhed, L., Teraoka, S. N., Begg, C. B., Olsen, J. H., Mellemkjaer, L., Liang, X., Diep, A. T., Borg, A., Concannon, P., Haile, R. W. 2013; 49 (14): 2979-2985

    Abstract

    Women with germline BRCA1 or BRCA2 (BRCA1/BRCA2) mutations are at very high risk of developing breast cancer, including asynchronous contralateral breast cancer (CBC). BRCA1/BRCA2 genes help maintain genome stability and assist in DNA repair. We examined whether the risk of CBC associated with radiation treatment was higher among women with germline BRCA1/BRCA2 mutations than among non-carriers.A population-based, nested case-control study was conducted within a cohort of 52,536 survivors of unilateral breast cancer (UBC). Cases were 603 women with CBC and controls were 1199 women with UBC individually matched on age at diagnosis, race, year of first diagnosis and cancer registry. All women were tested for BRCA1 and BRCA2 mutations. Radiation absorbed dose from the initial radiotherapy (RT) to the CBC location within the contralateral breast was reconstructed from measurements in a tissue-equivalent phantom and details available in the therapy records.Among women treated with radiation, the mean radiation dose was 1.1 Gy (range = 0.02-6.2 Gy). Risk of developing CBC was elevated among women who carried a deleterious BRCA1/BRCA2 mutation (rate ratio, RR = 4.5, confidence interval, CI = 3.0-6.8), and also among those treated with RT (RR = 1.2, CI = 1.0-1.6). However, among mutation carriers, an incremental increase in risk associated with radiation dose was not statistically significant.Multiplicative interaction of RT with mutation status would be reflected by a larger association of RT with CBC among carriers than among non-carriers, but this was not apparent. Accordingly, there was no clear indication that carriers of deleterious BRCA/BRCA2 mutations were more susceptible to the carcinogenic effects of radiation than non-carriers. These findings are reassuring and have important clinical implications for treatment decisions and the clinical management of patients harbouring deleterious BRCA1/BRCA2 mutations.All work associated with this study was supported by the U.S. National Cancer Institute [R01CA097397, U01CA083178].

    View details for DOI 10.1016/j.ejca.2013.04.028

    View details for Web of Science ID 000323604700004

    View details for PubMedID 23706288

  • Detection of large scale 3 ' deletions in the PMS2 gene amongst Colon-CFR participants: have we been missing anything? FAMILIAL CANCER Clendenning, M., Walsh, M. D., Gelpi, J. B., Thibodeau, S. N., Lindor, N., Potter, J. D., Newcomb, P., LeMarchand, L., Haile, R., Gallinger, S., Hopper, J. L., Jenkins, M. A., Rosty, C., Young, J. P., Buchanan, D. D. 2013; 12 (3): 563-566

    Abstract

    Current screening practices have been able to identify PMS2 mutations in 78 % of cases of colorectal cancer from the Colorectal Cancer Family Registry (Colon CFR) which showed solitary loss of the PMS2 protein. However the detection of large-scale deletions in the 3' end of the PMS2 gene has not been possible due to technical difficulties associated with pseudogene sequences. Here, we utilised a recently described MLPA/long-range PCR-based approach to screen the remaining 22 % (n = 16) of CRC-affected probands for mutations in the 3' end of the PMS2 gene. No deletions encompassing any or all of exons 12 through 15 were identified; therefore, our results suggest that 3' deletions in PMS2 are not a frequent occurrence in such families.

    View details for DOI 10.1007/s10689-012-9597-4

    View details for Web of Science ID 000325426200024

    View details for PubMedID 23288611

  • Genetic Variation in the Base Excision Repair Pathway, Environmental Risk Factors, and Colorectal Adenoma Risk PLOS ONE Corral, R., Lewinger, J. P., Joshi, A. D., Levine, A. J., Vandenberg, D. J., Haile, R. W., Stern, M. C. 2013; 8 (8)

    Abstract

    Cigarette smoking, high alcohol intake, and low dietary folate levels are risk factors for colorectal adenomas. Oxidative damage caused by these three factors can be repaired through the base excision repair pathway (BER). We hypothesized that genetic variation in BER might modify colorectal adenoma risk. In a sigmoidoscopy-based study, we examined associations between 182 haplotype tagging SNPs in 14 BER genes, and colorectal adenoma risk, and examined their potential role as modifiers of the effect cigarette smoking, alcohol intake, and dietary folate levels. Among all individuals, no statistically significant associations between BER SNPs and adenoma risk persisted after correction for multiple comparisons. However, among Asian-Pacific Islanders we observed two SNPs in FEN1 and one in NTHL1, and among African-Americans one SNP in APEX1 that were associated with colorectal adenoma risk. Significant associations were also observed between SNPs in the NEIL2 gene and rectal adenoma risk. Three SNPS modified the effect of smoking (MUTYH interaction p = 0.002; OGG1 interaction p = 0.013); FEN1 interaction p = 0.013)), one SNP in LIG3 modified the effect of alcohol consumption (interaction p = 0.024) and two SNPs in LIG3 modified the effect of dietary folate (interaction p = 0.001 and p = 0.08) on colorectal adenoma risk. These findings support a role for genetic variants in the BER pathway as potential modifiers of colorectal adenoma risk. Our findings strengthen the role of oxidative damage induced by key lifestyle and dietary risk factors in colorectal adenoma formation.

    View details for DOI 10.1371/journal.pone.0071211

    View details for Web of Science ID 000323097300101

    View details for PubMedID 23951112

  • Common variants in genes coding for chemotherapy metabolizing enzymes, transporters, and targets: a case-control study of contralateral breast cancer risk in the WECARE Study CANCER CAUSES & CONTROL Brooks, J. D., Teraoka, S. N., Bernstein, L., Mellemkjaer, L., Malone, K. E., Lynch, C. F., Haile, R. W., Concannon, P., Reiner, A. S., Duggan, D. J., Schiermeyer, K., Bernstein, J. L., Figueiredo, J. C. 2013; 24 (8): 1605-1614

    Abstract

    Women who receive chemotherapy for a first primary breast cancer have been observed to have a reduced risk of contralateral breast cancer (CBC), however, whether the genetic profile of a patient modifies this protective effect is currently not understood. The purpose of this study is to investigate the impact of germline genetic variation in genes coding for drug metabolizing enzymes, transporters, and targets on the association between chemotherapy and risk of CBC.From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 636 Caucasian women with CBC (cases) and 1,224 women with unilateral breast cancer (controls). The association between common chemotherapeutic regimens, CMF and FAC/FEC, and risk of CBC stratified by genotype of 180 single nucleotide polymorphisms in 14 genes selected for their known involvement in metabolism, action, and transport of breast cancer chemotherapeutic agents, were determined using conditional logistic regression.CMF (RR = 0.5, 95 % CI 0.4, 0.7) and FAC/FEC (RR = 0.7, 95 % CI 0.4, 1.0) are associated with lower CBC risk relative to no chemotherapy in multivariable-adjusted models. Here we show that genotype of selected genes involved in the metabolism and uptake of these therapeutic agents does not significantly alter the protective effect of either CMF or FAC/FEC on risk of CBC.The results of this study show that germline genetic variation in selected gene does not significantly alter the protective effect of CMF, FAC, and FEC on risk of CBC.

    View details for DOI 10.1007/s10552-013-0237-6

    View details for Web of Science ID 000321761400014

    View details for PubMedID 23775025

  • Associations Between Colorectal Cancer Molecular Markers and Pathways With Clinicopathologic Features in Older Women GASTROENTEROLOGY Samadder, N. J., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2013; 145 (2): 348-?

    Abstract

    Colorectal tumors have a large degree of molecular heterogeneity. Three integrated pathways of carcinogenesis (ie, traditional, alternate, and serrated) have been proposed, based on specific combinations of microsatellite instability (MSI), CpG island methylator phenotype (CIMP), and mutations in BRAF and KRAS. We used resources from the population-based Iowa Women's Health Study (n = 41,836) to associate markers of colorectal tumors, integrated pathways, and clinical and pathology characteristics, including survival times.We assessed archived specimens from 732 incident colorectal tumors and characterized them as microsatellite stable (MSS), MSI high or MSI low, CIMP high or CIMP low, CIMP negative, and positive or negative for BRAF and/or KRAS mutations. Informative marker data were collected from 563 tumors (77%), which were assigned to the following integrated pathways: traditional (MSS, CIMP negative, BRAF mutation negative, and KRAS mutation negative; n = 170), alternate (MSS, CIMP low, BRAF mutation negative, and KRAS mutation positive; n = 58), serrated (any MSI, CIMP high, BRAF mutation positive, and KRAS mutation negative; n = 142), or unassigned (n = 193). Multivariable-adjusted Cox proportional hazards regression models were used to assess the associations of interest.Patients' mean age (P = .03) and tumors' anatomic subsite (P = .0001) and grade (P = .0001) were significantly associated with integrated pathway assignment. Colorectal cancer (CRC) mortality was not associated with the traditional, alternate, or serrated pathways, but was associated with a subset of pathway-unassigned tumors (MSS or MSI low, CIMP negative, BRAF mutation negative, and KRAS mutation positive) (n = 96 cases; relative risk = 1.76; 95% confidence interval, 1.07-2.89, compared with the traditional pathway).We identified clinical and pathology features associated with molecularly defined CRC subtypes. However, additional studies are needed to determine how these features might influence prognosis.

    View details for DOI 10.1053/j.gastro.2013.05.001

    View details for Web of Science ID 000322630600024

    View details for PubMedID 23665275

  • Identification of Novel Variants in Colorectal Cancer Families by High-Throughput Exome Sequencing CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION DeRycke, M. S., Gunawardena, S. R., Middha, S., Asmann, Y. W., Schaid, D. J., McDonnell, S. K., Riska, S. M., Eckloff, B. W., Cunningham, J. M., Fridley, B. L., Serie, D. J., Bamlet, W. R., Cicek, M. S., Jenkins, M. A., Duggan, D. J., Buchanan, D., Clendenning, M., Haile, R. W., Woods, M. O., Gallinger, S. N., Casey, G., Potter, J. D., Newcomb, P. A., Le Marchand, L., Lindor, N. M., Thibodeau, S. N., Goode, E. L. 2013; 22 (7): 1239-1251

    Abstract

    Colorectal cancer (CRC) in densely affected families without Lynch Syndrome may be due to mutations in undiscovered genetic loci. Familial linkage analyses have yielded disparate results; the use of exome sequencing in coding regions may identify novel segregating variants.We completed exome sequencing on 40 affected cases from 16 multicase pedigrees to identify novel loci. Variants shared among all sequenced cases within each family were identified and filtered to exclude common variants and single-nucleotide variants (SNV) predicted to be benign.We identified 32 nonsense or splice-site SNVs, 375 missense SNVs, 1,394 synonymous or noncoding SNVs, and 50 indels in the 16 families. Of particular interest are two validated and replicated missense variants in CENPE and KIF23, which are both located within previously reported CRC linkage regions, on chromosomes 1 and 15, respectively.Whole-exome sequencing identified DNA variants in multiple genes. Additional sequencing of these genes in additional samples will further elucidate the role of variants in these regions in CRC susceptibility.Exome sequencing of familial CRC cases can identify novel rare variants that may influence disease risk.

    View details for DOI 10.1158/1055-9965.EPI-12-1226

    View details for Web of Science ID 000321323600006

    View details for PubMedID 23637064

  • Absence of PMS2 mutations in colon-CFR participants whose colorectal cancers demonstrate unexplained loss of MLH1 expression CLINICAL GENETICS Clendenning, M., Macrae, F. A., Walsh, M. D., Walters, R. J., Thibodeau, S. N., GUNAWARDENA, S. R., Potter, J. D., Haile, R. W., Gallinger, S., Hopper, J. L., Jenkins, M. A., Rosty, C., Young, J. P., Buchanan, D. D. 2013; 83 (6): 591-593

    View details for DOI 10.1111/cge.12011

    View details for Web of Science ID 000318164100019

    View details for PubMedID 23017166

  • Risk of Metachronous Colon Cancer Following Surgery for Rectal Cancer in Mismatch Repair Gene Mutation Carriers ANNALS OF SURGICAL ONCOLOGY Win, A. K., Parry, S., Parry, B., Kalady, M. F., Macrae, F. A., Ahnen, D. J., Young, G. P., Lipton, L., Winship, I., Boussioutas, A., Young, J. P., Buchanan, D. D., Arnold, J., Le Marchand, L., Newcomb, P. A., Haile, R. W., Lindor, N. M., Gallinger, S., Hopper, J. L., Jenkins, M. A. 2013; 20 (6): 1829-1836

    Abstract

    Despite regular surveillance colonoscopy, the metachronous colorectal cancer risk for mismatch repair (MMR) gene mutation carriers after segmental resection for colon cancer is high and total or subtotal colectomy is the preferred option. However, if the index cancer is in the rectum, management decisions are complicated by considerations of impaired bowel function. We aimed to estimate the risk of metachronous colon cancer for MMR gene mutation carriers who underwent a proctectomy for index rectal cancer.This retrospective cohort study comprised 79 carriers of germline mutation in a MMR gene (18 MLH1, 55 MSH2, 4 MSH6, and 2 PMS2) from the Colon Cancer Family Registry who had had a proctectomy for index rectal cancer. Cumulative risks of metachronous colon cancer were calculated using the Kaplan-Meier method.During median 9 years (range 1-32 years) of observation since the first diagnosis of rectal cancer, 21 carriers (27 %) were diagnosed with metachronous colon cancer (incidence 24.25, 95 % confidence interval [CI] 15.81-37.19 per 1,000 person-years). Cumulative risk of metachronous colon cancer was 19 % (95 % CI 9-31 %) at 10 years, 47 (95 % CI 31-68 %) at 20 years, and 69 % (95 % CI 45-89 %) at 30 years after surgical resection. The frequency of surveillance colonoscopy was 1 colonoscopy per 1.16 years (95 % CI 1.01-1.31 years). The AJCC stages of the metachronous cancers, where available, were 72 % stage I, 22 % stage II, and 6 % stage III.Given the high metachronous colon cancer risk for MMR gene mutation carriers diagnosed with an index rectal cancer, proctocolectomy may need to be considered.

    View details for DOI 10.1245/s10434-012-2858-5

    View details for Web of Science ID 000319169100011

    View details for PubMedID 23358792

  • Integrated analysis of genome-wide copy number alterations and gene expression in microsatellite stable, CpG island methylator phenotype-negative colon cancer GENES CHROMOSOMES & CANCER Loo, L. W., Tiirikainen, M., Cheng, I., Lum-Jones, A., Seifried, A., Church, J. M., Gryfe, R., Weisenberger, D. J., Lindor, N. M., Gallinger, S., Haile, R. W., Duggan, D. J., Thibodeau, S. N., Casey, G., Le Marchand, L. 2013; 52 (5): 450-466

    Abstract

    Microsatellite stable (MSS), CpG island methylator phenotype (CIMP)-negative colorectal tumors, the most prevalent molecular subtype of colorectal cancer, are associated with extensive copy number alteration (CNA) events and aneuploidy. We report on the identification of characteristic recurrent CNA (with frequency >25%) events and associated gene expression profiles for a total of 40 paired tumor and adjacent normal colon tissues using genome-wide microarrays. We observed recurrent CNAs, namely gains at 1q, 7p, 7q, 8p12-11, 8q, 12p13, 13q, 20p, 20q, Xp, and Xq and losses at 1p36, 1p31, 1p21, 4p15-12, 4q12-35, 5q21-22, 6q26, 8p, 14q, 15q11-12, 17p, 18p, 18q, 21q21-22, and 22q. Within these genomic regions we identified 356 genes with significant differential expression (P < 0.0001 and ±1.5-fold change) in the tumor compared to adjacent normal tissue. Gene ontology and pathway analyses indicated that many of these genes were involved in functional mechanisms that regulate cell cycle, cell death, and metabolism. An amplicon present in >70% of the tumor samples at 20q11-20q13 contained several cancer-related genes (AHCY, POFUT1, RPN2, TH1L, and PRPF6) that were upregulated and demonstrated a significant linear correlation (P < 0.05) for gene dosage and gene expression. Copy number loss at 8p, a CNA associated with adenocarcinoma and poor prognosis, was observed in >50% of the tumor samples and demonstrated a significant linear correlation for gene dosage and gene expression for two potential tumor suppressor genes, MTUS1 (8p22) and PPP2CB (8p12). The results from our integration analysis illustrate the complex relationship between genomic alterations and gene expression in colon cancer.

    View details for DOI 10.1002/gcc.22043

    View details for Web of Science ID 000316325700002

    View details for PubMedID 23341073

  • Are the common genetic variants associated with colorectal cancer risk for DNA mismatch repair gene mutation carriers? EUROPEAN JOURNAL OF CANCER Win, A. K., Hopper, J. L., Buchanan, D. D., Young, J. P., Tenesa, A., Dowty, J. G., Giles, G. G., Goldblatt, J., Winship, I., Boussioutas, A., Young, G. P., Parry, S., Baron, J. A., Duggan, D., Gallinger, S., Newcomb, P. A., Haile, R. W., Le Marchand, L., Lindor, N. M., Jenkins, M. A. 2013; 49 (7): 1578-1587

    Abstract

    Genome-wide association studies have identified at least 15 independent common genetic variants associated with colorectal cancer (CRC) risk. The aim of this study was to investigate whether 11 of these variants are associated with CRC risk for carriers of germline mutations in DNA mismatch repair (MMR) genes.A total of 927 MMR gene mutation carriers (360 MLH1, 442 MSH2, 85 MSH6 and 40 PMS2) from 315 families enrolled in the Colon Cancer Family Registry, were genotyped for the single nucleotide polymorphisms (SNPs): rs16892766 (8q23.3), rs6983267 (8q24.21), rs719725 (9p24), rs10795668 (10p14), rs3802842 (11q23.1), rs4444235 (14q22.2), rs4779584 (15q13.3), rs9929218 (16q22.1), rs4939827 (18q21.1), rs10411210 (19q13.1) and rs961253 (20p12.3). We used a weighted Cox regression to estimate CRC risk for homozygous and heterozygous carriers of the risk allele compared with homozygous non-carriers as well as for an additive per allele model (on the log scale).Over a total of 40,978 person-years observation, 426 (46%) carriers were diagnosed with CRC at a mean age of 44.3 years. For all carriers combined, we found no evidence of an association between CRC risk and the total number of risk alleles (hazard ratio [HR] per risk allele=0.97, 95% confidence interval [CI]=0.88-1.07, p=0.52).We found no evidence that the SNPs associated with CRC in the general population are modifiers of the risk for MMR gene mutation carriers overall, and therefore any evidence of proven clinical utility in Lynch syndrome.

    View details for DOI 10.1016/j.ejca.2013.01.029

    View details for Web of Science ID 000317563600008

    View details for PubMedID 23434150

  • Genetic Variations in SMAD7 Are Associated with Colorectal Cancer Risk in the Colon Cancer Family Registry PLOS ONE Jiang, X., Esteban Castelao, J., VanDenBerg, D., Carracedo, A., Redondo, C. M., Conti, D. V., Paredes Cotore, J. P., Potter, J. D., Newcomb, P. A., Passarelli, M. N., Jenkins, M. A., Hopper, J. L., Gallinger, S., Le Marchand, L., Martinez, M. E., Ahnen, D. J., Baron, J. A., Lindor, N. M., Haile, R. W., Gago-Dominguez, M. 2013; 8 (4)
  • Identification of Genetic Susceptibility Loci for Colorectal Tumors in a Genome-Wide Meta-analysis GASTROENTEROLOGY Peters, U., Jiao, S., Schumacher, F. R., Hutter, C. M., Aragaki, A. K., Baron, J. A., Berndt, S. I., Bezieau, S., Brenner, H., Butterbach, K., Caan, B. J., Campbell, P. T., Carlson, C. S., Casey, G., Chan, A. T., Chang-Claude, J., Chanock, S. J., Chen, L. S., Coetzee, G. A., Coetzee, S. G., Conti, D. V., Curtis, K. R., Duggan, D., Edwards, T., Fuchs, C. S., Gallinger, S., Giovannucci, E. L., Gogarten, S. M., Gruber, S. B., Haile, R. W., Harrison, T. A., Hayes, R. B., Henderson, B. E., Hoffmeister, M., Hopper, J. L., Hudson, T. J., Hunter, D. J., Jackson, R. D., Jee, S. H., Jenkins, M. A., Jia, W., Kolonel, L. N., Kooperberg, C., Kuery, S., LaCroix, A. Z., Laurie, C. C., Laurie, C. A., Le Marchand, L., Lemire, M., Levine, D., Lindor, N. M., Liu, Y., Ma, J., Makar, K. W., Matsuo, K., Newcomb, P. A., Potter, J. D., Prentice, R. L., Qu, C., Rohan, T., Rosse, S. A., Schoen, R. E., Seminara, D., Shrubsole, M., Shu, X., Slattery, M. L., Taverna, D., Thibodeau, S. N., Ulrich, C. M., White, E., Xiang, Y., Zanke, B. W., Zeng, Y., Zhang, B., Zheng, W., Hsu, L. 2013; 144 (4): 799-?

    Abstract

    Heritable factors contribute to the development of colorectal cancer. Identifying the genetic loci associated with colorectal tumor formation could elucidate the mechanisms of pathogenesis.We conducted a genome-wide association study that included 14 studies, 12,696 cases of colorectal tumors (11,870 cancer, 826 adenoma), and 15,113 controls of European descent. The 10 most statistically significant, previously unreported findings were followed up in 6 studies; these included 3056 colorectal tumor cases (2098 cancer, 958 adenoma) and 6658 controls of European and Asian descent.Based on the combined analysis, we identified a locus that reached the conventional genome-wide significance level at less than 5.0 × 10(-8): an intergenic region on chromosome 2q32.3, close to nucleic acid binding protein 1 (most significant single nucleotide polymorphism: rs11903757; odds ratio [OR], 1.15 per risk allele; P = 3.7 × 10(-8)). We also found evidence for 3 additional loci with P values less than 5.0 × 10(-7): a locus within the laminin gamma 1 gene on chromosome 1q25.3 (rs10911251; OR, 1.10 per risk allele; P = 9.5 × 10(-8)), a locus within the cyclin D2 gene on chromosome 12p13.32 (rs3217810 per risk allele; OR, 0.84; P = 5.9 × 10(-8)), and a locus in the T-box 3 gene on chromosome 12q24.21 (rs59336; OR, 0.91 per risk allele; P = 3.7 × 10(-7)).In a large genome-wide association study, we associated polymorphisms close to nucleic acid binding protein 1 (which encodes a DNA-binding protein involved in DNA repair) with colorectal tumor risk. We also provided evidence for an association between colorectal tumor risk and polymorphisms in laminin gamma 1 (this is the second gene in the laminin family to be associated with colorectal cancers), cyclin D2 (which encodes for cyclin D2), and T-box 3 (which encodes a T-box transcription factor and is a target of Wnt signaling to β-catenin). The roles of these genes and their products in cancer pathogenesis warrant further investigation.

    View details for DOI 10.1053/j.gastro.2012.12.020

    View details for Web of Science ID 000316735800039

    View details for PubMedID 23266556

  • Cancer Risks for MLH1 and MSH2 Mutation Carriers HUMAN MUTATION Dowty, J. G., Win, A. K., Buchanan, D. D., Lindor, N. M., Macrae, F. A., Clendenning, M., Antill, Y. C., Thibodeau, S. N., Casey, G., Gallinger, S., Le Marchand, L., Newcomb, P. A., Haile, R. W., Young, G. P., James, P. A., Giles, G. G., Gunawardena, S. R., Leggett, B. A., Gattas, M., Boussioutas, A., Ahnen, D. J., Baron, J. A., Parry, S., Goldblatt, J., Young, J. P., Hopper, J. L., Jenkins, M. A. 2013; 34 (3): 490-497

    Abstract

    We studied 17,576 members of 166 MLH1 and 224 MSH2 mutation-carrying families from the Colon Cancer Family Registry. Average cumulative risks of colorectal cancer (CRC), endometrial cancer (EC), and other cancers for carriers were estimated using modified segregation analysis conditioned on ascertainment criteria. Heterogeneity in risks was investigated using a polygenic risk modifier. Average CRC cumulative risks at the age of 70 years (95% confidence intervals) for MLH1 and MSH2 mutation carriers, respectively, were estimated to be 34% (25%-50%) and 47% (36%-60%) for male carriers and 36% (25%-51%) and 37% (27%-50%) for female carriers. Corresponding EC risks were 18% (9.1%-34%) and 30% (18%-45%). A high level of CRC risk heterogeneity was observed (P < 0.001), with cumulative risks at the age of 70 years estimated to follow U-shaped distributions. For example, 17% of male MSH2 mutation carriers have estimated lifetime risks of 0%-10% and 18% have risks of 90%-100%. Therefore, average risks are similar for the two genes but there is so much individual variation about the average that large proportions of carriers have either very low or very high lifetime cancer risks. Our estimates of CRC and EC cumulative risks for MLH1 and MSH2 mutation carriers are the most precise currently available.

    View details for DOI 10.1002/humu.22262

    View details for Web of Science ID 000315186400011

    View details for PubMedID 23255516

  • Risks of Colorectal and Other Cancers After Endometrial Cancer for Women With Lynch Syndrome JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Win, A. K., Lindor, N. M., Winship, I., Tucker, K. M., Buchanan, D. D., Young, J. P., Rosty, C., Leggett, B., Giles, G. G., Goldblatt, J., Macrae, F. A., Parry, S., Kalady, M. F., Baron, J. A., Ahnen, D. J., Le Marchand, L., Gallinger, S., Haile, R. W., Newcomb, P. A., Hopper, J. L., Jenkins, M. A. 2013; 105 (4): 274-279

    Abstract

    Lynch syndrome is an autosomal dominantly inherited disorder caused by germline mutations in DNA mismatch repair (MMR) genes. Previous studies have shown that MMR gene mutation carriers are at increased risk of colorectal, endometrial, and several other cancers following an initial diagnosis of colorectal cancer. We estimated cancer risks following an endometrial cancer diagnosis for women carrying MMR gene mutations.We obtained data from the Colon Cancer Family Registry for a cohort of 127 women who had a diagnosis of endometrial cancer and who carried a mutation in one of four MMR genes (30 carried a mutation in MLH1, 72 in MSH2, 22 in MSH6, and 3 in PMS2). We used the Kaplan-Meier method to estimate 10- and 20-year cumulative risks for each cancer. We estimated the age-, country-, and calendar period-specific standardized incidence ratios (SIRs) for each cancer, compared with the general population.Following endometrial cancer, women carrying MMR gene mutations had the following 20-year risks of other cancer cancers: colorectal cancer (48%, 95% confidence interval [CI] = 35% to 62%); cancer of the kidney, renal pelvis, or ureter (11%, 95% CI = 3% to 20%); urinary bladder cancer (9%, 95% CI = 2% to 17%); and breast cancer (11%, 95% CI = 4% to 19%). Compared with the general population, these women were at statistically significantly elevated risks of colorectal cancer (SIR = 39.9, 95% CI = 27.2 to 58.3), cancer of the kidney, renal pelvis, or ureter (SIR = 28.3, 95% CI = 11.9 to 48.6), urinary bladder cancer (SIR = 24.3, 95% CI = 8.56 to 42.9), and breast cancer (SIR = 2.51, 95% CI = 1.17 to 4.14).Women with Lynch syndrome who are diagnosed with endometrial cancer have increased risks of several cancers, including breast cancer.

    View details for DOI 10.1093/jnci/djs525

    View details for Web of Science ID 000315202900008

    View details for PubMedID 23385444

  • Comparison of the clinical prediction model PREMM1,2,6 and molecular testing for the systematic identification of Lynch syndrome in colorectal cancer GUT Kastrinos, F., Steyerberg, E. W., Balmana, J., Mercado, R., Gallinger, S., Haile, R., Casey, G., Hopper, J. L., LeMarchand, L., Lindor, N. M., Newcomb, P. A., Thibodeau, S. N., Syngal, S. 2013; 62 (2): 272-279

    Abstract

    Lynch syndrome is caused by germline mismatch repair (MMR) gene mutations. The PREMM(1,2,6) model predicts the likelihood of a MMR gene mutation based on personal and family cancer history.To compare strategies using PREMM(1,2,6) and tumour testing (microsatellite instability (MSI) and/or immunohistochemistry (IHC) staining) to identify mutation carriers.Data from population-based or clinic-based patients with colorectal cancers enrolled through the Colon Cancer Family Registry were analysed. Evaluation included MSI, IHC and germline mutation analysis for MLH1, MSH2, MSH6 and PMS2. Personal and family cancer histories were used to calculate PREMM(1,2,6) predictions. Discriminative ability to identify carriers from non-carriers using the area under the receiver operating characteristic curve (AUC) was assessed. Predictions were based on logistic regression models for (1) cancer assessment using PREMM(1,2,6), (2) MSI, (3) IHC for loss of any MMR protein expression, (4) MSI+IHC, (5) PREMM(1,2,6)+MSI, (6) PREMM(1,2,6)+IHC, (7) PREMM(1,2,6)+IHC+MSI.Among 1651 subjects, 239 (14%) had mutations (90 MLH1, 125 MSH2, 24 MSH6). PREMM(1,2,6) discriminated well with AUC 0.90 (95% CI 0.88 to 0.92). MSI alone, IHC alone, or MSI+IHC each had lower AUCs: 0.77, 0.82 and 0.82, respectively. The added value of IHC+PREMM(1,2,6) was slightly greater than PREMM(1,2,6)+MSI (AUC 0.94 vs 0.93). Adding MSI to PREMM(1,2,6)+IHC did not improve discrimination.PREMM(1,2,6) and IHC showed excellent performance in distinguishing mutation carriers from non-carriers and performed best when combined. MSI may have a greater role in distinguishing Lynch syndrome from other familial colorectal cancer subtypes among cases with high PREMM(1,2,6) scores where genetic evaluation does not disclose a MMR mutation.

    View details for DOI 10.1136/gutjnl-2011-301265

    View details for Web of Science ID 000313264400013

    View details for PubMedID 22345660

  • Risk of Asynchronous Contralateral Breast Cancer in Noncarriers of BRCA1 and BRCA2 Mutations With a Family History of Breast Cancer: A Report From the Women's Environmental Cancer and Radiation Epidemiology Study JOURNAL OF CLINICAL ONCOLOGY Reiner, A. S., John, E. M., Brooks, J. D., Lynch, C. F., Bernstein, L., Mellemkjaer, L., Malone, K. E., Knight, J. A., Capanu, M., Teraoka, S. N., Concannon, P., Liang, X., Figueiredo, J. C., Smith, S. A., Stovall, M., Pike, M. C., Haile, R. W., Thomas, D. C., Begg, C. B., Bernstein, J. L. 2013; 31 (4): 433-439

    Abstract

    To fully characterize the risk of contralateral breast cancer (CBC) in patients with breast cancer with a family history who test negative for BRCA1 and BRCA2 mutations.From our population-based case-control study comparing women with CBC to women with unilateral breast cancer (UBC), we selected women who tested negative for BRCA1 and BRCA2 mutations (594 patients with CBC/1,119 control patients with UBC). Rate ratios (RRs) and 95% CIs were estimated to examine the association between family history of breast cancer and risk of asynchronous CBC. Age- and family history-specific 10-year cumulative absolute risks of CBC were estimated.Family history of breast cancer was associated with increased CBC risk; risk was highest among young women (< 45 years) with first-degree relatives affected at young ages (< 45 years; RR, 2.5; 95% CI, 1.1 to 5.3) or women with first-degree relatives with bilateral disease (RR, 3.6; 95% CI, 2.0 to 6.4). Women diagnosed with UBC before age 55 years with a first-degree family history of CBC had a 10-year risk of CBC of 15.6%.Young women with breast cancer who have a family history of breast cancer and who test negative for deleterious mutations in BRCA1 and BRCA2 are at significantly greater risk of CBC than other breast cancer survivors. This risk varies with diagnosis age, family history of CBC, and degree of relationship to an affected relative. Women with a first-degree family history of bilateral disease have risks of CBC similar to mutation carriers. This has important implications for the clinical management of patients with breast cancer with family history of the disease.

    View details for DOI 10.1200/JCO.2012.43.2013

    View details for Web of Science ID 000314099800010

    View details for PubMedID 23269995

  • A Multifactorial Likelihood Model for MMR Gene Variant Classification Incorporating Probabilities Based on Sequence Bioinformatics and Tumor Characteristics: A Report from the Colon Cancer Family Registry HUMAN MUTATION Thompson, B. A., Goldgar, D. E., Paterson, C., Clendenning, M., Walters, R., Arnold, S., Parsons, M. T., Walsh, M. D., Gallinger, S., Haile, R. W., Hopper, J. L., Jenkins, M. A., LeMarchand, L., Lindor, N. M., Newcomb, P. A., Thibodeau, S. N., Young, J. P., Buchanan, D. D., Tavtigian, S. V., Spurdle, A. B. 2013; 34 (1): 200-209

    Abstract

    Mismatch repair (MMR) gene sequence variants of uncertain clinical significance are often identified in suspected Lynch syndrome families, and this constitutes a challenge for both researchers and clinicians. Multifactorial likelihood model approaches provide a quantitative measure of MMR variant pathogenicity, but first require input of likelihood ratios (LRs) for different MMR variation-associated characteristics from appropriate, well-characterized reference datasets. Microsatellite instability (MSI) and somatic BRAF tumor data for unselected colorectal cancer probands of known pathogenic variant status were used to derive LRs for tumor characteristics using the Colon Cancer Family Registry (CFR) resource. These tumor LRs were combined with variant segregation within families, and estimates of prior probability of pathogenicity based on sequence conservation and position, to analyze 44 unclassified variants identified initially in Australasian Colon CFR families. In addition, in vitro splicing analyses were conducted on the subset of variants based on bioinformatic splicing predictions. The LR in favor of pathogenicity was estimated to be ~12-fold for a colorectal tumor with a BRAF mutation-negative MSI-H phenotype. For 31 of the 44 variants, the posterior probabilities of pathogenicity were such that altered clinical management would be indicated. Our findings provide a working multifactorial likelihood model for classification that carefully considers mode of ascertainment for gene testing.

    View details for DOI 10.1002/humu.22213

    View details for Web of Science ID 000314476900028

    View details for PubMedID 22949379

  • Genetic variations in SMAD7 are associated with colorectal cancer risk in the colon cancer family registry. PloS one Jiang, X., Castelao, J. E., VanDenBerg, D., Carracedo, A., Redondo, C. M., Conti, D. V., Paredes Cotoré, J. P., Potter, J. D., Newcomb, P. A., Passarelli, M. N., Jenkins, M. A., Hopper, J. L., Gallinger, S., Le Marchand, L., Martínez, M. E., Ahnen, D. J., Baron, J. A., Lindor, N. M., Haile, R. W., Gago-Dominguez, M. 2013; 8 (4)

    Abstract

    Recent genome-wide studies identified a risk locus for colorectal cancer at 18q21, which maps to the SMAD7 gene. Our objective was to confirm the association between SMAD7 SNPs and colorectal cancer risk in the multi-center Colon Cancer Family Registry.23 tagging SNPs in the SMAD7 gene were genotyped among 1,592 population-based and 253 clinic-based families. The SNP-colorectal cancer associations were assessed in multivariable conditional logistic regression.Among the population-based families, both SNPs rs12953717 (odds ratio, 1.29; 95% confidence interval, 1.12-1.49), and rs11874392 (odds ratio, 0.80; 95% confidence interval, 0.70-0.92) were associated with risk of colorectal cancer. These associations were similar among the population- and the clinic-based families, though they were significant only among the former. Marginally significant differences in the SNP-colorectal cancer associations were observed by use of nonsteroidal anti-inflammatory drugs, cigarette smoking, body mass index, and history of polyps.SMAD7 SNPs were associated with colorectal cancer risk in the Colon Cancer Family Registry. There was evidence suggesting that the association between rs12953717 and colorectal cancer risk may be modified by factors such as smoking and use of nonsteroidal anti-inflammatory drugs.

    View details for DOI 10.1371/journal.pone.0060464

    View details for PubMedID 23560096

  • Variants in tamoxifen metabolizing genes: a case-control study of contralateral breast cancer risk in the WECARE study. International journal of molecular epidemiology and genetics Brooks, J. D., Teraoka, S. N., Malone, K. E., Haile, R. W., Bernstein, L., Lynch, C. F., Mellemkjær, L., Duggan, D. J., Reiner, A. S., Concannon, P., Schiermeyer, K., Lewinger, J. P., Bernstein, J. L., Figueiredo, J. C. 2013; 4 (1): 35-48

    Abstract

    Tamoxifen has been shown to greatly reduce risk of recurrence and contralateral breast cancer (CBC). Still, second primary contralateral breast cancer is the most common malignancy to follow a first primary breast cancer. Genetic variants in CYP2D6 and other drug-metabolizing enzymes that alter the metabolism of tamoxifen may be associated with CBC risk in women who receive the drug. This is the first study to investigate the impact of this variation on risk of CBC in women who receive tamoxifen. From the population-based Women's Environment Cancer and Radiation Epidemiology (WECARE) Study, we included 624 Caucasian women with CBC (cases) and 1,199 women with unilateral breast cancer (controls) with complete information on tumor characteristics and treatment. Conditional logistic regression was used to assess the risk of CBC associated with 112 single nucleotide polymorphisms (SNPs) in 8 genes involved in the metabolism of tamoxifen among tamoxifen users and non-users. After adjustment for multiple testing, no significant association was observed between any of the genotyped variants and CBC risk in either tamoxifen users or non-users. These results suggest that when using a tagSNP approach, common variants in selected genes involved in the metabolism of tamoxifen are not associated with risk of CBC among women treated with the drug.

    View details for PubMedID 23565321

  • Variation in Genes Related to Obesity, Weight, and Weight Change and Risk of Contralateral Breast Cancer in the WECARE Study Population CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brooks, J. D., Bernstein, L., Teraoka, S. N., Knight, J. A., Mellemkjaer, L., John, E. M., Malone, K. E., Reiner, A. S., Lynch, C. F., Concannon, P., Haile, R. W., Bernstein, J. L. 2012; 21 (12): 2261-2267

    Abstract

    Body mass index (BMI), a known breast cancer risk factor, could influence breast risk through mechanistic pathways related to sex hormones, insulin resistance, chronic inflammation, and altered levels of adipose-derived hormones. Results from studies of the relationship between BMI and second primary breast cancer have been mixed. To explore the relationship between BMI and asynchronous contralateral breast cancer (CBC), we examined whether variants in genes related to obesity, weight, and weight change are associated with CBC risk.Variants in 20 genes [182 single-nucleotide polymorphisms (SNP)] involved in adipose tissue metabolism, energy balance, insulin resistance, and inflammation, as well as those identified through genome-wide association studies (GWAS) of BMI and type II-diabetes were evaluated. We examined the association between variants in these genes and the risk of CBC among Caucasian participants [643 cases with CBC and 1,271 controls with unilateral breast cancer (UBC)] in the population-based Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study using conditional logistic regression.After adjustment for multiple comparisons, no statistically significant associations between any variant and CBC risk were seen. Stratification by menopausal or estrogen receptor (ER) status did not alter these findings.Among women with early-onset disease who survive a first breast cancer diagnosis, there was no association between variation in obesity-related genes and risk of CBC.Genetic variants in genes related to obesity are not likely to strongly influence subsequent risk of developing a second primary breast cancer.

    View details for DOI 10.1158/1055-9965.EPI-12-1036

    View details for Web of Science ID 000312280800015

    View details for PubMedID 23033454

  • Genetic variation in insulin pathway genes and distal colorectal adenoma risk INTERNATIONAL JOURNAL OF COLORECTAL DISEASE Levine, A. J., Ihenacho, U., Lee, W., Figueiredo, J. C., Vandenberg, D. J., Edlund, C. K., Davis, B. D., Stern, M. C., Haile, R. W. 2012; 27 (12): 1587-1595

    Abstract

    Insulin, glucose, and other insulin-related proteins that mediate insulin signaling are associated with colorectal neoplasia risk, but associations with common genetic variation in insulin axis genes are less clear. In this study, we used a comprehensive tag single-nucleotide polymorphisms (SNPs) approach to define genetic variation in six insulin axis genes (IGF1, IGF2, IGFBP1, IGFBP3, IRS1, and IRS2) and three genes associated with estrogen signaling (ESR1, ESR2, and PGR).We assessed associations between SNPs and distal colorectal adenoma (CRA) risk in a case-control study of 1,351 subjects. Cases were individuals with one or more adenomas diagnosed during sigmoidoscopy, and controls were individuals with no adenomas at the sigmoidoscopy exam. We used unconditional logistic regression assuming an additive model to assess SNP-specific risks adjusting for multiple comparisons with P (act).Distal adenoma risk was significantly increased for one SNP in IGF2 [per minor allele OR = 1.41; 95 % confidence interval (CI) = 1.16, 1.67; P (act) = 0.005] and decreased for an ESR2 SNP (per minor allele OR = 0.78; 95 % CI = 0.66, 0.91; P (act) = 0.041). There was no statistically significant heterogeneity of these associations by race, sex, BMI, physical activity, or, in women, hormone replacement therapy use. Risk estimates did not differ in the colon versus rectum or for smaller (<1 cm) versus larger (>1 cm) adenomas.These data suggest that selected genetic variability in IGF2 and ESR2 may be modifiers of CRA risk.

    View details for DOI 10.1007/s00384-012-1505-8

    View details for Web of Science ID 000312343700006

    View details for PubMedID 22645077

  • Reproductive Status at First Diagnosis Influences Risk of Radiation-Induced Second Primary Contralateral Breast Cancer in the WECARE Study INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Brooks, J. D., Boice, J. D., Stovall, M., Reiner, A. S., Bernstein, L., John, E. M., Lynch, C. F., Mellemkjaer, L., Knight, J. A., Thomas, D. C., Haile, R. W., Smith, S. A., Capanu, M., Bernstein, J. L., Shore, R. E. 2012; 84 (4): 917-924

    Abstract

    Our study examined whether reproductive and hormonal factors before, at the time of, or after radiation treatment for a first primary breast cancer modify the risk of radiation-induced second primary breast cancer.The Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study is a multicenter, population-based study of 708 women (cases) with asynchronous contralateral breast cancer (CBC) and 1399 women (controls) with unilateral breast cancer. Radiotherapy (RT) records, coupled with anthropomorphic phantom simulations, were used to estimate quadrant-specific radiation dose to the contralateral breast for each patient. Rate ratios (RR) and 95% confidence intervals (CI) were computed to assess the relationship between reproductive factors and risk of CBC.Women who were nulliparous at diagnosis and exposed to ?1 Gy to the contralateral breast had a greater risk for CBC than did matched unexposed nulliparous women (RR=2.2; 95% CI, 1.2-4.0). No increased risk was seen in RT-exposed parous women (RR=1.1; 95% CI, 0.8-1.4). Women treated with RT who later became pregnant (8 cases and 9 controls) had a greater risk for CBC (RR=6.0; 95% CI, 1.3-28.4) than unexposed women (4 cases and 7 controls) who also became pregnant. The association of radiation with risk of CBC did not vary by number of pregnancies, history of breastfeeding, or menopausal status at the time of first breast cancer diagnosis.Nulliparous women treated with RT were at an increased risk for CBC. Although based on small numbers, women who become pregnant after first diagnosis also seem to be at an increased risk for radiation-induced CBC.

    View details for DOI 10.1016/j.ijrobp.2012.01.047

    View details for Web of Science ID 000310565300027

    View details for PubMedID 22483700

  • Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies LANCET ONCOLOGY Beral, V., Bull, D., Pirie, K., Reeves, G., Peto, R., Skegg, D., LAVECCHIA, C., Magnusson, C., Pike, M. C., Thomas, D., Hamajima, N., Hirose, K., Tajima, K., Rohan, T., Friedenreich, C. M., Calle, E. E., Gapstur, S. M., Patel, A. V., Coates, R. J., Liff, J. M., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Marcou, Y., Kakouri, E., Duffy, S. W., Morabia, A., Schuman, L., Stewart, W., Szklo, M., Coogan, P. F., Palmer, J. R., Rosenberg, L., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Cummings, S. R., Canfell, K., Sitas, F., Chao, P., Lissowska, J., Horn-Ross, P. L., John, E. M., Kolonel, L. M., Nomura, A. M., Ghiasvand, R., Hu, J., Johnson, K. C., Mao, Y., Callaghan, K., Crossley, B., Goodill, A., Green, J., Hermon, C., Key, T., Lindgard, I., Liu, B., Pirie, K., Reeves, G., Collins, R., DOLL, R., Peto, R., Bishop, T., Fentiman, I. S., De Sanjose, S., Gonzaler, C. A., Lee, N., Marchbanks, P., Ory, H. W., Peterson, H. B., Wingo, P., Ebeling, K., Kunde, D., Nishan, P., Hopper, J. L., ELIASSEN, H., Gajalakshmi, V., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Neugut, A., Santella, R., Baines, C. J., Kreiger, N., Miller, A. B., WALL, C., Tjonneland, A., Jorgensen, T., Stahlberg, C., Pedersen, A. T., Flesch-Janys, D., Hakansson, N., Cauley, J., Heuch, I., Adami, H. O., Persson, I., Weiderpass, E., Magnusson, C., Chang-Claude, J., Kaaks, R., McCredie, M., Paul, C., Skegg, D. C., Spears, G. F., Iwasaki, M., Tsugane, S., Anderson, G., Daling, J. R., Hampton, J., Hutchinson, W. B., Li, C. I., Malone, K., Mandelson, M., Newcomb, P., NOONAN, E. A., Ray, R. M., Stanford, J. L., Tang, M. T., Thomas, D. B., Weiss, N. S., White, E., Izquierdo, A., Viladiu, P., Fourkala, E. O., Jacobs, I., Menon, U., Ryan, A., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., ARISTIZABAL, N., Cuadros, A., Tryggvadottir, L., Tulinius, H., Riboli, E., Andrieu, N., Bachelot, A., Le, M. G., Bremond, A., Gairard, B., Lansac, J., Piana, L., Renaud, R., Clavel-Chapelon, F., Fournier, A., Touillaud, M., Mesrine, S., Chabbert-Buffet, N., Boutron-Ruault, M. C., Wolk, A., Torres-Mejia, G., Franceschi, S., Romieu, I., Boyle, P., Lubin, F., Modan, B., Ron, E., Wax, Y., Friedman, G. D., Hiatt, R. A., Levi, F., Kosmelj, K., Primic-Zakelj, M., Ravnihar, B., Stare, J., Ekbom, A., Erlandsson, G., Persson, I., Beeson, W. L., Fraser, G., Peto, J., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. O., Weinstein, A. L., Hartman, M. L., Olsson, H., Goldbohm, R. A., van den Brandt, P. A., Palli, D., Teitelbaum, S., APELO, R. A., BAENS, J., de la Cruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., La Vecchia, C., Negri, E., Marubini, E., Ferraroni, M., Pike, M. C., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Freedman, M., Hoover, R., Schairer, C., Ziegler, R., Banks, E., Spirtas, R., Lee, H. P., Rookus, M. A., van Leeuwen, F. E., Schoenberg, J. A., Graff-Iversen, S., Selmer, R., Jones, L., McPherson, K., Neil, A., Vessey, M., Yeates, D., Mabuchi, K., Preston, D., Hannaford, P., Kay, C., McCann, S. E., Rosero-Bixby, L., Gao, Y. T., Jin, F., Yuan, J., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., Booth, J. C., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., Hadjisavvas, A., Kyriacou, K., Loisidou, M., Zhou, X., Wang, Q., Kawai, M., Minami, Y., Tsuji, I., Lund, E., Kumle, M., Stalsberg, H., Shu, X. O., Zheng, W., Monninkhof, E. M., Onland-Moret, N. C., Peeters, P. H., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., Tzonou, A., Baltzell, K. A., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, F. E., Anderson, K., Folsom, A. R., Gammon, M. D., Hulka, B. S., Millikan, R., Chilvers, C. E., Lumachi, F., Bain, C., Schofield, F., Siskind, V., Rebbeck, T. R., Bernstein, L. R., Enger, S., Haile, R. W., Paganini-Hill, A., Ross, R. K., Ursin, G., Wu, A. H., Yu, M. C., Ewertz, D. M., Clarke, E. A., Bergkvist, L., Anderson, G. L., Gass, M., O'Sullivan, M. J., Kalache, A., Farley, T. M., Holck, S., MEIRIK, O., Fukao, A. 2012; 13 (11): 1141-1151
  • Screening practices of Australian men and women categorized as "at or slightly above average risk" of colorectal cancer CANCER CAUSES & CONTROL Ouakrim, D. A., Lockett, T., Boussioutas, A., Keogh, L., Flander, L. B., Winship, I., Giles, G. G., Hopper, J. L., Jenkins, M. A. 2012; 23 (11): 1853-1864

    Abstract

    Australia has one of the highest incidences of colorectal cancer (CRC) in the world. In 2006, the federal government introduced a screening program consisting of a one-off fecal occult blood test offered to people turning 50, 55, or 65 years. We conducted a population-based study to estimate CRC screening practices existing outside the current program.A total of 1887 unaffected subjects categorized "at or slightly above average risk" of CRC were selected from the Australasian Colorectal Cancer Family Registry. We calculated the proportions of participants that reported appropriate, under- and over-screening according to national guidelines. We performed a logistic regression analysis to evaluate associations between over-screening and a set of socio-demographic factors.Of 532 participants at average risk of CRC, eligible for screening, 4 (0.75 %) reported appropriate screening, 479 (90 %) reported never having been screened, 18 (3 %) reported some but less than appropriate screening, and 31 (6 %) reported over-screening. Of 412 participants aged 50 years or over, slightly above average risk of CRC, 1 participant (0.25 %) reported appropriate screening, 316 (77 %) reported no screening, and 11 (3 %) reported some but less than appropriate screening. Among participants under age 50 years, 2 % of those at average risk and 10 % of those slightly above average risk reported over-screening. Middle-aged people, those with a family history of CRC and those with a university degree, were more likely to be over-screened.Overall, the level of CRC screening participation was low and the vast majority of screening tests undertaken were inappropriate in terms of timing, modality, or frequency.

    View details for DOI 10.1007/s10552-012-0067-y

    View details for Web of Science ID 000309671300011

    View details for PubMedID 23011536

  • Identification of Lynch Syndrome Among Patients With Colorectal Cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Moreira, L., Balaguer, F., Lindor, N., De la Chapelle, A., Hampel, H., Aaltonen, L. A., Hopper, J. L., Le Marchand, L., Gallinger, S., Newcomb, P. A., Haile, R., Thibodeau, S. N., Gunawardena, S., Jenkins, M. A., Buchanan, D. D., Potter, J. D., Baron, J. A., Ahnen, D. J., Moreno, V., Andreu, M., De Leon, M. P., Rustgi, A. K., Castells, A. 2012; 308 (15): 1555-1565

    Abstract

    Lynch syndrome is the most common form of hereditary colorectal cancer (CRC) and is caused by germline mutations in DNA mismatch repair (MMR) genes. Identification of gene carriers currently relies on germline analysis in patients with MMR-deficient tumors, but criteria to select individuals in whom tumor MMR testing should be performed are unclear.To establish a highly sensitive and efficient strategy for the identification of MMR gene mutation carriers among CRC probands.Pooled-data analysis of 4 large cohorts of newly diagnosed CRC probands recruited between 1994 and 2010 (n = 10,206) from the Colon Cancer Family Registry, the EPICOLON project, the Ohio State University, and the University of Helsinki examining personal, tumor-related, and family characteristics, as well as microsatellite instability, tumor MMR immunostaining, and germline MMR mutational status data.Performance characteristics of selected strategies (Bethesda guidelines, Jerusalem recommendations, and those derived from a bivariate/multivariate analysis of variables associated with Lynch syndrome) were compared with tumor MMR testing of all CRC patients (universal screening).Of 10,206 informative, unrelated CRC probands, 312 (3.1%) were MMR gene mutation carriers. In the population-based cohorts (n = 3671 probands), the universal screening approach (sensitivity, 100%; 95% CI, 99.3%-100%; specificity, 93.0%; 95% CI, 92.0%-93.7%; diagnostic yield, 2.2%; 95% CI, 1.7%-2.7%) was superior to the use of Bethesda guidelines (sensitivity, 87.8%; 95% CI, 78.9%-93.2%; specificity, 97.5%; 95% CI, 96.9%-98.0%; diagnostic yield, 2.0%; 95% CI, 1.5%-2.4%; P < .001), Jerusalem recommendations (sensitivity, 85.4%; 95% CI, 77.1%-93.6%; specificity, 96.7%; 95% CI, 96.0%-97.2%; diagnostic yield, 1.9%; 95% CI, 1.4%-2.3%; P < .001), and a selective strategy based on tumor MMR testing of cases with CRC diagnosed at age 70 years or younger and in older patients fulfilling the Bethesda guidelines (sensitivity, 95.1%; 95% CI, 89.8%-99.0%; specificity, 95.5%; 95% CI, 94.7%-96.1%; diagnostic yield, 2.1%; 95% CI, 1.6%-2.6%; P < .001). This selective strategy missed 4.9% of Lynch syndrome cases but resulted in 34.8% fewer cases requiring tumor MMR testing and 28.6% fewer cases undergoing germline mutational analysis than the universal approach.Universal tumor MMR testing among CRC probands had a greater sensitivity for the identification of Lynch syndrome compared with multiple alternative strategies, although the increase in the diagnostic yield was modest.

    View details for DOI 10.1001/jama.2012.13088

    View details for Web of Science ID 000309858100022

    View details for PubMedID 23073952

  • Environmental epigenetics: prospects for studying epigenetic mediation of exposure-response relationships HUMAN GENETICS Cortessis, V. K., Thomas, D. C., Levine, A. J., Breton, C. V., Mack, T. M., Siegmund, K. D., Haile, R. W., Laird, P. W. 2012; 131 (10): 1565-1589

    Abstract

    Changes in epigenetic marks such as DNA methylation and histone acetylation are associated with a broad range of disease traits, including cancer, asthma, metabolic disorders, and various reproductive conditions. It seems plausible that changes in epigenetic state may be induced by environmental exposures such as malnutrition, tobacco smoke, air pollutants, metals, organic chemicals, other sources of oxidative stress, and the microbiome, particularly if the exposure occurs during key periods of development. Thus, epigenetic changes could represent an important pathway by which environmental factors influence disease risks, both within individuals and across generations. We discuss some of the challenges in studying epigenetic mediation of pathogenesis and describe some unique opportunities for exploring these phenomena.

    View details for DOI 10.1007/s00439-012-1189-8

    View details for Web of Science ID 000308249300005

    View details for PubMedID 22740325

  • Risks of Primary Extracolonic Cancers Following Colorectal Cancer in Lynch Syndrome JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Win, A. K., Lindor, N. M., Young, J. P., Macrae, F. A., Young, G. P., Williamson, E., Parry, S., Goldblatt, J., Lipton, L., Winship, I., Leggett, B., Tucker, K. M., Giles, G. G., Buchanan, D. D., Clendenning, M., Rosty, C., Arnold, J., Levine, A. J., Haile, R. W., Gallinger, S., Le Marchand, L., Newcomb, P. A., Hopper, J. L., Jenkins, M. A. 2012; 104 (18): 1363-1372

    Abstract

    Lynch syndrome is a highly penetrant cancer predisposition syndrome caused by germline mutations in DNA mismatch repair (MMR) genes. We estimated the risks of primary cancers other than colorectal cancer following a diagnosis of colorectal cancer in mutation carriers.We obtained data from the Colon Cancer Family Registry for 764 carriers of an MMR gene mutation (316 MLH1, 357 MSH2, 49 MSH6, and 42 PMS2), who had a previous diagnosis of colorectal cancer. The Kaplan-Meier method was used to estimate their cumulative risk of cancers 10 and 20 years after colorectal cancer. We estimated the age-, sex-, country- and calendar period-specific standardized incidence ratios (SIRs) of cancers following colorectal cancer, compared with the general population.Following colorectal cancer, carriers of MMR gene mutations had the following 10-year risk of cancers in other organs: kidney, renal pelvis, ureter, and bladder (2%, 95% confidence interval [CI] = 1% to 3%); small intestine, stomach, and hepatobiliary tract (1%, 95% CI = 0.2% to 2%); prostate (3%, 95% CI = 1% to 5%); endometrium (12%, 95% CI = 8% to 17%); breast (2%, 95% CI = 1% to 4%); and ovary (1%, 95% CI = 0% to 2%). They were at elevated risk compared with the general population: cancers of the kidney, renal pelvis, and ureter (SIR = 12.54, 95% CI = 7.97 to 17.94), urinary bladder (SIR = 7.22, 95% CI = 4.08 to 10.99), small intestine (SIR = 72.68, 95% CI = 39.95 to 111.29), stomach (SIR = 5.65, 95% CI = 2.32 to 9.69), and hepatobiliary tract (SIR = 5.94, 95% CI = 1.81 to 10.94) for both sexes; cancer of the prostate (SIR = 2.05, 95% CI = 1.23 to 3.01), endometrium (SIR = 40.23, 95% CI = 27.91 to 56.06), breast (SIR = 1.76, 95% CI = 1.07 to 2.59), and ovary (SIR = 4.19, 95% CI = 1.28 to 7.97).Carriers of MMR gene mutations who have already had a colorectal cancer are at increased risk of a greater range of cancers than the recognized spectrum of Lynch syndrome cancers, including breast and prostate cancers.

    View details for DOI 10.1093/jnci/djs351

    View details for Web of Science ID 000309132500007

    View details for PubMedID 22933731

  • Postmenopausal hormone therapy and colorectal cancer risk by molecularly defined subtypes among older women GUT Limsui, D., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2012; 61 (9): 1299-1305

    Abstract

    Postmenopausal hormone (PMH) therapy may reduce colorectal cancer (CRC) risk, but existing data are inconclusive.To evaluate associations between PMH therapy and incident CRC, overall and by molecularly defined subtypes, in the population-based Iowa Women's Health Study of older women.Exposure data were collected from Iowa Women's Health Study participants (55-69 years) at baseline (1986). Archived, paraffin-embedded tissue specimens for 553 CRC cases were collected and analysed to determine microsatellite instability (MSI-L/MSS or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive) and BRAF mutation (BRAF-wildtype or BRAF-mutated) status. Multivariable Cox regression models were fit to estimate RRs and 95% CIs.PMH therapy (ever vs never use) was inversely associated with incident CRC overall (RR=0.82; 95% CI 0.72 to 0.93), with a significantly lower risk for MSI-L/MSS tumours (RR=0.75; 95% CI 0.60 to 0.94), and borderline significantly lower risks for CIMP-negative (RR=0.79; 95% CI 0.63 to 1.01) and BRAF-wildtype (RR=0.83; 95% CI 0.66 to 1.04) tumours. For PMH therapy >5 years, the subtype-specific risk estimates for MSI-L/MSS, CIMP-negative and BRAF-wildtype tumours were: RR=0.60, 95% CI 0.40 to 0.91; RR=0.68, 95% CI 0.45 to 1.03; and RR=0.70, 95% CI 0.47 to 1.05, respectively. PMH therapy was not significantly associated with the MSI-H, CIMP-positive or BRAF-mutated CRC subtypes.In this prospective cohort study, PMH therapy was inversely associated with distinct molecularly defined CRC subtypes, which may be related to differential effects from oestrogen and/or progestin on heterogeneous pathways of colorectal carcinogenesis.

    View details for DOI 10.1136/gutjnl-2011-300719

    View details for Web of Science ID 000307809900012

    View details for PubMedID 22027477

  • Performance of PREM1,2,6, MMRpredict, and MMRpro in detecting Lynch syndrome among endometrial cancer cases GENETICS IN MEDICINE Mercado, R. C., Hampel, H., Kastrinos, F., Steyerberg, E., Balmana, J., Stoffel, E., Cohn, D. E., Backes, F. J., Hopper, J. L., Jenkins, M. A., Lindor, N. M., Casey, G., Haile, R., Madhavan, S., De la Chapelle, A., Syngal, S. 2012; 14 (7): 670-680

    Abstract

    Lynch syndrome accounts for 2-5% of endometrial cancer cases. Lynch syndrome prediction models have not been evaluated among endometrial cancer cases.Area under the receiver operating curve (AUC), sensitivity and specificity of PREMM(1,2,6), MMRpredict, and MMRpro scores were assessed among 563 population-based and 129 clinic-based endometrial cancer cases.A total of 14 (3%) population-based and 80 (62%) clinic-based subjects had pathogenic mutations. PREMM(1,2,6), MMRpredict, and MMRpro were able to distinguish mutation carriers from noncarriers (AUC of 0.77, 0.76, and 0.77, respectively), among population-based cases. All three models had lower discrimination for the clinic-based cohort, with AUCs of 0.67, 0.64, and 0.54, respectively. Using a 5% cutoff, sensitivity and specificity were as follows: PREMM(1,2,6), 93% and 5% among population-based cases and 99% and 2% among clinic-based cases; MMRpredict, 71% and 64% for the population-based cohort and 91% and 0% for the clinic-based cohort; and MMRpro, 57% and 85% among population-based cases and 95% and 10% among clinic-based cases.Currently available prediction models have limited clinical utility in determining which patients with endometrial cancer should undergo genetic testing for Lynch syndrome. Immunohistochemical analysis and microsatellite instability testing may be the best currently available tools to screen for Lynch syndrome in endometrial cancer patients.

    View details for DOI 10.1038/gim.2012.18

    View details for Web of Science ID 000306241800006

    View details for PubMedID 22402756

  • Decreased cyclooxygenase inhibition by aspirin in polymorphic variants of human prostaglandin H synthase-1 PHARMACOGENETICS AND GENOMICS Liu, W., Poole, E. M., Ulrich, C. M., Kulmacz, R. J. 2012; 22 (7): 525-537

    Abstract

    Aspirin (ASA), a major antiplatelet and cancer-preventing drug, irreversibly blocks the cyclooxygenase (COX) activity of prostaglandin H synthase-1 (PGHS-1). Considerable differences in ASA effectiveness are observed between individuals, and some of this variability may be due to PGHS-1 protein variants. Our overall aim is to determine which, if any, of the known variants in the mature PGHS-1 protein lead to functional alterations in COX catalysis or inhibition by ASA. The present study targeted four PGHS-1 variants: R53H, R108Q, L237M, and V481I.Wild-type human PGHS-1 and the four polymorphic variants were expressed as histidine-tagged, homodimeric proteins in insect cells using baculovirus vectors, solubilized with a detergent, and purified by affinity chromatography. The purified proteins were characterized in vitro to evaluate COX and peroxidase (POX) catalytic parameters and the kinetics of COX inhibition by ASA and NS-398.Compared with the wild type, several variants showed a higher COX/POX ratio (up to 1.5-fold, for R108Q), an elevated arachidonate Km (up to 1.9-fold, for R108Q), and/or a lower ASA reactivity (up to 60% less, for R108Q). The decreased ASA reactivity in R108Q reflected both a 70% increase in the Ki for ASA and a 30% decrease in the rate constant for acetyl group transfer to the protein. Computational modeling of the brief ASA pulses experienced by PGHS-1 in circulating platelets during daily ASA dosing predicted that the 60% lower ASA reactivity in R108Q yields a 15-fold increase in surviving COX activity; smaller, approximately two-fold increases in surviving COX activity were predicted for L237M and V481I. NS-398 competitively inhibited COX catalysis of the wild type (Ki=6 µmol/l) and inhibited COX inactivation by 1.0 mmol/l ASA in both the wild type (IC50=0.8 µmol/l) and R108Q (IC50=2.1 µmol/l).Of the four PGHS-1 variants examined, R108Q exerts the largest functional effects, with evidence for impaired interactions with a COX substrate and inhibitors. As Arg108 is located on the protein surface and not in the active site, the effects of R108Q suggest a novel, unsuspected mechanism for the modulation of the PGHS-1 active site structure. The lower intrinsic ASA reactivity of R108Q, V481I, and L237M, combined with the rapid hydrolysis of ASA in the blood, suggests that these variants decrease the antiplatelet effectiveness of the drug. These PGHS-1 variants are uncommon but ASA is used widely; hence, a considerable number of individuals could be affected. Further examination of these and other PGHS-1 variants will be needed to determine whether PGHS-1 genotyping can be used to personalize anti-COX therapy.

    View details for DOI 10.1097/FPC.0b013e32835366f6

    View details for Web of Science ID 000305429900006

    View details for PubMedID 22513397

  • Colorectal Cancer Linkage on Chromosomes 4q21, 8q13, 12q24, and 15q22 PLOS ONE Cicek, M. S., Cunningham, J. M., Fridley, B. L., Serie, D. J., Bamlet, W. R., Diergaarde, B., Haile, R. W., Le Marchand, L., Krontiris, T. G., Younghusband, H. B., Gallinger, S., Newcomb, P. A., Hopper, J. L., Jenkins, M. A., Casey, G., Schumacher, F., Chen, Z., DeRycke, M. S., Templeton, A. S., Winship, I., Green, R. C., Green, J. S., Macrae, F. A., Parry, S., Young, G. P., Young, J. P., Buchanan, D., Thomas, D. C., Bishop, D. T., Lindor, N. M., Thibodeau, S. N., Potter, J. D., Goode, E. L. 2012; 7 (5)

    Abstract

    A substantial proportion of familial colorectal cancer (CRC) is not a consequence of known susceptibility loci, such as mismatch repair (MMR) genes, supporting the existence of additional loci. To identify novel CRC loci, we conducted a genome-wide linkage scan in 356 white families with no evidence of defective MMR (i.e., no loss of tumor expression of MMR proteins, no microsatellite instability (MSI)-high tumors, or no evidence of linkage to MMR genes). Families were ascertained via the Colon Cancer Family Registry multi-site NCI-supported consortium (Colon CFR), the City of Hope Comprehensive Cancer Center, and Memorial University of Newfoundland. A total of 1,612 individuals (average 5.0 per family including 2.2 affected) were genotyped using genome-wide single nucleotide polymorphism linkage arrays; parametric and non-parametric linkage analysis used MERLIN in a priori-defined family groups. Five lod scores greater than 3.0 were observed assuming heterogeneity. The greatest were among families with mean age of diagnosis less than 50 years at 4q21.1 (dominant HLOD = 4.51, α = 0.84, 145.40 cM, rs10518142) and among all families at 12q24.32 (dominant HLOD = 3.60, α = 0.48, 285.15 cM, rs952093). Among families with four or more affected individuals and among clinic-based families, a common peak was observed at 15q22.31 (101.40 cM, rs1477798; dominant HLOD = 3.07, α = 0.29; dominant HLOD = 3.03, α = 0.32, respectively). Analysis of families with only two affected individuals yielded a peak at 8q13.2 (recessive HLOD = 3.02, α = 0.51, 132.52 cM, rs1319036). These previously unreported linkage peaks demonstrate the continued utility of family-based data in complex traits and suggest that new CRC risk alleles remain to be elucidated.

    View details for DOI 10.1371/journal.pone.0038175

    View details for Web of Science ID 000305338500103

    View details for PubMedID 22675446

  • Cigarette Smoking and Colorectal Cancer Risk by KRAS Mutation Status Among Older Women AMERICAN JOURNAL OF GASTROENTEROLOGY Samadder, N. J., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2012; 107 (5): 782-789

    Abstract

    Existing data support a modest association between cigarette smoking and incident colorectal cancer (CRC) overall. In this study, we evaluated associations between cigarette smoking and CRC risk stratified by KRAS mutation status, using data and tissue resources from the Iowa Women's Health Study (IWHS).The IWHS is a population-based cohort study of cancer incidence among 41,836 randomly selected Iowa women, ages 55-69 years of age at enrollment (1986). Exposure data, including cigarette smoking, were obtained by self-report at baseline. Incident CRCs (n=1,233) were ascertained by annual linkage with the Iowa Cancer Registry. Archived tissue specimens from CRC cases recorded through 2002 were recently requested for molecular epidemiology investigations. Tumor KRAS mutation status was determined by direct sequencing of exon 2, with informative results in 507/555 (91%) available CRC cases (342 mutation negative and 165 mutation positive). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs) for associations between cigarette smoking variables and KRAS-defined CRC subtypes.Multiple smoking variables were associated with increased risk for KRAS mutation-negative tumors, including age at initiation (P=0.02), average number of cigarettes per day (P=0.01), cumulative pack-years (P=0.05), and induction period (P=0.04), with the highest point estimate observed for women who smoked ≥40 cigarettes per day on average (RR=2.38; 95% CI=1.25-4.51; compared with never smokers). Further consideration of CRC subsite suggested that cigarette smoking may be a stronger risk factor for KRAS mutation-negative tumors located in the proximal colon than in the distal colorectum. None of the smoking variables were significantly associated with KRAS mutation-positive CRCs (overall or stratified by anatomic subsite).Data from this prospective study of older women demonstrate differential associations between cigarette smoking and CRC subtypes defined by KRAS mutation status, and are consistent with the hypothesis that smoking adversely affects the serrated pathway of colorectal carcinogenesis.

    View details for DOI 10.1038/ajg.2012.21

    View details for Web of Science ID 000303679700019

    View details for PubMedID 22349355

  • Carcinogen metabolism genes, red meat and poultry intake, and colorectal cancer risk INTERNATIONAL JOURNAL OF CANCER Wang, J., Joshi, A. D., Corral, R., Siegmund, K. D., Le Marchand, L., Martinez, M. E., Haile, R. W., Ahnen, D. J., Sandler, R. S., Lance, P., Stern, M. C. 2012; 130 (8): 1898-1907

    Abstract

    Diets high in red meat are established risk factors for colorectal cancer (CRC). Carcinogenic compounds generated during meat cooking have been implicated as causal agents. We conducted a family-based case-control study to investigate the association between polymorphisms in carcinogen metabolism genes (CYP1A2 -154A>C, CYP1B1 Leu432Val, CYP2E1 -1054C>T, GSTP1 Ile105Val, PTGS2 5UTR -765, EPHX1 Tyr113His, NAT2 Ile114Thr, NAT2 Arg197Gln and NAT2 Gly286Glu) and CRC risk. We tested for gene-environment interactions using case-only analyses (N = 577) and compared statistically significant results to those obtained using case-unaffected sibling comparisons (N = 307 sibships). Our results suggested that CYP1A2 -154A>C might modify the association between intake of red meat cooked using high temperature methods and well done on the inside and CRC risk (case-only interaction OR = 1.53; 95% CI = 1.19-1.97; p = 0.0008) and the association between intake of red meat heavily browned on the outside and rectal cancer risk (case-only interaction OR = 0.65; 95% CI = 0.48-0.86; p = 0.003). We also found that GSTP1 Ile105Val might modify the association between intake of poultry cooked with high temperature methods and CRC risk (p = 0.0035), a finding that was stronger among rectal cancer cases. Our results support a role for heterocyclic amines that form in red meat as a potential explanation for the observed association between diets high in red meat and CRC. Our findings also suggest a possible role for diets high in poultry cooked at high temperatures in CRC risk.

    View details for DOI 10.1002/ijc.26199

    View details for Web of Science ID 000300692300020

    View details for PubMedID 21618522

  • Postmenopausal Hormone Therapy and Colorectal Cancer Risk in Relation to Somatic KRAS Mutation Status among Older Women CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Limburg, P. J., Limsui, D., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R. 2012; 21 (4): 681-684

    Abstract

    Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Because colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women [Iowa Women's Health Study (IWHS)].The IWHS enrolled 41,836 randomly selected women, ages 55 to 69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI).PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI, 0.66-1.06; P = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI, 0.58-1.16; P = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI, 0.43-0.96; P = 0.03).To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum).Findings from this prospective cohort study provide novel insights about the molecular biology of PMH therapy-related CRC risk reduction.

    View details for DOI 10.1158/1055-9965.EPI-11-1168

    View details for Web of Science ID 000302220600014

    View details for PubMedID 22337533

  • Rare germline mutations in PALB2 and breast cancer risk: A population-based study HUMAN MUTATION Tischkowitz, M., Capanu, M., Sabbaghian, N., Li, L., Liang, X., Vallee, M. P., Tavtigian, S. V., Concannon, P., Foulkes, W. D., Bernstein, L., Bernstein, J. L., Begg, C. B. 2012; 33 (4): 674-680

    Abstract

    Germline mutations in the PALB2 gene are associated with an increased risk of developing breast cancer but little is known about the frequencies of rare variants in PALB2 and the nature of the variants that influence risk. We selected participants recruited to the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study and screened lymphocyte DNA from cases with contralateral breast cancer (n = 559) and matched controls with unilateral breast cancer (n = 565) for PALB2 mutations. Five pathogenic PALB2 mutations were identified among the cases (0.9%) versus none among the controls (P = 0.04). The first-degree female relatives of these five carriers demonstrated significantly higher incidence of breast cancer than relatives of noncarrier cases, indicating that pathogenic PALB2 mutations confer an estimated 5.3-fold increase in risk (95% CI: 1.8-13.2). The frequency of rare (<1% MAF) missense mutations was similar in both groups (23 vs. 21). Our findings confirm in a population-based study setting of women with breast cancer the strong risk associated with truncating mutations in PALB2 that has been reported in family studies. Conversely, there is no evidence from this study that rare PALB2 missense mutations strongly influence breast cancer risk.

    View details for DOI 10.1002/humu.22022

    View details for Web of Science ID 000301338900015

    View details for PubMedID 22241545

  • Colorectal and Other Cancer Risks for Carriers and Noncarriers From Families With a DNA Mismatch Repair Gene Mutation: A Prospective Cohort Study JOURNAL OF CLINICAL ONCOLOGY Win, A. K., Young, J. P., Lindor, N. M., Tucker, K. M., Ahnen, D. J., Young, G. P., Buchanan, D. D., Clendenning, M., Giles, G. G., Winship, I., Macrae, F. A., Goldblatt, J., Southey, M. C., Arnold, J., Thibodeau, S. N., Gunawardena, S. R., Bapat, B., Baron, J. A., Casey, G., Gallinger, S., Le Marchand, L., Newcomb, P. A., Haile, R. W., Hopper, J. L., Jenkins, M. A. 2012; 30 (9): 958-964

    Abstract

    To determine whether cancer risks for carriers and noncarriers from families with a mismatch repair (MMR) gene mutation are increased above the risks of the general population.We prospectively followed a cohort of 446 unaffected carriers of an MMR gene mutation (MLH1, n = 161; MSH2, n = 222; MSH6, n = 47; and PMS2, n = 16) and 1,029 their unaffected relatives who did not carry a mutation every 5 years at recruitment centers of the Colon Cancer Family Registry. For comparison of cancer risk with the general population, we estimated country-, age-, and sex-specific standardized incidence ratios (SIRs) of cancer for carriers and noncarriers.Over a median follow-up of 5 years, mutation carriers had an increased risk of colorectal cancer (CRC; SIR, 20.48; 95% CI, 11.71 to 33.27; P < .001), endometrial cancer (SIR, 30.62; 95% CI, 11.24 to 66.64; P < .001), ovarian cancer (SIR, 18.81; 95% CI, 3.88 to 54.95; P < .001), renal cancer (SIR, 11.22; 95% CI, 2.31 to 32.79; P < .001), pancreatic cancer (SIR, 10.68; 95% CI, 2.68 to 47.70; P = .001), gastric cancer (SIR, 9.78; 95% CI, 1.18 to 35.30; P = .009), urinary bladder cancer (SIR, 9.51; 95% CI, 1.15 to 34.37; P = .009), and female breast cancer (SIR, 3.95; 95% CI, 1.59 to 8.13; P = .001). We found no evidence of their noncarrier relatives having an increased risk of any cancer, including CRC (SIR, 1.02; 95% CI, 0.33 to 2.39; P = .97).We confirmed that carriers of an MMR gene mutation were at increased risk of a wide variety of cancers, including some cancers not previously recognized as being a result of MMR mutations, and found no evidence of an increased risk of cancer for their noncarrier relatives.

    View details for DOI 10.1200/JCO.2011.39.5590

    View details for Web of Science ID 000302628400015

    View details for PubMedID 22331944

  • Development of a Panel of Genome-Wide Ancestry Informative Markers to Study Admixture Throughout the Americas PLOS GENETICS Galanter, J. M., Carlos Fernandez-Lopez, J., Gignoux, C. R., Barnholtz-Sloan, J., Fernandez-Rozadilla, C., Via, M., Hidalgo-Miranda, A., Contreras, A. V., Uribe Figueroa, L., Raska, P., Jimenez-Sanchez, G., Silva Zolezzi, I., Torres, M., Ruiz Ponte, C., Ruiz, Y., Salas, A., Nguyen, E., Eng, C., Borjas, L., Zabala, W., Barreto, G., Rondon Gonzalez, F., Ibarra, A., Taboada, P., Porras, L., Moreno, F., Bigham, A., Gutierrez, G., Brutsaert, T., Leon-Velarde, F., Moore, L. G., Vargas, E., Cruz, M., Escobedo, J., Rodriguez-Santana, J., Rodriguez-Cintron, W., Chapela, R., Ford, J. G., Bustamante, C., Seminara, D., Shriver, M., Ziv, E., Burchard, E. G., Haile, R., Parra, E., Carracedo, A. 2012; 8 (3)

    Abstract

    Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R² > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.

    View details for DOI 10.1371/journal.pgen.1002554

    View details for Web of Science ID 000302254800030

    View details for PubMedID 22412386

  • The Family Health Promotion Project (FHPP): Design and baseline data from a randomized trial to increase colonoscopy screening in high risk families CONTEMPORARY CLINICAL TRIALS Lowery, J. T., Marcus, A., Kinney, A., Bowen, D., Finkelstein, D. M., Horick, N., Garrett, K., Haile, R., Sandler, R., Ahnen, D. J. 2012; 33 (2): 426-435

    Abstract

    Colorectal cancer (CRC) is a significant cause of mortality and morbidity in the United States, much of which could be prevented through adequate screening. Consensus guidelines recommend that high-risk groups initiate screening earlier with colonoscopy and more frequently than average risk persons. However, a large proportion of high risk individuals do not receive regular colonoscopic screening. The Family Health Promotion Project (FHPP) is a randomized-controlled trial to test the effectiveness of a telephone-based counseling intervention to increase adherence to risk-appropriate colonoscopy screening in high risk individuals. Unaffected members of CRC families from two national cancer family registries were enrolled (n=632) and randomized to receive either a single session telephone counseling intervention using Motivational Interviewing techniques or a minimal mail-out intervention. The primary endpoint, rate of colonoscopy screening, was assessed at 6, 12 and 24 months post-enrollment. In this paper, we describe the research design and telephone counseling intervention of the FHPP trial, and report baseline data obtained from the two high risk cohorts recruited into this trial. Results obtained at baseline confirm the need for interventions to promote colonoscopy screening among these high risk individuals, as well as highlighting several key opportunities for intervention, including increasing knowledge about risk-appropriate screening guidelines, and providing both tailored risk information and barriers counseling.

    View details for DOI 10.1016/j.cct.2011.11.005

    View details for Web of Science ID 000300962000023

    View details for PubMedID 22101228

  • cis-Expression QTL Analysis of Established Colorectal Cancer Risk Variants in Colon Tumors and Adjacent Normal Tissue PLOS ONE Loo, L. W., Cheng, I., Tiirikainen, M., Lum-Jones, A., Seifried, A., Dunklee, L. M., Church, J. M., Gryfe, R., Weisenberger, D. J., Haile, R. W., Gallinger, S., Duggan, D. J., Thibodeau, S. N., Casey, G., Le Marchand, L. 2012; 7 (2)

    Abstract

    Genome-wide association studies (GWAS) have identified 19 risk variants associated with colorectal cancer. As most of these risk variants reside outside the coding regions of genes, we conducted cis-expression quantitative trait loci (cis-eQTL) analyses to investigate possible regulatory functions on the expression of neighboring genes. Forty microsatellite stable and CpG island methylator phenotype-negative colorectal tumors and paired adjacent normal colon tissues were used for genome-wide SNP and gene expression profiling. We found that three risk variants (rs10795668, rs4444235 and rs9929218, using near perfect proxies rs706771, rs11623717 and rs2059252, respectively) were significantly associated (FDR q-value ≤0.05) with expression levels of nearby genes (<2 Mb up- or down-stream). We observed an association between the low colorectal cancer risk allele (A) for rs10795668 at 10p14 and increased expression of ATP5C1 (q = 0.024) and between the colorectal cancer high risk allele (C) for rs4444235 at 14q22.2 and increased expression of DLGAP5 (q = 0.041), both in tumor samples. The colorectal cancer low risk allele (A) for rs9929218 at 16q22.1 was associated with a significant decrease in expression of both NOL3 (q = 0.017) and DDX28 (q = 0.046) in the adjacent normal colon tissue samples. Of the four genes, DLGAP5 and NOL3 have been previously reported to play a role in colon carcinogenesis and ATP5C1 and DDX28 are mitochondrial proteins involved in cellular metabolism and division, respectively. The combination of GWAS findings, prior functional studies, and the cis-eQTL analyses described here suggest putative functional activities for three of the colorectal cancer GWAS identified risk loci as regulating the expression of neighboring genes.

    View details for DOI 10.1371/journal.pone.0030477

    View details for Web of Science ID 000302853600032

    View details for PubMedID 22363440

  • A Review of Cancer in US Hispanic Populations CANCER PREVENTION RESEARCH Haile, R. W., John, E. M., Levine, A. J., Cortessis, V. K., Unger, J. B., Gonzales, M., Ziv, E., Thompson, P., Spruijt-Metz, D., Tucker, K. L., Bernstein, J. L., Rohan, T. E., Ho, G. Y., Bondy, M. L., Martinez, M. E., Cook, L., Stern, M. C., Correa, M. C., Wright, J., Schwartz, S. J., Baezconde-Garbanati, L., Blinder, V., Miranda, P., Hayes, R., Friedman-Jimenez, G., Monroe, K. R., Haiman, C. A., Henderson, B. E., Thomas, D. C., Boffetta, P. 2012; 5 (2): 150-163

    Abstract

    There are compelling reasons to conduct studies of cancer in Hispanics, the fastest growing major demographic group in the United States (from 15% to 30% of the U.S. population by 2050). The genetically admixed Hispanic population coupled with secular trends in environmental exposures and lifestyle/behavioral practices that are associated with immigration and acculturation offer opportunities for elucidating the effects of genetics, environment, and lifestyle on cancer risk and identifying novel risk factors. For example, traditional breast cancer risk factors explain less of the breast cancer risk in Hispanics than in non-Hispanic whites (NHW), and there is a substantially greater proportion of never-smokers with lung cancer in Hispanics than in NHW. Hispanics have higher incidence rates for cancers of the cervix, stomach, liver, and gall bladder than NHW. With respect to these cancers, there are intriguing patterns that warrant study (e.g., depending on country of origin, the five-fold difference in gastric cancer rates for Hispanic men but not Hispanic women). Also, despite a substantially higher incidence rate and increasing secular trend for liver cancer in Hispanics, there have been no studies of Hispanics reported to date. We review the literature and discuss study design options and features that should be considered in future studies.

    View details for DOI 10.1158/1940-6207.CAPR-11-0447

    View details for Web of Science ID 000300043500002

    View details for PubMedID 22307564

  • Meta-analysis of new genome-wide association studies of colorectal cancer risk HUMAN GENETICS Peters, U., Hutter, C. M., Hsu, L., Schumacher, F. R., Conti, D. V., Carlson, C. S., Edlund, C. K., Haile, R. W., Gallinger, S., Zanke, B. W., Lemire, M., Rangrej, J., Vijayaraghavan, R., Chan, A. T., Hazra, A., Hunter, D. J., Ma, J., Fuchs, C. S., Giovannucci, E. L., Kraft, P., Liu, Y., Chen, L., Jiao, S., Makar, K. W., Taverna, D., Gruber, S. B., Rennert, G., Moreno, V., Ulrich, C. M., Woods, M. O., Green, R. C., Parfrey, P. S., Prentice, R. L., Kooperberg, C., Jackson, R. D., LaCroix, A. Z., Caan, B. J., Hayes, R. B., Berndt, S. I., Chanock, S. J., Schoen, R. E., Chang-Claude, J., Hoffmeister, M., Brenner, H., Frank, B., Bezieau, S., Kuery, S., Slattery, M. L., Hopper, J. L., Jenkins, M. A., Le Marchand, L., Lindor, N. M., Newcomb, P. A., Seminara, D., Hudson, T. J., Duggan, D. J., Potter, J. D., Casey, G. 2012; 131 (2): 217-234

    Abstract

    Colorectal cancer is the second leading cause of cancer death in developed countries. Genome-wide association studies (GWAS) have successfully identified novel susceptibility loci for colorectal cancer. To follow up on these findings, and try to identify novel colorectal cancer susceptibility loci, we present results for GWAS of colorectal cancer (2,906 cases, 3,416 controls) that have not previously published main associations. Specifically, we calculated odds ratios and 95% confidence intervals using log-additive models for each study. In order to improve our power to detect novel colorectal cancer susceptibility loci, we performed a meta-analysis combining the results across studies. We selected the most statistically significant single nucleotide polymorphisms (SNPs) for replication using ten independent studies (8,161 cases and 9,101 controls). We again used a meta-analysis to summarize results for the replication studies alone, and for a combined analysis of GWAS and replication studies. We measured ten SNPs previously identified in colorectal cancer susceptibility loci and found eight to be associated with colorectal cancer (p value range 0.02 to 1.8 × 10(-8)). When we excluded studies that have previously published on these SNPs, five SNPs remained significant at p < 0.05 in the combined analysis. No novel susceptibility loci were significant in the replication study after adjustment for multiple testing, and none reached genome-wide significance from a combined analysis of GWAS and replication. We observed marginally significant evidence for a second independent SNP in the BMP2 region at chromosomal location 20p12 (rs4813802; replication p value 0.03; combined p value 7.3 × 10(-5)). In a region on 5p33.15, which includes the coding regions of the TERT-CLPTM1L genes and has been identified in GWAS to be associated with susceptibility to at least seven other cancers, we observed a marginally significant association with rs2853668 (replication p value 0.03; combined p value 1.9 × 10(-4)). Our study suggests a complex nature of the contribution of common genetic variants to risk for colorectal cancer.

    View details for DOI 10.1007/s00439-011-1055-0

    View details for Web of Science ID 000299123000006

    View details for PubMedID 21761138

  • Cancer Risks for the Relatives of Colorectal Cancer Cases with a Methylated MLH1 Promoter Region: Data from the Colorectal Cancer Family Registry CANCER PREVENTION RESEARCH Levine, A. J., Win, A. K., Buchanan, D. D., Jenkins, M. A., Baron, J. A., Young, J. P., Long, T. I., Weisenberger, D. J., Laird, P. W., McCall, R. L., Duggan, D. J., Haile, R. W. 2012; 5 (2): 328-335

    Abstract

    Methylation of the MLH1 gene promoter region is an underlying cause of colorectal cancer (CRC) with high microsatellite instability (MSI-H) diagnosed in persons without a germ line mutation in a mismatch repair (MMR) gene (non-Lynch Syndrome CRC). It is unclear whether relatives of CRC cases with MLH1 methylation have an increased risk of colorectal or other cancers. In this retrospective cohort study, we assessed risk of CRC and other cancers for the first- and second-degree relatives of CRC cases with a methylated MLH1 gene, by comparing observed numbers of cases with those expected on the basis of age-, sex-, and country-specific cancer incidences (standardized incidence ratios). The cohort consisted of 3,128 first- and second-degree relatives of the 233 MLH1-methylated CRC cases with no MMR or MUTYH gene mutations. The standardized incidence ratio (SIR) for CRC was 1.60 [95% confidence interval (CI), 1.22-2.16] for first-degree relatives and 1.08 (0.74-1.60) for second-degree relatives. The SIR for gastric cancer was 2.58 (1.52-4.71) for first-degree relatives and 4.52 (2.23-10.61) for second-degree relatives and, for ovarian cancer, it was 2.16 (1.29-3.86) for first-degree relatives. The risk of liver cancer was also increased significantly in first-degree relatives but the estimate was on the basis of only two cases. These data imply that relatives of CRC cases with MLH1 methylation may be at increased risk of CRC and stomach cancer and possibly ovarian and liver cancer, suggesting that there may be a heritable factor for CRC and other cancers associated with MLH1 methylation in non-Lynch syndrome CRCs.

    View details for DOI 10.1158/1940-6207.CAPR-11-0419

    View details for Web of Science ID 000300043500020

    View details for PubMedID 22144422

  • Associations Between Intake of Folate and Related Micronutrients with Molecularly Defined Colorectal Cancer Risks in the Iowa Women's Health Study NUTRITION AND CANCER-AN INTERNATIONAL JOURNAL Razzak, A. A., Oxentenko, A. S., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2012; 64 (7): 899-910

    Abstract

    Folate and related micronturients may affect colorectal cancer (CRC) risk, but the molecular mechanism(s) remain incompletely defined. We analyzed associations between dietary folate, vitamin B6, vitamin B12, and methionine with incident CRC, overall and by microsatellite instability (MSS/MSI-L or MSI-H), CpG island methylator phenotype (CIMP-negative or CIMP-positive), BRAF mutation (negative or positive), and KRAS mutation (negative or positive) status in the prospective, population-based Iowa Women's Health Study (IWHS; 55-69 years at baseline; n = 41,836). Intake estimates were obtained from baseline, self-reported food frequency questionnaires. Molecular marker data were obtained for 514 incident CRC cases. Folate intake was inversely associated with overall CRC risk in age-adjusted Cox regression models, whereas methionine intake was inversely associated with overall CRC risk in multivariable-adjusted models [relative risk (RR) = 0.81; 95% CI = 0.69-0.95; P trend = 0.001 and RR = 0.72; 95% CI = 0.54-0.96; P trend = 0.03 for highest vs. lowest quartiles, respectively]. None of the dietary exposures were associated with MSI, CIMP, BRAF, or KRAS defined CRC subtypes. These data provide minimal support for major effects from the examined micronutrients on overall or molecularly defined CRC risks in the IWHS cohort.

    View details for DOI 10.1080/01635581.2012.714833

    View details for Web of Science ID 000310310600001

    View details for PubMedID 23061900

  • Variants in Activators and Downstream Targets of ATM, Radiation Exposure, and Contralateral Breast Cancer Risk in the WECARE Study HUMAN MUTATION Brooks, J. D., Teraoka, S. N., Reiner, A. S., Satagopan, J. M., Bernstein, L., Thomas, D. C., Capanu, M., Stovall, M., Smith, S. A., Wei, S., Shore, R. E., Boice, J. D., Lynch, C. F., Mellemkaer, L., Malone, K. E., Liang, X., Haile, R. W., Concannon, P., Bernstein, J. L. 2012; 33 (1): 158-164

    Abstract

    Ionizing radiation (IR) is a breast carcinogen that induces DNA double-strand breaks (DSBs), and variation in genes involved in the DNA DSB response has been implicated in radiation-induced breast cancer. The Women's Environmental, Cancer, and Radiation Epidemiology (WECARE) study is a population-based study of cases with contralateral breast cancer (CBC) and matched controls with unilateral breast cancer. The location-specific radiation dose received by the contralateral breast was estimated from radiotherapy records and mathematical models. One hundred fifty-two SNPs in six genes (CHEK2, MRE11A, MDC1, NBN, RAD50, TP53BP1) involved in the DNA DSBs response were genotyped. No variants or haplotypes were associated with CBC risk (649 cases and 1,284 controls) and no variants were found to interact with radiation dose. Carriers of a RAD50 haplotype exposed to ?1 gray (Gy) had an increased risk of CBC compared with unexposed carriers (Rate ratios [RR] = 4.31 [95% confidence intervals [CI] 1.93-9.62]); with an excess relative risk (ERR) per Gy = 2.13 [95% CI 0.61-5.33]). Although the results of this study were largely null, carriers of a haplotype in RAD50 treated with radiation had a greater CBC risk than unexposed carriers. This suggests that carriers of this haplotype may be susceptible to the DNA-damaging effects of radiation therapy associated with radiation-induced breast cancer.

    View details for DOI 10.1002/humu.21604

    View details for Web of Science ID 000300705300020

    View details for PubMedID 21898661

  • Hematopoietic prostaglandin D synthase (HPGDS): A high stability, Val187Ile isoenzyme common among African Americans and its relationship to risk for colorectal cancer PROSTAGLANDINS & OTHER LIPID MEDIATORS Tippin, B. L., Levine, A. J., Materi, A. M., Song, W., Keku, T. O., Goodman, J. E., Sansbury, L. B., Das, S., Dai, A., Kwong, A. M., Lin, A. M., Lin, J. M., Park, J. M., Patterson, R. E., Chlebowski, R. T., Garavito, R. M., Inoue, T., Cho, W., Lawson, J. A., Kapoor, S., Kolonel, L. N., Le Marchand, L., Haile, R. W., Sandler, R. S., Lin, H. J. 2012; 97 (1-2): 22-28

    Abstract

    Intestinal tumors in Apc(Min/+) mice are suppressed by over-production of HPGDS, which is a glutathione transferase that forms prostaglandin D(2) (PGD(2)). We characterized naturally occurring HPGDS isoenzymes, to see if HPGDS variation is associated with human colorectal cancer risk. We used DNA heteroduplex analysis and sequencing to identify HPGDS variants among healthy individuals. HPGDS isoenzymes were produced in bacteria, and their catalytic activities were tested. To determine in vivo effects, we conducted pooled case-control analyses to assess whether there is an association of the isoenzyme with colorectal cancer. Roughly 8% of African Americans and 2% of Caucasians had a highly stable Val187lle isoenzyme (with isoleucine instead of valine at position 187). At 37°C, the wild-type enzyme lost 15% of its activity in 1h, whereas the Val187Ile form remained >95% active. At 50°C, the half life of native HPGDS was 9min, compared to 42 min for Val187Ile. The odds ratio for colorectal cancer among African Americans with Val187Ile was 1.10 (95% CI, 0.75-1.62; 533 cases, 795 controls). Thus, the Val187Ile HPGDS isoenzyme common among African Americans is not associated with colorectal cancer risk. Other approaches will be needed to establish a role for HPGDS in occurrence of human intestinal tumors, as indicated by a mouse model.

    View details for DOI 10.1016/j.prostaglandins.2011.07.006

    View details for Web of Science ID 000300654400003

    View details for PubMedID 21821144

  • Body mass index and risk of second primary breast cancer: The WECARE Study BREAST CANCER RESEARCH AND TREATMENT Brooks, J. D., John, E. M., Mellemkjaer, L., Reiner, A. S., Malone, K. E., Lynch, C. F., Figueiredo, J. C., Haile, R. W., Shore, R. E., Bernstein, J. L., Bernstein, L. 2012; 131 (2): 571-580

    Abstract

    The identification of potentially modifiable risk factors, such as body size, could allow for interventions that could help reduce the burden of contralateral breast cancer (CBC) among breast cancer survivors. Studies examining the relationship between body mass index (BMI) and CBC have yielded mixed results. From the population-based, case-control, Women's Environmental, Cancer and Radiation Epidemiology (WECARE) Study, we included 511 women with CBC (cases) and 999 women with unilateral breast cancer (controls) who had never used postmenopausal hormone therapy. Rate ratios (RR) and 95% confidence intervals (CI) were used to assess the relationship between BMI and CBC risk. No associations between BMI at first diagnosis or weight-change between first diagnosis and date of CBC diagnosis (or corresponding date in matched controls) and CBC risk were seen. However, obese (BMI ? 30 kg/m(2)) postmenopausal women with estrogen receptor (ER)-negative first primary tumors (n = 12 cases and 9 controls) were at an increased risk of CBC compared with normal weight women (BMI < 25 kg/m(2)) (n = 43 cases and 98 controls) (RR = 5.64 (95% CI 1.76, 18.1)). No association between BMI and CBC risk was seen in premenopausal or postmenopausal women with ER-positive first primaries. Overall, BMI is not associated with CBC risk in this population of young breast cancer survivors. Our finding of an over five-fold higher risk of CBC in a small subgroup of obese postmenopausal women with an ER-negative first primary breast cancer is based on limited numbers and requires confirmation in a larger study.

    View details for DOI 10.1007/s10549-011-1743-4

    View details for Web of Science ID 000298752200021

    View details for PubMedID 21892703

  • Alcohol Intake and Colorectal Cancer Risk by Molecularly Defined Subtypes in a Prospective Study of Older Women CANCER PREVENTION RESEARCH Razzak, A. A., Oxentenko, A. S., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2011; 4 (12): 2035-2043

    Abstract

    Increased alcohol consumption is a putative colorectal cancer (CRC) risk factor. However, existing data are less conclusive for women than men. Also, to date, relatively few studies have reported alcohol-related CRC risks based on molecularly defined tumor subtypes. We evaluated associations between alcohol intake and incident CRC, overall and by microsatellite instability [MSI high (MSI-H) or MSI low/microsatellite stable (MSI-L/MSS)], CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation (mutated or wild-type) status in the prospective, population-based Iowa Women's Health Study (IWHS; n = 41,836). Subjects were 55 to 69 years at baseline (1986), and exposure data were obtained by self-report. Incident CRCs were prospectively identified and archived, paraffin-embedded tissue specimens were collected from 732 representative cases, diagnosed through December 31, 2002. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). Among alcohol consumers, the median intake (range) was 3.4 (0.9-292.8) g/d. Compared with nonconsumers, alcohol intake levels of 3.4 g/d or less (RR = 1.00; 95% CI, 0.86-1.15) and more than 3.4 g/d (RR = 1.06; 95% CI, 0.91-1.24) were not significantly associated with overall CRC risk. Analyses based on alcohol intake levels of 30 g/d or less and more than 30 g/d or quartile distributions yielded similar risk estimates. Null associations were also observed between each alcohol intake level and the MSI-, CIMP- or, BRAF-defined CRC subtypes (P > 0.05 for each comparison). These data do not support an adverse effect from alcohol intake on CRC risk, overall or by specific molecularly defined subtypes, among older women.

    View details for DOI 10.1158/1940-6207.CAPR-11-0276

    View details for Web of Science ID 000298178000010

    View details for PubMedID 21900595

  • Risk factors by molecular subtypes of breast cancer across a population-based study of women 56 years or younger BREAST CANCER RESEARCH AND TREATMENT Gaudet, M. M., Press, M. F., Haile, R. W., Lynch, C. F., Glaser, S. L., Schildkraut, J., Gammon, M. D., Thompson, W. D., Bernstein, J. L. 2011; 130 (2): 587-597

    Abstract

    Differences in incidence, prognosis, and treatment response suggest gene expression patterns may discern breast cancer subtypes with unique risk factor profiles; however, previous results were based predominantly on older women. In this study, we examined similar relationships in women ? 56 years, classified by immunohistochemical staining for estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 for 890 breast cancer cases and 3,432 frequency-matched population-based controls. Odds ratios (OR) and 95% confidence intervals (CI) for tumor subtypes were calculated using multivariate polytomous regression models. A total of 455 (51.1%) tumors were considered luminal A, 72 (8.1%) luminal B, 117 (13.1%) non-luminal HER-2/neu+, and 246 (27.6%) triple negative. Triple negative tumors were associated with breast feeding duration (per 6 months: OR = 0.76, 95% CI 0.64-0.90). Among premenopausal women, increasing body size was more strongly associated with luminal B (OR = 1.73, 95% CI 1.07-2.77) and triple negative tumors (OR = 1.67, 95% CI 1.22-2.28). A history of benign breast disease was associated only with increased risk of luminal A tumors (OR = 1.89, 95% CI 1.43-2.50). A family history of breast cancer was a risk factor for luminal A tumors (OR = 1.93, 95% CI 1.38-2.70) regardless of age, and triple negative tumors with higher risks for women <45 (OR = 5.02, 95% CI 2.82-8.92; P for age interaction = 0.005). We found that little-to-no breastfeeding and high BMI were associated with increased risk of triple negative breast cancer. That some risk factors differ by molecular subtypes suggests etiologic heterogeneity in breast carcinogenesis among young women.

    View details for DOI 10.1007/s10549-011-1616-x

    View details for Web of Science ID 000295675700023

    View details for PubMedID 21667121

  • Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer INTERNATIONAL JOURNAL OF CANCER Win, A. K., Cleary, S. P., Dowty, J. G., Baron, J. A., Young, J. P., Buchanan, D. D., Southey, M. C., Burnett, T., Parfrey, P. S., Green, R. C., Le Marchand, L., Newcomb, P. A., Haile, R. W., Lindor, N. M., Hopper, J. L., Gallinger, S., Jenkins, M. A. 2011; 129 (9): 2256-2262

    Abstract

    Cancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first- and second-degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country-, age- and sex-specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56-2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18-4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07-12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18-5.08; p = 0.02) for endometrial cancer. Age-specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5-8%) for men and 4% (95%CI 3-6%) for women; for gastric cancer, 2% (95%CI 1-3%) for men and 0.7% (95%CI 0.5-1%) for women; for liver cancer, 1% (95%CI 0.3-3%) for men and 0.3% (95%CI 0.1-1%) for women and for endometrial cancer, 4% (95%CI 2-8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple-case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.

    View details for DOI 10.1002/ijc.25870

    View details for Web of Science ID 000295230500020

    View details for PubMedID 21171015

  • Assessment of Rare BRCA1 and BRCA2 Variants of Unknown Significance Using Hierarchical Modeling GENETIC EPIDEMIOLOGY Capanu, M., Concannon, P., Haile, R. W., Bernstein, L., Malone, K. E., Lynch, C. F., Liang, X., Teraoka, S. N., Diep, A. T., Thomas, D. C., Bernstein, J. L., Begg, C. B. 2011; 35 (5): 389-397

    Abstract

    Current evidence suggests that the genetic risk of breast cancer may be caused primarily by rare variants. However, while classification of protein-truncating mutations as deleterious is relatively straightforward, distinguishing as deleterious or neutral the large number of rare missense variants is a difficult on-going task. In this article, we present one approach to this problem, hierarchical statistical modeling of data observed in a case-control study of contralateral breast cancer (CBC) in which all the participants were genotyped for variants in BRCA1 and BRCA2. Hierarchical modeling permits leverage of information from observed correlations of characteristics of groups of variants with case-control status to infer with greater precision the risks of individual rare variants. A total of 181 distinct rare missense variants were identified among the 705 cases with CBC and the 1,398 controls with unilateral breast cancer. The model identified three bioinformatic hierarchical covariates, align-GV, align-GD, and SIFT scores, each of which was modestly associated with risk. Collectively, the 11 variants that were classified as adverse on the basis of all the three bioinformatic predictors demonstrated a stronger risk signal. This group included five of six missense variants that were classified as deleterious at the outset by conventional criteria. The remaining six variants can be considered as plausibly deleterious, and deserving of further investigation (BRCA1 R866C; BRCA2 G1529R, D2665G, W2626C, E2663V, and R3052W). Hierarchical modeling is a strategy that has promise for interpreting the evidence from future association studies that involve sequencing of known or suspected cancer genes.

    View details for DOI 10.1002/gepi.20587

    View details for Web of Science ID 000291591100011

    View details for PubMedID 21520273

  • Metachronous colorectal cancer risk for mismatch repair gene mutation carriers: the advantage of more extensive colon surgery GUT Parry, S., Win, A. K., Parry, B., Macrae, F. A., Gurrin, L. C., Church, J. M., Baron, J. A., Giles, G. G., Leggett, B. A., Winship, I., Lipton, L., Young, G. P., Young, J. P., Lodge, C. J., Southey, M. C., Newcomb, P. A., Le Marchand, L., Haile, R. W., Lindor, N. M., Gallinger, S., Hopper, J. L., Jenkins, M. A. 2011; 60 (7): 950-957

    Abstract

    Surgical management of colon cancer for patients with Lynch syndrome who carry a mismatch repair (MMR) gene mutation is controversial. The decision to remove more or less of the colon involves the consideration of a relatively high risk of metachronous colorectal cancer (CRC) with the impact of more extensive surgery.To estimate and compare the risks of metachronous CRC for patients with Lynch syndrome undergoing either segmental or extensive (subtotal or total) resection for first colon cancer.Risk of metachronous CRC was estimated for 382 MMR gene mutation carriers (172 MLH1, 167 MSH2, 23 MSH6 and 20 PMS2) from the Colon Cancer Family Registry, who had surgery for their first colon cancer, using retrospective cohort analysis. Age-dependent cumulative risks of metachronous CRC were calculated using the Kaplan-Meier method. Risk factors for metachronous CRC were assessed by a Cox proportional hazards regression.None of 50 subjects who had extensive colectomy was diagnosed with metachronous CRC (incidence rate 0.0; 95% CI 0.0 to 7.2 per 1000 person-years). Of 332 subjects who had segmental resections, 74 (22%) were diagnosed with metachronous CRC (incidence rate 23.6; 95% CI 18.8 to 29.7 per 1000 person-years). For those who had segmental resections, incidence was statistically higher than for those who had extensive surgery (P <0.001). Cumulative risk of metachronous CRC was 16% (95% CI 10% to 25%) at 10 years, 41% (95% CI 30% to 52%) at 20 years and 62% (95% CI 50% to 77%) at 30 years after segmental colectomy. Risk of metachronous CRC reduced by 31% (95% CI 12% to 46%; p=0.002) for every 10 cm of bowel removed.Patients with Lynch syndrome with first colon cancer treated with more extensive colonic resection have a lower risk of metachronous CRC than those receiving less extensive surgery. This finding will better inform decision-making about the extent of primary surgical resection.

    View details for DOI 10.1136/gut.2010.228056

    View details for Web of Science ID 000291306900014

    View details for PubMedID 21193451

  • Body mass index in early adulthood and colorectal cancer risk for carriers and non-carriers of germline mutations in DNA mismatch repair genes BRITISH JOURNAL OF CANCER Win, A. K., Dowty, J. G., English, D. R., Campbell, P. T., Young, J. P., Winship, I., Macrae, F. A., Lipton, L., Parry, S., Young, G. P., Buchanan, D. D., Martinez, M. E., Jacobs, E. T., Ahnen, D. J., Haile, R. W., Casey, G., Baron, J. A., Lindor, N. M., Thibodeau, S. N., Newcomb, P. A., Potter, J. D., Le Marchand, L., Gallinger, S., Hopper, J. L., Jenkins, M. A. 2011; 105 (1): 162-169

    Abstract

    Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry.During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56).Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.

    View details for DOI 10.1038/bjc.2011.172

    View details for Web of Science ID 000292182400025

    View details for PubMedID 21559014

  • Prevalence of Alterations in DNA Mismatch Repair Genes in Patients With Young-Onset Colorectal Cancer CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Limburg, P. J., Harmsen, W. S., Chen, H. H., Gallinger, S., Haile, R. W., Baron, J. A., Casey, G., Woods, M. O., Thibodeau, S. N., Lindor, N. M. 2011; 9 (6): 497-502

    Abstract

    Direct germline analysis could be used to screen high-risk patients for mutations in DNA mismatch repair genes associated with Lynch Syndrome. We examined the prevalence of mutations in MLH1, MSH2, and MSH6 in a population-based sample of patients with young-onset (age <50 years) colorectal cancer (CRC).Young-onset CRC cases were randomly selected from 3 Colon Cancer Family Registry sites. DNA was extracted from peripheral blood leukocytes; MLH1, MSH2, and MSH6 were sequenced, and duplication and deletion analyses was performed for MLH1 and MSH2. Results were reported as deleterious or suspected deleterious, likely neutral, variant of uncertain significance, or no alteration detected. Germline data were compared to Amsterdam II criteria (ACII) and immunohistochemistry results in secondary analyses.Among 195 subjects, 11 had deleterious/suspected deleterious mutations (5.6%; 95% confidence interval [CI], 2.8%-9.9%), 12 had likely neutral alterations (6.2%; 95% CI, 3.2%-10.5%), 14 had variants of uncertain significance (7.2%; 95% CI, 4.0%-11.8%), 2 had a likely neutral alteration and a variant of uncertain significance (1.0%; 95% CI, 0.1%-3.7%), and 156 had no alteration detected (80.0%; 95% CI, 73.7%-85.4%). Sensitivity, specificity, and positive and negative predictive values for detecting deleterious/suspected deleterious mutations, based on ACII, were 36.4% (4/11), 96.7% (178/184), 40.0% (4/10), and 96.2% (178/185), respectively; based on immunohistochemistry these values were 85.7% (6/7), 91.9% (136/148), 33.3% (6/18), and 99.3% (136/137), respectively.In a population-based sample of young-onset CRC cases, germline mutations in MLH1, MSH, and/or MSH6 were more prevalent than reported for CRC patients overall. Because only about 5% of young-onset CRC cases had confirmed deleterious or suspected deleterious mutations, further comparative effectiveness research is needed to determine the most appropriate screening strategy for Lynch Syndrome in this high-risk group.

    View details for DOI 10.1016/j.cgh.2010.10.021

    View details for Web of Science ID 000291693300016

    View details for PubMedID 21056691

  • Risk of contralateral breast cancer associated with common variants in BRCA1 and BRCA2: potential modifying effect of BRCA1/BRCA2 mutation carrier status BREAST CANCER RESEARCH AND TREATMENT Figueiredo, J. C., Brooks, J. D., Conti, D. V., Poynter, J. N., Teraoka, S. N., Malone, K. E., Bernstein, L., Lee, W. D., Duggan, D. J., Siniard, A., Concannon, P., Capanu, M., Lynch, C. F., Olsen, J. H., Haile, R. W., Bernstein, J. L. 2011; 127 (3): 819-829

    Abstract

    Rare deleterious mutations in BRCA1 and BRCA2 are associated with an elevated risk of breast and ovarian cancer. Whether or not common variants in these genes are independently associated with risk of breast cancer remains unclear. In this study, we included 632 Caucasian women with asynchronous contralateral breast cancer (CBC, cases) and 1,221 women with unilateral breast cancer (UBC, controls) from the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study. BRCA1 and BRCA2 deleterious mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing, yielding including 88 BRCA1 and 60 BRCA2 deleterious mutation carriers. We also genotyped samples on the Illumina Omni1-Quad platform. We assessed the association between CBC risk and common (minor allele frequency (MAF) > 0.05) single-nucleotide polymorphisms (SNPs) in BRCA1 (n SNPs = 22) and BRCA2 (n SNPs = 30) and haplotypes using conditional logistic regression accounting for BRCA1/BRCA2 mutation status. We found no significant associations between any single-SNPs or haplotypes of BRCA1 or BRCA2 and risk of CBC among all women. When we stratified by BRCA1 and BRCA2 mutation carrier status, we found suggestive evidence that risk estimates for selected SNPs in BRCA1 (rs8176318, rs1060915, and rs16940) and BRCA2 (rs11571686, rs206115, and rs206117) may differ in non-carriers and carriers of deleterious mutations in BRCA1 and BRCA2. One common haplotype on BRCA1 was inversely significantly associated with risk only among non-BRCA1 and BRCA2 carriers. The association between common variants in BRCA1 and BRCA2 and risk of CBC may differ depending on BRCA1 and BRCA2 mutation carrier status.

    View details for DOI 10.1007/s10549-010-1285-1

    View details for Web of Science ID 000290811500026

    View details for PubMedID 21161372

  • Quality Assessment and Correlation of Microsatellite Instability and Immunohistochemical Markers among Population- and Clinic-Based Colorectal Tumors Results from the Colon Cancer Family Registry JOURNAL OF MOLECULAR DIAGNOSTICS Cicek, M. S., Lindor, N. M., Gallinger, S., Bapat, B., Hopper, J. L., Jenkins, M. A., Young, J., Buchanan, D., Walsh, M. D., Le Marchand, L., Burnett, T., Newcomb, P. A., Grady, W. M., Haile, R. W., Casey, G., Plummer, S. J., Krumroy, L. A., Baron, J. A., Thibodeau, S. N. 2011; 13 (3): 271-281

    Abstract

    The detection of defective mismatch repair (MMR), as assessed by the presence of tumor microsatellite instability (MSI) and/or loss of MMR protein expression by IHC, has been useful for risk assessment, prognosis, and prediction of treatment in patients with colorectal cancer. We analyzed tumors for the presence of defective MMR from 5927 Colorectal Cancer Family Registry patients recruited at six international consortium sites. We evaluated the appropriate percentage instability cutoff used to distinguish the three MSI phenotypes [ie, stable (MSS), low instability (MSI-L), and high instability (MSI-H)]; the sensitivity, specificity, and performance characteristics of individual markers; and the concordance between MSI and IHC phenotypes. Guided by the results of the IHC testing, our findings indicate that the distinction between an MSI-H phenotype from a low-instability or MSS phenotype can best be accomplished by using a cutoff of 30% or greater of the markers showing instability. The sensitivity and specificity of the mononucleotide markers were higher than those of the dinucleotide markers. Specifically, BAT26 and BAT25 had the highest sensitivity (94%) and specificity (98%), and the use of mononucleotide markers alone identified 97% of the MSI-H cases correctly. As expected, the presence of MSI-H correlated with an older age of diagnosis, the presence of tumor in the proximal colon, and female sex.

    View details for DOI 10.1016/j.jmoldx.2010.12.004

    View details for Web of Science ID 000298306400004

    View details for PubMedID 21497289

  • Genotype-Environment Interactions in Microsatellite Stable/Microsatellite Instability-Low Colorectal Cancer: Results from a Genome-Wide Association Study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Figueiredo, J. C., Lewinger, J. P., Song, C., Campbell, P. T., Conti, D. V., Edlund, C. K., Duggan, D. J., Rangrej, J., Lemire, M., Hudson, T., Zanke, B., Cotterchio, M., Gallinger, S., Jenkins, M., Hopper, J., Haile, R., Newcomb, P., Potter, J., Baron, J. A., Le Marchand, L., Casey, G. 2011; 20 (5): 758-766

    Abstract

    Genome-wide association studies (GWAS) have led to the identification of a number of common susceptibility loci for colorectal cancer (CRC); however, none of these GWAS have considered gene-environment (G × E) interactions. Therefore, it is unclear whether current hits are modified by environmental exposures or whether there are additional hits whose effects are dependent on environmental exposures.We conducted a systematic search for G × E interactions using genome wide data from the Colon Cancer Family Registry that included 1,191 cases of microsatellite stable (MSS) or microsatellite instability-low (MSI-L) CRC and 999 controls genotyped using either the Illumina Human1M or Human1M-Duo BeadChip. We tested for interactions between genotypes and 14 environmental factors using 3 methods: a traditional case-control test, a case-only test, and the recently proposed 2-step method by Murcray and colleagues. All potentially significant findings were replicated in the ARCTIC Study.No G × E interactions were identified that reached genome-wide significance by any of the 3 methods. When analyzing previously reported susceptibility loci, 7 significant G × E interactions were found at a 5% significance level. We investigated these 7 interactions in an independent sample and none of the interactions were replicated.Identifying G × E interactions will present challenges in a GWAS setting. Our power calculations illustrate the need for larger sample sizes; however, as CRC is a heterogeneous disease, a tradeoff between increasing sample size and heterogeneity needs to be considered.The results from this first genome-wide analysis of G × E in CRC identify several challenges, which may be addressed by large consortium efforts.

    View details for DOI 10.1158/1055-9965.EPI-10-0675

    View details for Web of Science ID 000290251000007

    View details for PubMedID 21357381

  • Variation in folate pathway genes and distal colorectal adenoma risk: a sigmoidoscopy-based case-control study CANCER CAUSES & CONTROL Levine, A. J., Lee, W., Figueiredo, J. C., Conti, D. V., Vandenberg, D. J., Davis, B. D., Edlund, C. K., Henning, S. M., Heber, D., Stern, M. C., Haile, R. W. 2011; 22 (4): 541-552

    Abstract

    Folate-associated one-carbon metabolism (FOCM) is an important pathway in colorectal neoplasia risk but data on genetic variation in this pathway are largely limited to studies of single SNPs in selected genes.We used a comprehensive tagSNP approach to study the association between genetic variation in 11 genes in the FOCM pathway and risk of incident distal colorectal adenomas in a sigmoidoscopy-based case-control study. We included 655 cases (one or more adenomas) and 695 controls (no adenomas) recruited from one of two Kaiser Permanente clinics between 1991 and 1995. We assessed a total of 159 tagSNPs selected using Haploview Tagger as well as selected non-synonymous SNPs. We used unconditional logistic regression to model the association between SNPs and risk of distal adenomas, assuming a log-additive model.Five SNPs in the SLC19A1 (RFC1) gene: rs1051266 (G80A), rs283895, rs2236484, rs12482346, and rs2838958 were associated with adenoma risk after correction for multiple testing (all corrected p values ≤ 0.043). The non-synonymous SLC19A1 SNP G80A interacted significantly with the MTHFR C677T genotype (interaction p value = 0.018).Our data suggest that genetic variation in SLC19A1 may modify the risk of distal colorectal adenoma.

    View details for DOI 10.1007/s10552-011-9726-7

    View details for Web of Science ID 000288509100002

    View details for PubMedID 21274745

  • Body Mass Index in Early Adulthood and Endometrial Cancer Risk for Mismatch Repair Gene Mutation Carriers OBSTETRICS AND GYNECOLOGY Win, A. K., Dowty, J. G., Antill, Y. C., English, D. R., Baron, J. A., Young, J. P., Giles, G. G., Southey, M. C., Winship, I., Lipton, L., Parry, S., Thibodeau, S. N., Haile, R. W., Gallinger, S., Le Marchand, L., Lindor, N. M., Newcomb, P. A., Hopper, J. L., Jenkins, M. A. 2011; 117 (4): 899-905

    Abstract

    To investigate the association of body mass index (BMI) in early adulthood and endometrial cancer risk for carriers of a germline mutation in a DNA mismatch repair gene.We estimated the association between BMI at age 18-20 years and endometrial cancer risk for mismatch repair gene mutation carriers and, as a comparison group, noncarriers using 601 female carriers of a germline mutation in a mismatch repair gene (245 MLH1, 299 MSH2, 38 MSH6, and 19 PMS2) and 533 female noncarriers from the Colon Cancer Family Registry using a weighted Cox proportional hazards regression.During 51,693 person-years of observation, we observed diagnoses of endometrial cancer for 126 carriers and eight noncarriers. For carriers, there was no evidence of an association between BMI at age 20 years and endometrial cancer (adjusted hazard ratio 0.73 per 5 kg/m²; 95% confidence interval [CI], 0.40-1.34; P=.31). For noncarriers, endometrial cancer risk increased by 74% for each 5-kg/m² increment in BMI (adjusted hazard ratio 1.74; 95% CI 1.27-2.37; P<.001). The hazard ratio for BMI and endometrial cancer for noncarriers was greater than for carriers (P=.04).The effect of body mass on endometrial cancer risk depends on the woman's mismatch repair gene mutation carrier status, suggesting obesity-independent endometrial carcinogenesis for carriers.II.

    View details for DOI 10.1097/AOG.0b013e3182110ea3

    View details for Web of Science ID 000288647500021

    View details for PubMedID 21422863

  • Single nucleotide polymorphisms associated with risk for contralateral breast cancer in the Women's Environment, Cancer, and Radiation Epidemiology (WECARE) Study BREAST CANCER RESEARCH Teraoka, S. N., Bernstein, J. L., Reiner, A. S., Haile, R. W., Bernstein, L., Lynch, C. F., Malone, K. E., Stovall, M., Capanu, M., Liang, X., Smith, S. A., Mychaleckyj, J., Hou, X., Mellemkjaer, L., Boice, J. D., Siniard, A., Duggan, D., Thomas, D. C., Concannon, P. 2011; 13 (6)

    Abstract

    Genome-wide association studies, focusing primarily on unilateral breast cancer, have identified single nucleotide polymorphisms (SNPs) in a number of genomic regions that have alleles associated with a significantly increased risk of breast cancer. In the current study we evaluate the contributions of these previously identified regions to the risk of developing contralateral breast cancer. The most strongly disease-associated SNPs from prior studies were tested for association with contralateral breast cancer. A subset of these SNPs, selected upon their main effects on contralateral breast cancer risk was further evaluated for interaction with treatment modalities and estrogen receptor (ER) status.We genotyped 21 SNPs in 708 women with contralateral breast cancer and 1394 women with unilateral breast cancer who serve as the cases and controls in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study. Records of treatment and ER status were available for most of WECARE Study participants. Associations of SNP genotypes and risk for contralateral breast cancer were calculated with multivariable adjusted conditional logistic regression methods.Multiple SNPs in the FGFR2 locus were significantly associated with contralateral breast cancer, including rs1219648 (per allele rate ratio (RR) = 1.25, 95%CI = 1.08-1.45). Statistically significant associations with contralateral breast cancer were also observed at rs7313833, near the PTHLH gene (per allele RR = 1.26, 95%CI = 1.08-1.47), rs13387042 (2q35) (per allele RR = 1.19, 95%CI = 1.02-1.37), rs13281615 (8q24) (per allele RR = 1.21, 95%CI = 1.04-1.40), and rs11235127 near TMEM135 (per allele RR = 1.26, 95%CI = 1.04-1.53). The A allele of rs13387042 (2q35) was significantly associated with contralateral breast cancer in ER negative first tumors while the A allele of rs11235127 (near TMEM135) was significantly associated with contralateral breast cancer in ER positive first tumors. Although some SNP genotypes appeared to modify contralateral breast cancer risk with respect to tamoxifen treatment or particular radiation doses, trend tests for such effects were not significant.Our results indicate that some common risk variants associated with primary breast cancer also increase risk for contralateral breast cancer, and that these risks vary with the ER status of the first tumor.

    View details for DOI 10.1186/bcr3057

    View details for Web of Science ID 000301173700006

    View details for PubMedID 22087758

  • Frequency of Deletions of EPCAM (TACSTD1) in MSH2-Associated Lynch Syndrome Cases JOURNAL OF MOLECULAR DIAGNOSTICS Rumilla, K., Schowalter, K. V., Lindor, N. M., Thomas, B. C., Mensink, K. A., Gallinger, S., Holter, S., Newcomb, P. A., Potter, J. D., Jenkins, M. A., Hopper, J. L., Long, T. I., Weisenberger, D. J., Haile, R. W., Casey, G., Laird, P. W., Le Marchand, L., Thibodeau, S. N. 2011; 13 (1): 93-99

    Abstract

    Lynch syndrome is an autosomal dominant cancer predisposition syndrome characterized by loss of function of DNA mismatch repair enzyme MLH1, MSH2, MSH6, or PMS2. Mutations in MLH1 and MSH2 account for ∼80% of the inherited cases. However, in up to 20% of cases suspected of having a germline mutation in MSH2 due to loss of MSH2 expression, a germline mutation is not identified. Recent studies have shown that some Lynch syndrome cases are due to 3' EPCAM/TACSTD1 deletions that subsequently lead to MSH2 promoter hypermethylation. In this study, we examined the frequency of this novel mechanism for MSH2 inactivation in cases recruited through the Colon Cancer Family Registry and from the Mayo Clinic Molecular Diagnostics Laboratory. From the combined cohort, 58 cases were selected in which immunohistochemical staining suggested a mutation in MSH2 or MSH6, but no mutations were identified on follow-up testing. Of these 58 cases, 11 demonstrated a deletion of EPCAM/TACSTD1. Of cases with a deletion, the methylation status of the MSH2 promoter was confirmed in tumor tissue using methylation-sensitive PCR primers. One case showed MSH2 promoter hypermethylation in the absence of a detectable EPCAM/TACSTD1 deletion. These results indicate that approximately 20% to 25% of cases suspected of having a mutation in MSH2 but in which a germline mutation is not detected, can be accounted for by germline deletions in EPCAM/TACSTD1. These data also suggest the presence of other alterations leading to MSH2 promoter hypermethylation.

    View details for DOI 10.1016/j.jmoldx.2010.11.011

    View details for Web of Science ID 000286287200013

    View details for PubMedID 21227399

  • Association between Folate Levels and CpG Island Hypermethylation in Normal Colorectal Mucosa CANCER PREVENTION RESEARCH Wallace, K., Grau, M. V., Levine, A. J., Shen, L., Hamdan, R., Chen, X., Gui, J., Haile, R. W., Barry, E. L., Ahnen, D., McKeown-Eyssen, G., Baron, J. A., Issa, J. P. 2010; 3 (12): 1552-1564

    Abstract

    Gene-specific promoter methylation of several genes occurs in aging normal tissues and may predispose to tumorigenesis. In the present study, we investigate the association of blood folate levels and dietary and lifestyle factors with CpG island (CGI) methylation in normal colorectal mucosa. Subjects were enrolled in a multicenter chemoprevention trial of aspirin or folic acid for the prevention of large bowel adenomas. We collected 1,000 biopsy specimens from 389 patients, 501 samples from the right colon and 499 from the rectum at the follow-up colonoscopy. We measured DNA methylation of estrogen receptor alpha (ERα) and secreted frizzled related protein-1 (SFRP1), using bisulfite pyrosequencing. We used generalized estimating equations regression analysis to examine the association between methylation and selected variables. For both ERα and SFRP1, percentage methylation was significantly higher in the rectum than in the right colon (P = 0.001). For each 10 years of age, we observed a 1.7% increase in methylation level for ERα and a 2.9% increase for SFRP1 (P < 0.0001). African Americans had a significantly lower level of ERα and SFRP1 methylation than Caucasians and Hispanics. Higher RBC folate levels were associated with higher levels of both ERα (P = 0.03) and SFRP1 methylation (P = 0.01). Our results suggest that CGI methylation in normal colorectal mucosa is related to advancing age, race, rectal location, and RBC folate levels. These data have important implications regarding the safety of supplementary folate administration in healthy adults, given the hypothesis that methylation in normal mucosa may predispose to colorectal neoplasia.

    View details for DOI 10.1158/1940-6207.CAPR-10-0047

    View details for Web of Science ID 000285189400008

    View details for PubMedID 21149331

  • Polymorphisms in Base Excision Repair Genes as Colorectal Cancer Risk Factors and Modifiers of the Effect of Diets High in Red Meat CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Brevik, A., Joshi, A. D., Corral, R., Onland-Moret, N. C., Siegmund, K. D., Le Marchand, L., Baron, J. A., Martinez, M. E., Haile, R. W., Ahnen, D. J., Sandler, R. S., Lance, P., Stern, M. C. 2010; 19 (12): 3167-3173

    Abstract

    A diet high in red meat is an established colorectal cancer (CRC) risk factor. Carcinogens generated during meat cooking have been implicated as causal agents and can induce oxidative DNA damage, which elicits repair by the base excision repair (BER) pathway.Using a family-based study, we investigated the role of polymorphisms in 4 BER genes (APEX1 Gln51His, Asp148Glu; OGG1 Ser236Cys; PARP Val742Ala; and XRCC1 Arg194Trp, Arg280His, Arg399Gln) as potential CRC risk factors and modifiers of the association between diets high in red meat or poultry and CRC risk. We tested for gene-environment interactions using case-only analyses (n = 577) and compared statistically significant results with those obtained using case-unaffected sibling comparisons (n = 307 sibships).Carriers of the APEX1 codon 51 Gln/His genotype had a reduced CRC risk compared with carriers of the Gln/Gln genotype (odds ratio (OR) = 0.15, 95% CI = 0.03-0.69, P = 0.015). The association between higher red meat intake (>3 servings per week) and CRC was modified by the PARP Val762Ala single-nucleotide polymorphisms (SNP; case-only interaction P = 0.026). This SNP also modified the association between higher intake of high-temperature cooked red meat (case-only interaction P = 0.0009).We report evidence that the BER pathway PARP gene modifies the association of diets high in red meat cooked at high temperatures with risk of CRC.Our findings suggest a contribution to colorectal carcinogenesis of free radical damage as one of the possible harmful effects of a diet high in red meat.

    View details for DOI 10.1158/1055-9965.EPI-10-0606

    View details for Web of Science ID 000285285900018

    View details for PubMedID 21037106

  • Risk of endometrial cancer for women diagnosed with HNPCC-related colorectal carcinoma INTERNATIONAL JOURNAL OF CANCER Obermair, A., Youlden, D. R., Young, J. P., Lindor, N. M., Baron, J. A., Newcomb, P., Parry, S., Hopper, J. L., Haile, R., Jenkins, M. A. 2010; 127 (11): 2678-2684

    Abstract

    The risk of endometrial cancer (EC) subsequent to a diagnosis of colorectal cancer in women with a germline mutation in a mismatch repair gene [Lynch syndrome or hereditary non-polyposis colon cancer (HNPCC)] is unknown. We estimated the risk of EC following a diagnosis of colorectal carcinoma (CRC) for women with Lynch syndrome. A retrospective cohort study was performed on women diagnosed with CRC with a germline mutation in a mismatch repair (MMR) gene (Lynch syndrome cases), and women with microsatellite stable (MSS) CRC who were not known to carry a germline mutation (non-Lynch cases), identified from the Colon Cancer Family Registry. The incidence of EC following CRC was estimated and compared for women with and without Lynch syndrome, using adjusted hazards ratios calculated for time at risk among each group. A total of 112 women with Lynch syndrome and a previous diagnosis of CRC were compared with 908 women without Lynch and with a MSS CRC diagnosis. The estimated 10-year cumulative risk of EC subsequent to CRC was 23.4% [95% confidence interval (CI): 15-36%] for Lynch syndrome women compared with 1.6% (95% CI: 0.7-3.8%) for non-Lynch women. After adjusting for ascertainment, age at diagnosis and diagnosis of other cancers, risk of subsequent diagnosis with EC was elevated sixfold in women with Lynch syndrome compared with non-Lynch women (HR 6.2; 95% CI 2.2-17.3; p = 0.001). Approximately one quarter of women diagnosed with Lynch syndrome-associated CRC developed EC within 10 years. This supports the sentinel cancer concept and suggests that active and early management is important for these women.

    View details for DOI 10.1002/ijc.25501

    View details for Web of Science ID 000283609500020

    View details for PubMedID 20533284

  • Adjuvant systemic therapy for breast cancer in BRCA1/BRCA2 mutation carriers in a population-based study of risk of contralateral breast cancer BREAST CANCER RESEARCH AND TREATMENT Reding, K. W., Bernstein, J. L., Langholz, B. M., Bernstein, L., Haile, R. W., Begg, C. B., Lynch, C. F., Concannon, P., Borg, A., Teraoka, S. N., Torngren, T., Diep, A., Xue, S., Bertelsen, L., Liang, X., Reiner, A. S., Capanu, M., Malone, K. E. 2010; 123 (2): 491-498

    Abstract

    Given the greatly elevated risks of contralateral breast cancer (CBC) observed in breast cancer patients who carry mutations in BRCA1 and BRCA2, it is critical to determine the effectiveness of standard adjuvant therapies in preventing CBC in mutation carriers. The WECARE study is a matched, case-control study of 708 women with CBC as cases and 1,399 women with unilateral breast cancer (UBC) as controls, including 181 BRCA1/BRCA2 mutation carriers. Interviews and medical record reviews provided detailed information on risk factors and breast cancer therapy. All study participants were screened for BRCA1 and BRCA2 mutations using denaturing high-performance liquid chromatography (DHPLC) to detect genetic variants in the coding and flanking regions of the genes. Conditional logistic regression was used to compare the risk of CBC associated with chemotherapy and tamoxifen in BRCA1/BRCA2 mutation carriers and non-carriers. Chemotherapy was associated with lower CBC risk both in non-carriers (RR = 0.6 [95% CI: 0.5-0.7]) and carriers (RR = 0.5 [95% CI: 0.2-1.0]; P value = 0.04). Tamoxifen was associated with a reduced CBC risk in non-carriers (RR = 0.7 [95% CI: 0.6-1.0]; P value = 0.03). We observed a similar but non-significant reduction associated with tamoxifen in mutation carriers (RR = 0.7 [95% CI: 0.3-1.8]). The tests of heterogeneity comparing carriers to non-carriers did not provide evidence for a difference in the associations with chemotherapy (P value = 0.51) nor with tamoxifen (P value = 0.15). Overall, we did not observe a difference in the relative risk reduction associated with adjuvant treatment between BRCA1/BRCA2 mutation carriers and non-carriers. However, given the higher absolute CBC risk in mutation carriers, the potentially greater impact of adjuvant therapy in reducing CBC risk among mutation carriers should be considered when developing treatment plans for these patients.

    View details for DOI 10.1007/s10549-010-0769-3

    View details for Web of Science ID 000280807900019

    View details for PubMedID 20135344

  • Genetic variation in the retinoid X receptor and calcium-sensing receptor and risk of colorectal cancer in the Colon Cancer Family Registry CARCINOGENESIS Jacobs, E. T., Martinez, M. E., Campbell, P. T., Conti, D. V., Duggan, D., Figueiredo, J. C., Haile, R. W., LeRoy, E. C., Poynter, J. N., Thompson, P. A., Baron, J. A. 2010; 31 (8): 1412-1416

    Abstract

    Genetic variants in the calcium/vitamin D metabolic pathway may be related to risk for colorectal cancer. While several investigations of vitamin D receptor (VDR) polymorphisms and colorectal cancer have been conducted, no studies to date have evaluated the association of genetic variation in the heterodimer partner for VDR, the retinoid X receptor (RXR). Another important gene in this pathway is the calcium-sensing receptor (CASR). Employing a discordant-sibship case-control design, we examined the association between single nucleotide polymorphisms (SNPs) in RXRA and CASR and risk for colorectal cancer overall and by colorectal subsite and microsatellite instability (MSI) status using data from the Colon Cancer Family Registry. No gene-level relationships between RXRA or CASR and colorectal cancer overall were observed. However, for RXRA SNP rs7861779, a high-interest SNP selected for study a priori, there was a statistically significantly increased risk for proximal colorectal cancer among those with at least one A allele [odds ratio (OR) = 1.42; 95% confidence interval (CI) = 1.03-1.97]. Another selected RXRA SNP, rs12004589, was significantly associated with risk of MSI-high cancers (OR = 2.27; 95% CI = 1.13-4.56). Additionally, CASR SNP rs1801726 was significantly associated with a reduced risk for rectal cancer (OR = 0.53; 95% CI = 0.29-0.96). These results provide support that RXRA SNPs rs7861779 and rs12004589 and CASR SNP rs1801726 may be important markers for colorectal neoplasia. Further work is needed to elucidate their role in the carcinogenic pathway.

    View details for DOI 10.1093/carcin/bgq127

    View details for Web of Science ID 000280703800015

    View details for PubMedID 20558521

  • Use of Folic Acid-Containing Supplements after a Diagnosis of Colorectal Cancer in the Colon Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Holmes, R. S., Zheng, Y., Baron, J. A., Li, L., McKeown-Eyssen, G., Newcomb, P. A., Stern, M. C., Haile, R. W., Grady, W. M., Potter, J. D., Le Marchand, L., Campbell, P. T., Figueiredo, J. C., Limburg, P. J., Jenkins, M. A., Hopper, J. L., Ulrich, C. M. 2010; 19 (8): 2023-2034

    Abstract

    Supplement use among cancer patients is high, and folic acid intake in particular may adversely affect the progression of colorectal cancer. Few studies have evaluated the use of folic acid-containing supplements (FAS) and its predictors in colorectal cancer patients.To assess the use of FAS, change in use, and its predictors after colorectal cancer diagnosis.We used logistic regression models to investigate predictors of FAS use and its initiation after colorectal cancer diagnosis in 1,092 patients recruited through the Colon Cancer Family Registry.The prevalence of FAS use was 35.4% before and 55.1% after colorectal cancer diagnosis (P = 0.004). Women were more likely than men to use FAS after diagnosis [odds ratio (OR), 1.47; 95% confidence interval (95% CI), 1.14-1.89], as were those consuming more fruit (P(trend) < 0.0001) or vegetables (P(trend) = 0.001), and U.S. residents (P < 0.0001). Less likely to use FAS after diagnosis were nonwhite patients (OR, 0.66; 95% CI, 0.45-0.97), current smokers (OR, 0.67; 95% CI, 0.46-0.96), and those with higher meat intake (P(trend) = 0.03). Predictors of FAS initiation after diagnosis were generally similar to those of FAS use after diagnosis, although associations with race and vegetable intake were weaker and those with exercise stronger.Our analysis showed substantial increases in the use of FAS after diagnosis with colorectal cancer, with use or initiation more likely among women, Caucasians, U.S. residents, and those with a health-promoting life-style.Studies of cancer prognosis that rely on prediagnostic exposure information may result in substantial misclassification.

    View details for DOI 10.1158/1055-9965.EPI-09-1097

    View details for Web of Science ID 000280675000016

    View details for PubMedID 20696661

  • Cigarette Smoking and Colorectal Cancer Risk by Molecularly Defined Subtypes JOURNAL OF THE NATIONAL CANCER INSTITUTE Limsui, D., Vierkant, R. A., Tillmans, L. S., Wang, A. H., Weisenberger, D. J., Laird, P. W., Lynch, C. F., Anderson, K. E., French, A. J., Haile, R. W., Harnack, L. J., Potter, J. D., Slager, S. L., Smyrk, T. C., Thibodeau, S. N., Cerhan, J. R., Limburg, P. J. 2010; 102 (14): 1012-1022

    Abstract

    Cigarette smoking is an established risk factor for colorectal cancer. Because colorectal carcinogenesis is a heterogeneous process, we investigated whether cigarette smoking is differentially associated with molecularly defined subtypes of colorectal cancer.We evaluated associations between smoking and incident colorectal cancer, overall and by microsatellite instability (MSI) phenotype (MSI-high vs MSI-low or microsatellite stable), CpG island methylator phenotype (CIMP positive or CIMP negative), and BRAF mutation status (BRAF mutation positive or BRAF mutation negative), among 37 399 participants in a population-based cohort study (the Iowa Women's Health Study). Cigarette smoking (and other exposures) was assessed by self-report at baseline in 1986, including smoking status (never and ever [former or current]), age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period. Vital status and state of residence were determined by mailed follow-up questionnaires in 1987, 1989, 1992, and 1997 and by linkage to Iowa death certificate records. Nonrespondents were checked via the National Death Index to identify descendants. Participants with newly diagnosed (ie, incident) colorectal cancer were identified through annual linkage with the Iowa Cancer Registry. Archived paraffin-embedded tumor tissue specimens were obtained for 555 patients with colorectal cancer who were diagnosed from January 1, 1986, through December 31, 2002, and MSI status, CIMP status, and BRAF status were determined. Multivariable Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs).Ever-smokers were at moderately increased risk for incident colorectal cancer (RR = 1.19, 95% CI = 1.05 to 1.35) compared with never-smokers. Higher risk estimates were observed for current smokers with MSI-high tumors (RR = 1.99, 95% CI = 1.26 to 3.14), CIMP-positive tumors (RR = 1.88, 95% CI = 1.22 to 2.90), and BRAF mutation-positive tumors (RR = 1.92, 95% CI = 1.22 to 3.02). Other smoking-related variables (ie, age at initiation, total duration, average number of cigarettes smoked per day, cumulative pack-years, and induction period) were also associated with MSI-high, CIMP-positive, and BRAF mutation-positive tumor subtypes. Conversely, cigarette smoking status (ever vs never) was not associated with the MSI-low or microsatellite stable (RR = 1.00, 95% CI = 0.79 to 1.25), CIMP-negative (RR = 1.02, 95% CI = 0.81 to 1.30), or BRAF mutation-negative subtypes (RR = 1.00, 95% CI = 0.65 to 1.27).In this prospective study of older women, cigarette smoking was associated with the MSI-high, CIMP-positive, and BRAF mutation-positive colorectal cancer subtypes, which indicates that epigenetic modification may be functionally involved in smoking-related colorectal carcinogenesis.

    View details for DOI 10.1093/jnci/djq201

    View details for Web of Science ID 000280269400008

    View details for PubMedID 20587792

  • Risk Factors for Colorectal Cancer in Patients with Multiple Serrated Polyps: A Cross-Sectional Case Series from Genetics Clinics PLOS ONE Buchanan, D. D., Sweet, K., Drini, M., Jenkins, M. A., Win, A. K., English, D. R., Walsh, M. D., Clendenning, M., McKeone, D. M., Walters, R. J., Roberts, A., Pearson, S., Pavluk, E., Hopper, J. L., Gattas, M. R., Goldblatt, J., George, J., Suthers, G. K., Phillips, K. D., Woodall, S., Arnold, J., Tucker, K., Muir, A., Field, M., Greening, S., Gallinger, S., Perrier, R., Baron, J. A., Potter, J. D., Haile, R., Frankel, W., De la Chapelle, A., Macrae, F., Rosty, C., Walker, N. I., Parry, S., Young, J. P. 2010; 5 (7)

    Abstract

    Patients with multiple serrated polyps are at an increased risk for developing colorectal cancer (CRC). Recent reports have linked cigarette smoking with the subset of CRC that develops from serrated polyps. The aim of this work therefore was to investigate the association between smoking and the risk of CRC in high-risk genetics clinic patients presenting with multiple serrated polyps.We identified 151 Caucasian individuals with multiple serrated polyps including at least 5 outside the rectum, and classified patients into non-smokers, current or former smokers at the time of initial diagnosis of polyposis. Cases were individuals with multiple serrated polyps who presented with CRC. Controls were individuals with multiple serrated polyps and no CRC. Multivariate logistic regression was performed to estimate associations between smoking and CRC with adjustment for age at first presentation, sex and co-existing traditional adenomas, a feature that has been consistently linked with CRC risk in patients with multiple serrated polyps. CRC was present in 56 (37%) individuals at presentation. Patients with at least one adenoma were 4 times more likely to present with CRC compared with patients without adenomas (OR = 4.09; 95%CI 1.27 to 13.14; P = 0.02). For females, the odds of CRC decreased by 90% in current smokers as compared to never smokers (OR = 0.10; 95%CI 0.02 to 0.47; P = 0.004) after adjusting for age and adenomas. For males, there was no relationship between current smoking and CRC. There was no statistical evidence of an association between former smoking and CRC for both sexes.A decreased odds for CRC was identified in females with multiple serrated polyps who currently smoke, independent of age and the presence of a traditional adenoma. Investigations into the biological basis for these observations could lead to non-smoking-related therapies being developed to decrease the risk of CRC and colectomy in these patients.

    View details for DOI 10.1371/journal.pone.0011636

    View details for Web of Science ID 000279980800020

    View details for PubMedID 20661287

  • Parent of origin effects on age at colorectal cancer diagnosis INTERNATIONAL JOURNAL OF CANCER Lindor, N. M., Rabe, K. G., Petersen, G. M., Chen, H., Bapat, B., Hopper, J., Young, J., Jenkins, M., Potter, J., Newcomb, P., Templeton, A., LeMarchand, L., Grove, J., Burgio, M. R., Haile, R., Green, J., Woods, M. O., Seminara, D., Limburg, P. J., Thibodeau, S. N. 2010; 127 (2): 361-366

    Abstract

    Genomic imprinting refers to a parent-of-origin specific effect on gene expression. At least 1% of genes in the human genome are modulated in this manner. We sought evidence for genomic imprinting in colorectal cancer by studying the ages at diagnosis in the offspring of 2,061 parent-child pairs in which both parent and child were affected by nonsyndromic colorectal cancer. Families were ascertained through the colon Cancer Family Registry [http://epi.grants.cancer.gov/CFR/] from both population-based and clinic-based sources. We found that the affected offspring of affected fathers were on average younger than offspring of affected mothers (55.8 vs. 53.7 years; p = 0.0003), but when divided into sons and daughters, this difference was driven entirely by younger age at diagnosis in daughters of affected fathers compared to sons (52.3 years vs. 55.1 years; p = 0.0004). A younger age at diagnosis in affected daughters of affected fathers was also observable in various subsets including families that met Amsterdam II Criteria, families that did not meet Amsterdam Criteria, and in families with documented normal DNA mismatch repair in tumors. Imprinting effects are not expected to be affected by the sex of the offspring. Possible explanations for these unexpected findings include: (i) an imprinted gene on the pseudoautosomal regions of the X chromosome; (ii) an imprinted autosomal gene that affects a sex-specific pathway; or (iii) an X-linked gene unmasked because of colonic tissue-specific preferential inactivation of the maternal X chromosome.

    View details for DOI 10.1002/ijc.25037

    View details for Web of Science ID 000278919000012

    View details for PubMedID 19904757

  • A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Levine, A. J., Figueiredo, J. C., Lee, W., Conti, D. V., Kennedy, K., Duggan, D. J., Poynter, J. N., Campbell, P. T., Newcomb, P., Martinez, M. E., Hopper, J. L., Le Marchand, L., Baron, J. A., Limburg, P. J., Ulrich, C. M., Haile, R. W. 2010; 19 (7): 1812-1821

    Abstract

    Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer.This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B(12) metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model.In the log additive model, two linked (r(2) = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r(2) = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements.Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users.This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.

    View details for DOI 10.1158/1055-9965.EPI-10-0151

    View details for Web of Science ID 000279590100017

    View details for PubMedID 20615890

  • Reproductive factors and risk of contralateral breast cancer by BRCA1 and BRCA2 mutation status: results from the WECARE study CANCER CAUSES & CONTROL Poynter, J. N., Langholz, B., Largent, J., Mellemkjaer, L., Bernstein, L., Malone, K. E., Lynch, C. F., Borg, A., Concannon, P., Teraoka, S. N., Xue, S., Diep, A. T., Torngren, T., Begg, C. B., Capanu, M., Haile, R. W., Bernstein, J. L. 2010; 21 (6): 839-846

    Abstract

    Reproductive factors, such as early age at menarche, late age at menopause, and nulliparity are known risk factors for breast cancer. Previously, we reported these factors to be associated with risk of developing contralateral breast cancer (CBC). In this study, we evaluated the association between these factors and CBC risk among BRCA1 and BRCA2 (BRCA1/2) mutation carriers and non-carriers.The WECARE Study is a population-based multi-center case-control study of 705 women with CBC (cases) and 1,397 women with unilateral breast cancer (controls). All participants were screened for BRCA1/2 mutations and 181 carriers were identified. Conditional logistic regression models were used to evaluate associations between reproductive factors and CBC for mutation carriers and non-carriers.None of the associations between reproductive factors and CBC risk differed between mutation carriers and non-carriers. The increase in risk with younger age at menarche and decrease in risk in women with more than two full-term pregnancies seen in non-carriers were not significantly different in carriers (adjusted RRs = 1.31, 95% CI 0.65-2.65 and 0.53, 95% CI 0.19-1.51, respectively). No significant associations between the other reproductive factors and CBC risk were observed in mutation carriers or non-carriers.For two reproductive factors previously shown to be associated with CBC risk, we observed similar associations for BRCA1/2 carriers. This suggests that reproductive variables that affect CBC risk may have similar effects in mutation carriers and non-carriers.

    View details for DOI 10.1007/s10552-010-9510-0

    View details for Web of Science ID 000277709800005

    View details for PubMedID 20130978

  • Population-Based Study of the Risk of Second Primary Contralateral Breast Cancer Associated With Carrying a Mutation in BRCA1 or BRCA2 JOURNAL OF CLINICAL ONCOLOGY Malone, K. E., Begg, C. B., Haile, R. W., Borg, A., Concannon, P., Tellhed, L., Xue, S., Teraoka, S., Bernstein, L., Capanu, M., Reiner, A. S., Riedel, E. R., Thomas, D. C., Mellemkjaer, L., Lynch, C. F., Boice, J. D., Anton-Culver, H., Bernstein, J. L. 2010; 28 (14): 2404-2410

    Abstract

    Women with breast cancer diagnosed early in life comprise a substantial portion of those tested for BRCA1/BRCA2 mutations; however, little information is available on the subsequent risks of contralateral breast cancer in mutation carriers. This study assessed the risk of subsequent contralateral breast cancer associated with carrying a BRCA1 or BRCA2 mutation.In this nested case-control study, patients with contralateral breast cancer diagnosed 1 year or more after a first primary breast cancer (n = 705) and controls with unilateral breast cancer (n = 1,398) were ascertained from an underlying population-based cohort of 52,536 women diagnosed with a first invasive breast cancer before age 55 years. Interviews and medical record reviews were used to collect risk factor and treatment histories. All women were tested for BRCA1/BRCA2 mutations. Relative (rate ratios) and absolute (5- and 10-year cumulative) risks of developing contralateral breast cancer following a first invasive breast cancer were computed.Compared with noncarriers, BRCA1 and BRCA2 mutation carriers had 4.5-fold (95% CI, 2.8- to 7.1-fold) and 3.4-fold (95% CI, 2.0- to 5.8-fold) increased risks of contralateral breast cancer, respectively. The relative risk of contralateral breast cancer for BRCA1 mutation carriers increased as age of first diagnosis decreased. Age-specific cumulative risks are provided for clinical guidance.The risks of subsequent contralateral breast cancer are substantial for women who carry a BRCA1/BRCA2 mutation. These findings have important clinical relevance regarding the assessment of BRCA1/BRCA2 status in patients with breast cancer and the counseling and clinical management of patients found to carry a mutation.

    View details for DOI 10.1200/JCO.2009.24.2495

    View details for Web of Science ID 000277389600013

    View details for PubMedID 20368571

  • Radiation Exposure, the ATM Gene, and Contralateral Breast Cancer in the Women's Environmental Cancer and Radiation Epidemiology Study JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Bernstein, J. L., Haile, R. W., Stovall, M., Boice, J. D., Shore, R. E., Langholz, B., Thomas, D. C., Bernstein, L., Lynch, C. F., Olsen, J. H., Malone, K. E., Mellemkjaer, L., Borresen-Dale, A., Rosenstein, B. S., Teraoka, S. N., Diep, A. T., Smith, S. A., Capanu, M., Reiner, A. S., Liang, X., Gatti, R. A., Concannon, P. 2010; 102 (7): 475-483

    Abstract

    Ionizing radiation is a known mutagen and an established breast carcinogen. The ATM gene is a key regulator of cellular responses to the DNA damage induced by ionizing radiation. We investigated whether genetic variants in ATM play a clinically significant role in radiation-induced contralateral breast cancer in women.The Women's Environmental, Cancer, and Radiation Epidemiology Study is an international population-based case-control study nested within a cohort of 52,536 survivors of unilateral breast cancer diagnosed between 1985 and 2000. The 708 case subjects were women with contralateral breast cancer, and the 1397 control subjects were women with unilateral breast cancer matched to the case subjects on age, follow-up time, registry reporting region, and race and/or ethnicity. All women were interviewed and underwent full mutation screening of the entire ATM gene. Complete medical treatment history information was collected, and for all women who received radiotherapy, the radiation dose to the contralateral breast was reconstructed using radiotherapy records and radiation measurements. Rate ratios (RRs) and corresponding 95% confidence intervals (CIs) were estimated by using multivariable conditional logistic regression. All P values are two-sided.Among women who carried a rare ATM missense variant (ie, one carried by <1% of the study participants) that was predicted to be deleterious, those who were exposed to radiation (mean radiation exposure = 1.2 Gy, SD = 0.7) had a statistically significantly higher risk of contralateral breast cancer compared with unexposed women who carried the wild-type genotype (0.01-0.99 Gy: RR = 2.8, 95% CI = 1.2 to 6.5; > or =1.0 Gy: RR = 3.3, 95% CI = 1.4 to 8.0) or compared with unexposed women who carried the same predicted deleterious missense variant (0.01-0.99 Gy: RR = 5.3, 95% CI = 1.6 to 17.3; > or =1.0 Gy: RR = 5.8, 95% CI = 1.8 to 19.0; P(trend) = .044).Women who carry rare deleterious ATM missense variants and who are treated with radiation may have an elevated risk of developing contralateral breast cancer. However, the rarity of these deleterious missense variants in human populations implies that ATM mutations could account for only a small portion of second primary breast cancers.

    View details for DOI 10.1093/jnci/djq055

    View details for Web of Science ID 000276527800008

    View details for PubMedID 20305132

  • Lynch Syndrome-Associated Breast Cancers: Clinicopathologic Characteristics of a Case Series from the Colon Cancer Family Registry CLINICAL CANCER RESEARCH Walsh, M. D., Buchanan, D. D., Cummings, M. C., Pearson, S., Arnold, S. T., Clendenning, M., Walters, R., McKeone, D. M., Spurdle, A. B., Hopper, J. L., Jenkins, M. A., Phillips, K. D., Suthers, G. K., George, J., Goldblatt, J., Muir, A., Tucker, K., Pelzer, E., Gattas, M. R., Woodall, S., Parry, S., Macrae, F. A., Haile, R. W., Baron, J. A., Potter, J. D., Le Marchand, L., Bapat, B., Thibodeau, S. N., Lindor, N. M., Mcguckin, M. A., Young, J. P. 2010; 16 (7): 2214-2224

    Abstract

    The recognition of breast cancer as a spectrum tumor in Lynch syndrome remains controversial. The aim of this study was to explore features of breast cancers arising in Lynch syndrome families.This observational study involved 107 cases of breast cancer identified from the Colorectal Cancer Family Registry (Colon CFR) from 90 families in which (a) both breast and colon cancer co-occurred, (b) families met either modified Amsterdam criteria, or had at least one early-onset (<50 years) colorectal cancer, and (c) breast tissue was available within the biospecimen repository for mismatch repair (MMR) testing. Eligibility criteria for enrollment in the Colon CFR are available online. Breast cancers were reviewed by one pathologist. Tumor sections were stained for MLH1, PMS2, MSH2, and MSH6, and underwent microsatellite instability testing.Breast cancer arose in 35 mutation carriers, and of these, 18 (51%) showed immunohistochemical absence of MMR protein corresponding to the MMR gene mutation segregating the family. MMR-deficient breast cancers were more likely to be poorly differentiated (P = 0.005) with a high mitotic index (P = 0.002), steroid hormone receptor-negative (estrogen receptor, P = 0.031; progesterone receptor, P = 0.022), and to have peritumoral lymphocytes (P = 0.015), confluent necrosis (P = 0.002), and growth in solid sheets (P < 0.001) similar to their colorectal counterparts. No difference in age of onset was noted between the MMR-deficient and MMR-intact groups.MMR deficiency was identified in 51% of breast cancers arising in known mutation carriers. Breast cancer therefore may represent a valid tissue option for the detection of MMR deficiency in which spectrum tumors are lacking.

    View details for DOI 10.1158/1078-0432.CCR-09-3058

    View details for Web of Science ID 000278595800026

    View details for PubMedID 20215533

  • Genes involved with folate uptake and distribution and their association with colorectal cancer risk CANCER CAUSES & CONTROL Figueiredo, J. C., Levine, A. J., Lee, W. H., Conti, D. V., Poynter, J. N., Campbell, P. T., Duggan, D., Lewinger, J. P., Martinez, M. E., Ulrich, C. M., Newcomb, P., Potter, J., Limburg, P. J., Hopper, J., Jenkins, M. A., Le Marchand, L., Baron, J. A., Haile, R. W. 2010; 21 (4): 597-608

    Abstract

    Folate status is an important predictor of colorectal cancer risk. Common genetic variants in genes involved in regulating cellular folate levels might also predict risk, but there are limited data on this issue. We conducted a family-based case-control association study of variants in four genes involved in folate uptake and distribution: FOLR1, FPGS, GGH and SLC19A1, using 1,750 population-based and 245 clinic-based cases of pathologically confirmed colorectal cancer and their unaffected relatives participating in the Colon Cancer Family Registries. Standardized questionnaires, administered to all participants, collected information on risk factors and diet. Standard molecular techniques were used to determine microsatellite instability (MSI) status on cases. tagSNPs (n = 29) were selected based on coverage as assessed by pairwise r2. We found no evidence that tagSNPs in these genes were associated with risk of colorectal cancer. For the SLC19A1-rs1051266 (G80A, Arg27His) missense polymorphism, the A/A genotype was not associated with risk of colorectal cancer using population-based (OR = 1.00; 95% CI = 0.81-1.23) or clinic-based (OR = 0.75; 95% CI = 0.44-1.29) families compared to the G/A and G/G genotypes. We found no evidence that the association between any tagSNP and CRC risk was modified by multivitamin use, folic acid use and dietary folate intake and total folate intake. The odds ratios were similar, irrespective of MSI status, tumor subsite and family history of colorectal cancer. In conclusion, we found no significant evidence that genetic variants in FOLR1, GGH, FPGS and SLC19A1 are associated with the risk of colorectal cancer.

    View details for DOI 10.1007/s10552-009-9489-6

    View details for Web of Science ID 000275631900010

    View details for PubMedID 20037791

  • Case-Control Study of Overweight, Obesity, and Colorectal Cancer Risk, Overall and by Tumor Microsatellite Instability Status JOURNAL OF THE NATIONAL CANCER INSTITUTE Campbell, P. T., Jacobs, E. T., Ulrich, C. M., Figueiredo, J. C., Poynter, J. N., McLaughlin, J. R., Haile, R. W., Jacobs, E. J., Newcomb, P. A., Potter, J. D., Le Marchand, L., Green, R. C., Parfrey, P., Younghusband, H. B., Cotterchio, M., Gallinger, S., Jenkins, M. A., Hopper, J. L., Baron, J. A., Thibodeau, S. N., Lindor, N. M., Limburg, P. J., Martinez, M. E. 2010; 102 (6): 391-400

    Abstract

    Being overweight or obese is an established risk factor for colorectal cancer, more so for men than for women. Approximately 10%-20% of colorectal tumors display microsatellite instability (MSI), defined as the expansion or contraction of small repeated sequences in the DNA of tumor tissue relative to nearby normal tissue. We evaluated associations between overweight or obesity and colorectal cancer risk, overall and by tumor MSI status.The study included 1794 case subjects with incident colorectal cancer who were identified through population-based cancer registries and 2684 of their unaffected sex-matched siblings as control subjects. Recent body mass index (BMI), BMI at age 20 years, and adult weight change were derived from self-reports of height and weight. Tumor MSI status, assessed at as many as 10 markers, was obtained for 69.7% of the case subjects and classified as microsatellite (MS)-stable (0% of markers unstable; n = 913), MSI-low (>0% but <30% of markers unstable; n = 149), or MSI-high (> or =30% of markers unstable; n = 188). Multivariable conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (95% CIs). All statistical tests were two-sided.Recent BMI, modeled in 5 kg/m(2) increments, was positively associated with risk of colorectal cancer for men and women combined (OR = 1.24; 95% CI = 1.15 to 1.34), for women only (OR = 1.20; 95% CI = 1.10 to 1.32), and for men only (OR = 1.30; 95% CI = 1.15 to 1.47). There was no interaction with sex (P = .22). Recent BMI, per 5 kg/m(2), was positively associated with the risk of MS-stable (OR = 1.38; 95% CI = 1.24 to 1.54) and MSI-low (OR = 1.33; 95% CI = 1.04 to 1.72) colorectal tumors, but not with the risk of MSI-high tumors (OR = 1.05; 95% CI = 0.84 to 1.31).The increased risk of colorectal cancer associated with a high BMI might be largely restricted to tumors that display the more common MS-stable phenotype, suggesting further that colorectal cancer etiology differs by tumor MSI status.

    View details for DOI 10.1093/jnci/djq011

    View details for Web of Science ID 000275884900007

    View details for PubMedID 20208017

  • Characterization of BRCA1 and BRCA2 Deleterious Mutations and Variants of Unknown Clinical Significance in Unilateral and Bilateral Breast Cancer: The WECARE Study HUMAN MUTATION Borg, A., Haile, R. W., Malone, K. E., Capanu, M., Diep, A., Torngren, T., Teraoka, S., Begg, C. B., Thomas, D. C., Concannon, P., Mellemkjaer, L., Bernstein, L., Tellhed, L., Xue, S., Olson, E. R., Liang, X., Dolle, J., Borresen-Dale, A., Bernstein, J. L. 2010; 31 (3): E1200-E1240

    Abstract

    BRCA1 and BRCA2 screening in women at high-risk of breast cancer results in the identification of both unambiguously defined deleterious mutations and sequence variants of unknown clinical significance (VUS). We examined a population-based sample of young women with contralateral breast cancer (CBC, n=705) or unilateral breast cancer (UBC, n=1398). We identified 470 unique sequence variants, of which 113 were deleterious mutations. The remaining 357 VUS comprised 185 unique missense changes, 60% were observed only once, while 3% occurred with a frequency of >10%. Deleterious mutations occurred three times more often in women with CBC (15.3%) than in women with UBC (5.2%), whereas combined, VUS were observed in similar frequencies in women with CBC and UBC. A protein alignment algorithm defined 16 rare VUS, occurring at highly conserved residues and/or conferring a considerable biochemical difference, the majority located in the BRCA2 DNA-binding domain. We confirm a multiplicity of BRCA1 and BRCA2 VUS that occur at a wide range of allele frequencies. Although some VUS inflict chemical differences at conserved residues, suggesting a deleterious effect, the majority are not associated with an increased risk of CBC.

    View details for DOI 10.1002/humu.21202

    View details for Web of Science ID 000279981700003

    View details for PubMedID 20104584

  • Smoking and Colorectal Cancer in Lynch Syndrome: Results from the Colon Cancer Family Registry and The University of Texas MD Anderson Cancer Center CLINICAL CANCER RESEARCH Pande, M., Lynch, P. M., Hopper, J. L., Jenkins, M. A., Gallinger, S., Haile, R. W., LeMarchand, L., Lindor, N. M., Campbell, P. T., Newcomb, P. A., Potter, J. D., Baron, J. A., Frazier, M. L., Amos, C. I. 2010; 16 (4): 1331-1339

    Abstract

    Lynch syndrome family members with inherited germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), and cases typically have tumors that exhibit a high level of microsatellite instability (MSI). There is some evidence that smoking is a risk factor for CRCs with high MSI; however, the association of smoking with CRC among those with Lynch syndrome is unknown.A multicentered retrospective cohort of 752 carriers of pathogenic MMR gene mutations was analyzed, using a weighted Cox regression analysis, adjusting for sex, ascertainment source, the specific mutated gene, year of birth, and familial clustering.Compared with never smokers, current smokers had a significantly increased CRC risk [adjusted hazard ratio (HR), 1.62; 95% confidence interval (95% CI), 1.01-2.57] and former smokers who had quit smoking for 2 or more years were at decreased risk (HR, 0.53; 95% CI, 0.35-0.82). CRC risk did not vary according to age at starting. However, light smoking (<10 cigarettes per day) and shorter duration of smoking (<10 years) were associated with decreased CRC risk (HR, 0.51; 95% CI, 0.29-0.91 and HR, 0.52; 95% CI, 0.30-0.89, respectively). For former smokers, CRC risk decreased with years since quitting (P trend <0.01).People with Lynch syndrome may be at increased risk of CRC if they smoke regularly. Although our data suggest that former smokers, short-term smokers, and light smokers are at decreased CRC risk, these findings need further confirmation, preferably using prospective designs.

    View details for DOI 10.1158/1078-0432.CCR-09-1877

    View details for Web of Science ID 000278545200028

    View details for PubMedID 20145170

  • Risks of Lynch Syndrome Cancers for MSH6 Mutation Carriers JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Baglietto, L., Lindor, N. M., Dowty, J. G., White, D. M., Wagner, A., Garcia, E. B., Vriends, A. H., Cartwright, N. R., Barnetson, R. A., Farrington, S. M., Tenesa, A., Hampel, H., Buchanan, D., Arnold, S., Young, J., Walsh, M. D., Jass, J., Macrae, F., Antill, Y., Winship, I. M., Giles, G. G., Goldblatt, J., Parry, S., Suthers, G., Leggett, B., Butz, M., Aronson, M., Poynter, J. N., Baron, J. A., Le Marchand, L., Haile, R., Gallinger, S., Hopper, J. L., Potter, J., De la Chapelle, A., Vasen, H. F., Dunlop, M. G., Thibodeau, S. N., Jenkins, M. A. 2010; 102 (3): 193-201

    Abstract

    Germline mutations in MSH6 account for 10%-20% of Lynch syndrome colorectal cancers caused by hereditary DNA mismatch repair gene mutations. Because there have been only a few studies of mutation carriers, their cancer risks are uncertain.We identified 113 families of MSH6 mutation carriers from five countries that we ascertained through family cancer clinics and population-based cancer registries. Mutation status, sex, age, and histories of cancer, polypectomy, and hysterectomy were sought from 3104 of their relatives. Age-specific cumulative risks for carriers and hazard ratios (HRs) for cancer risks of carriers, compared with those of the general population of the same country, were estimated by use of a modified segregation analysis with appropriate conditioning depending on ascertainment.For MSH6 mutation carriers, the estimated cumulative risks to ages 70 and 80 years, respectively, were as follows: for colorectal cancer, 22% (95% confidence interval [CI] = 14% to 32%) and 44% (95% CI = 28% to 62%) for men and 10% (95% CI = 5% to 17%) and 20% (95% CI = 11% to 35%) for women; for endometrial cancer, 26% (95% CI = 18% to 36%) and 44% (95% CI = 30% to 58%); and for any cancer associated with Lynch syndrome, 24% (95% CI = 16% to 37%) and 47% (95% CI = 32% to 66%) for men and 40% (95% CI = 32% to 52%) and 65% (95% CI = 53% to 78%) for women. Compared with incidence for the general population, MSH6 mutation carriers had an eightfold increased incidence of colorectal cancer (HR = 7.6, 95% CI = 5.4 to 10.8), which was independent of sex and age. Women who were MSH6 mutation carriers had a 26-fold increased incidence of endometrial cancer (HR = 25.5, 95% CI = 16.8 to 38.7) and a sixfold increased incidence of other cancers associated with Lynch syndrome (HR = 6.0, 95% CI = 3.4 to 10.7).We have obtained precise and accurate estimates of both absolute and relative cancer risks for MSH6 mutation carriers.

    View details for DOI 10.1093/jnci/djp473

    View details for Web of Science ID 000274345800010

    View details for PubMedID 20028993

  • Genetic Variation in the Vitamin D Receptor (VDR) and the Vitamin D-Binding Protein (GC) and Risk for Colorectal Cancer: Results from the Colon Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Poynter, J. N., Jacobs, E. T., Figueiredo, J. C., Lee, W. H., Conti, D. V., Campbell, P. T., Levine, A. J., Limburg, P., Le Marchand, L., Cotterchio, M., Newcomb, P. A., Potter, J. D., Jenkins, M. A., Hopper, J. L., Duggan, D. J., Baron, J. A., Haile, R. W. 2010; 19 (2): 525-536

    Abstract

    Epidemiologic evidence supports a role for vitamin D in colorectal cancer (CRC) risk. Variants in vitamin D-related genes might modify the association between vitamin D levels and CRC risk. In this analysis, we did a comprehensive evaluation of common variants in the vitamin D receptor (VDR) and the vitamin D-binding protein (GC; group-specific component) genes using a population-based case-unaffected sibling control design that included 1,750 sibships recruited into the Colon Cancer Family Registry. We also evaluated whether any associations differed by calcium supplement use, family history of CRC, or tumor characteristics. Heterogeneity by calcium and vitamin D intake was evaluated for a subset of 585 cases and 837 sibling controls who completed a detailed food frequency questionnaire. Age- and sex-adjusted associations were estimated using conditional logistic regression. Overall, we did not find evidence for an association between any single-nucleotide polymorphism (SNP) in VDR or GC and risk for CRC (range of unadjusted P values 0.01-0.98 for VDR and 0.07-0.95 for GC). None of these associations was significant after adjustment for multiple comparisons. We also found no evidence that calcium or vitamin D intake (food and supplement) from the food frequency questionnaire modified the association estimates between VDR and GC SNPs and CRC. We did observe associations between SNPs in GC and microsatellite unstable CRC, although these results should be confirmed in additional studies. Overall, our results do not provide evidence for a role of common genetic variants in VDR or GC in susceptibility to CRC.

    View details for DOI 10.1158/1055-9965.EPI-09-0662

    View details for Web of Science ID 000278403900027

    View details for PubMedID 20086113

  • Oral contraceptives and postmenopausal hormones and risk of contralateral breast cancer among BRCA1 and BRCA2 mutation carriers and noncarriers: the WECARE Study BREAST CANCER RESEARCH AND TREATMENT Figueiredo, J. C., Haile, R. W., Bernstein, L., Malone, K. E., Largent, J., Langholz, B., Lynch, C. F., Bertelsen, L., Capanu, M., Concannon, P., Borg, A., Borresen-Dale, A., Diep, A., Teraoka, S., Torngren, T., Xue, S., Bernstein, J. L. 2010; 120 (1): 175-183

    Abstract

    The potential effects of oral contraceptive (OC) and postmenopausal hormone (PMH) use are not well understood among BRCA1 or BRCA2 (BRCA1/2) deleterious mutation carriers with a history of breast cancer. We investigated the association between OC and PMH use and risk of contralateral breast cancer (CBC) in the WECARE (Women's Environment, Cancer, and Radiation Epidemiology) Study. The WECARE Study is a population-based case-control study of 705 women with asynchronous CBC and 1,398 women with unilateral breast cancer, including 181 BRCA1/2 mutation carriers. Risk-factor information was assessed by telephone interview. Mutation status was measured using denaturing high-performance liquid chromatography followed by direct sequencing in all participants. Outcomes, treatment, and tumor characteristics were abstracted from medical records. Ever use of OCs was not associated with risk among noncarriers (RR = 0.87; 95% CI = 0.66-1.15) or BRCA2 carriers (RR = 0.82; 95% CI = 0.21-3.13). BRCA1 carriers who used OCs had a nonsignificant greater risk than nonusers (RR = 2.38; 95% CI = 0.72-7.83). Total duration of OC use and at least 5 years of use before age 30 were associated with a nonsignificant increased risk among mutation carriers but not among noncarriers. Few women had ever used PMH and we found no significant associations between lifetime use and CBC risk among carriers and noncarriers. In conclusion, the association between OC/PMH use and risk of CBC does not differ significantly between carriers and noncarriers; however, because carriers have a higher baseline risk of second primaries, even a potential small increase in risk as a result of OC use may be clinically relevant.

    View details for DOI 10.1007/s10549-009-0455-5

    View details for Web of Science ID 000273743500020

    View details for PubMedID 19597986

  • Alpha-1-antitrypsin deficiency and smoking as risk factors for mismatch repair deficient colorectal cancer: A study from the colon cancer family registry MOLECULAR GENETICS AND METABOLISM Lindor, N. M., Yang, P., Evans, I., Schowalter, K., de Andrade, M., Li, J., Jeavons, E., Peterson, G., Gallinger, S., Bapat, B., Hopper, J., Jass, J., Jenkins, M., Templeton, A., Potter, J., Newcomb, P. A., LeMarchand, L., Grove, J., Haile, R., Baron, J., Seminara, D., Limburg, P., Thibodeau, S. N. 2010; 99 (2): 157-159

    Abstract

    In a previous study, alpha-1-antitrypsin (A1AT) deficiency alleles were found to be over represented among individuals with microsatellite unstable (MSI-high) colorectal cancers, and this was most significant in former or current smokers. We evaluated this association in a larger case-control study, stratified by microsatellite instability phenotypes. Concordant with prior observations, gender (female) and smoking history were positively associated with colorectal cancers having an MSI-high phenotype. No difference in frequency of A1AT deficiency alleles was found between cases and controls, irrespective of the MSI subtype.

    View details for DOI 10.1016/j.ymgme.2009.09.010

    View details for Web of Science ID 000274004300008

    View details for PubMedID 19853488

  • Genetic Variability in the MTHFR Gene and Colorectal Cancer Risk Using the Colorectal Cancer Family Registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Levine, A. J., Figueiredo, J. C., Lee, W., Poynter, J. N., Conti, D., Duggan, D. J., Campbell, P. T., Newcomb, P., Martinez, M. E., Hopper, J. L., Le Marchand, L., Baron, J. A., Limburg, P. J., Ulrich, C. M., Haile, R. W. 2010; 19 (1): 89-100

    Abstract

    The MTHFR C677T TT genotype is associated with a 15% to 18% reduction in colorectal cancer risk, but it is not clear if other variants of the gene are associated with colorectal cancer risk.We used a tagSNP approach to comprehensively evaluate associations between variation in the MTHFR gene and colorectal cancer risk using a large family-based case-control study of 1,750 population-based and 245 clinic-based families from the Colon Cancer Family Registry. We assessed 22 TagSNPs, selected based on pairwise r(2) >95%, using the Haploview Tagger and genotyped the TagSNPs on the Illumina GoldenGate or Sequenom platforms. The association between single nucleotide polymorphisms and colorectal cancer was assessed using log-additive, codominant, and recessive models.From studying the population-based families, the C677T (rs1801133) and A1298C (rs1801131) polymorphisms were associated with a decreased colorectal cancer risk overall [odds ratio (OR), 0.81; 95% confidence interval (95% CI), 0.63-1.04; and OR, 0.82; 95% CI, 0.64-1.07, respectively]. The 677 TT genotype was associated with a decreased risk of microsatellite-stable/microsatellite-low tumors (OR, 0.69; 95% CI, 0.49-0.97) and an increased risk of microsatellite-high tumors (OR, 2.22; 95% CI, 0.91-5.43; P(interaction) = 0.01), as well as an increased risk of proximal cancers and a decreased risk of distal and rectal cancers (P(interaction) = 0.02). No other single nucleotide polymorphism was associated with risk overall or within subgroups.The 677 TT and 1298 CC genotypes may each be associated with a decrease in colorectal cancer risk. We observed little evidence of additional genetic variability in the MTHFR gene relevant to colorectal cancer risk.

    View details for DOI 10.1158/1055-9965.EPI-09-0727

    View details for Web of Science ID 000273586700011

    View details for PubMedID 20056627

  • Methodological Issues in Multistage Genome-Wide Association Studies STATISTICAL SCIENCE Thomas, D. C., Casey, G., Conti, D. V., Haile, R. W., Lewinger, J. P., Stram, D. O. 2009; 24 (4): 414-429

    View details for DOI 10.1214/09-STS288

    View details for Web of Science ID 000277257000004

  • Associations between Smoking, Alcohol Consumption, and Colorectal Cancer, Overall and by Tumor Microsatellite Instability Status CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Poynter, J. N., Haile, R. W., Siegmund, K. D., Campbell, P. T., Figueiredo, J. C., Limburg, P., Young, J., Le Marchand, L., Potter, J. D., Cotterchio, M., Casey, G., Hopper, J. L., Jenkins, M. A., Thibodeau, S. N., Newcomb, P. A., Baronlo, J. A. 2009; 18 (10): 2745-2750

    Abstract

    Both smoking and alcohol consumption have been associated with modestly increased risks of colorectal cancer (CRC). Reports have suggested that these associations may differ by tumor molecular subtype, with stronger associations for microsatellite unstable (MSI-H) tumors.We used a population-based case-unaffected sibling design including 2,248 sibships (2,253 cases; 4,486 siblings) recruited to the Colon Cancer Family Registry to evaluate the association between smoking, alcohol consumption, and CRC. Associations were assessed using conditional logistic regression, treating sibship as the matching factor.Although there were no statistically significant associations between any smoking variable and CRC overall, smoking did confer an increased risk of certain types of CRC. We observed an association between pack-years of smoking and rectal cancer [odds ratio (OR), 1.85; 95% confidence interval (CI), 1.23-2.79 for >40 pack-years versus nonsmokers; P(trend) = 0.03], and there was an increased risk of MSI-H CRC with increasing duration of smoking (OR, 1.94; 95% CI, 1.09-3.46 for >30 years of smoking versus nonsmokers). Alcohol intake was associated with a modest increase in risk for CRC overall (OR, 1.21; 95% CI, 1.03-1.44 for 12+ drinks per week versus nondrinkers), with more marked increases in risk for MSI-L CRC (OR, 1.85; 95% CI, 1.06-3.24) and rectal cancer (OR, 1.48; 95% CI, 1.08-2.02).We found associations between cigarette smoking and increased risks of rectal cancer and MSI-H CRC. Alcohol intake was associated with increased risks of rectal cancer and MSI-L CRC. These results highlight the importance of considering tumor phenotype in studies of risk factors for CRC.

    View details for DOI 10.1158/1055-9965.EPI-09-0517

    View details for Web of Science ID 000270702100024

    View details for PubMedID 19755657

  • The Association of Lifestyle and Dietary Factors with the Risk for Serrated Polyps of the Colorectum CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wallace, K., Grau, M. V., Ahnen, D., Snover, D. C., Robertson, D. J., Mahnke, D., Gui, J., Barry, E. L., Summers, R. W., McKeown-Eyssen, G., Haile, R. W., Baron, J. A. 2009; 18 (8): 2310-2317

    Abstract

    Some serrated polyps of the colorectum are likely preinvasive lesions, evolving through a newly recognized serrated pathway to colorectal cancer. To assess possible risk and protective factors for serrated polyps and particularly to explore differences in risk factors between polyps in the right and left colorectum, we pooled data from three large multicenter chemoprevention trials. A serrated polyp was defined broadly as any serrated lesion (hyperplastic, sessile serrated adenoma, "traditional" serrated adenoma, mixed adenoma) diagnosed during each trial's main treatment period of approximately 3 to 4 years. Using generalized linear regression, we computed risk ratios and 95% confidence intervals as measures of the association between risk for serrated polyps and demographic, lifestyle, and dietary variables. Of the 2,830 subjects that completed at least one follow-up exam after randomization, 675 (23.9%) had at least one left-sided serrated polyp and 261 (9.2%) had at least one right-sided lesion. In the left colorectum, obesity, cigarette smoking, dietary fat, total energy intake, and red meat intake were associated with an increased risk for serrated polyps. In the right colon, aspirin treatment was associated with a reduced risk and family history of polyps and folate treatment were associated with an increased risk for serrated polyps. Our results suggest that several common lifestyle and dietary variables are associated with risk for serrated polyps, and some of these may differ for the right and left colorectum.

    View details for DOI 10.1158/1055-9965.EPI-09-0211

    View details for Web of Science ID 000268958600026

    View details for PubMedID 19661090

  • Using the Results of a Baseline and a Surveillance Colonoscopy to Predict Recurrent Adenomas With High-Risk Characteristics ANNALS OF INTERNAL MEDICINE Robertson, D. J., Burke, C. A., Welch, H. G., Haile, R. W., Sandler, R. S., Greenberg, E. R., Ahnen, D. J., Bresalier, R. S., Rothstein, R. I., Cole, B., Mott, L. A., Baron, J. A. 2009; 151 (2): 103-W26

    Abstract

    Suggested intervals for postpolypectomy surveillance colonoscopy are currently based on the adenoma findings from the most recent examination.To determine the risk for clinically significant adenoma recurrence on the basis of the results of 2 previous colonoscopies.Prospective cohort study.Academic and private centers in North America.Participants in an adenoma chemoprevention trial in which all participants had 1 or more adenoma found on complete colonoscopy at entry. For this analysis, only participants whose qualifying adenoma was their first were included. All participants then underwent second and third study colonoscopies at roughly 3-year intervals.Proportion of patients with high-risk findings at the third study colonoscopy--either at least 1 advanced (> or = 1 cm or advanced histology) adenoma or multiple (> or = 3) adenomas.Fifty-eight of 564 participants (10.3%) had high-risk findings at the third study examination. If the second examination showed high-risk findings, then results from the first examination added no significant information about the probability of high-risk findings on the third examination (18.2% for high-risk findings on the first examination vs. 20.0% for low-risk findings on the first examination; P = 0.78). If the second examination showed no adenomas, then the results from the first examination added significant information about the probability of high-risk findings on the third examination (12.3% if the first examination had high-risk findings vs. 4.9% if the first examination had low-risk findings; P = 0.015).This observational study cannot specifically examine adenoma recurrence risk at intervals suggested for patients with low-risk adenomas (for example, 5 years vs. 10 years).Information from 2 previous examinations may help identify low-risk populations that benefit little from intense surveillance. Surveillance guidelines might be tailored in selected patients to use information from 2 previous examinations, not just the most recent one.National Institutes of Health.

    View details for Web of Science ID 000268605300004

    View details for PubMedID 19620162

  • Alcohol Intake and Cigarette Smoking and Risk of a Contralateral Breast Cancer AMERICAN JOURNAL OF EPIDEMIOLOGY Knight, J. A., Bernstein, L., Largent, J., Capanu, M., Begg, C. B., Mellemkjaer, L., Lynch, C. F., Malone, K. E., Reiner, A. S., Liang, X., Haile, R. W., Boice, J. D., Bernstein, J. L. 2009; 169 (8): 962-968

    Abstract

    Women with primary breast cancer are at increased risk of developing second primary breast cancer. Few studies have evaluated risk factors for the development of asynchronous contralateral breast cancer in women with breast cancer. In the Women's Environmental Cancer and Radiation Epidemiology Study (1985-2001), the roles of alcohol and smoking were examined in 708 women with asynchronous contralateral breast cancer (cases) compared with 1,399 women with unilateral breast cancer (controls). Cases and controls aged less than 55 years at first breast cancer diagnosis were identified from 5 population-based cancer registries in the United States and Denmark. Controls were matched to cases on birth year, diagnosis year, registry region, and race and countermatched on radiation treatment. Risk factor information was collected by telephone interview. Rate ratios and 95% confidence intervals were estimated by using conditional logistic regression. Ever regular drinking was associated with an increased risk of asynchronous contralateral breast cancer (rate ratio = 1.3, 95% confidence interval: 1.0, 1.6), and the risk increased with increasing duration (P = 0.03). Smoking was not related to asynchronous contralateral breast cancer. In this, the largest study of asynchronous contralateral breast cancer to date, alcohol is a risk factor for the disease, as it is for a first primary breast cancer.

    View details for DOI 10.1093/aje/kwn422

    View details for Web of Science ID 000264634900006

    View details for PubMedID 19211621

  • Germline MutY Human Homologue Mutations and Colorectal Cancer: A Multisite Case-Control Study GASTROENTEROLOGY Cleary, S. P., Cotterchio, M., Jenkins, M. A., Kim, H., Bristow, R., Green, R., Haile, R., Hopper, J. L., LeMarchand, L., Lindor, N., Parfrey, P., Potter, J., Younghusband, B., Gallinger, S. 2009; 136 (4): 1251-1260

    Abstract

    The MutY human homologue (MYH) gene is a member of the base-excision repair pathway involved in the repair of oxidative DNA damage. The objective of this study was to determine colorectal cancer (CRC) risk associated with mutations in the MYH gene.A total of 3811 CRC cases and 2802 controls collected from a multisite CRC registry were screened for 9 germline MYH mutations; subjects with any mutation underwent screening of the entire MYH gene. Logistic regression was used to estimate age- and sex-adjusted odds ratios (AOR). Clinicopathologic and epidemiologic data were reviewed to describe the phenotype associated with MYH mutation status and assess for potential confounding and effect modification.Twenty-seven cases and 1 control subject carried homozygous or compound heterozygous MYH mutations (AOR, 18.1; 95% confidence interval, 2.5-132.7). CRC cases with homozygous/compound heterozygous mutations were younger at diagnosis (P=.01), had a higher proportion of right-sided (P=.01), synchronous cancers (P<.01), and personal history of adenomatous polyps (P=.003). Heterozygous MYH mutations were identified in 87 CRC cases and 43 controls; carriers were at increased risk of CRC (AOR, 1.48; 95% confidence interval, 1.02-2.16). There was a higher prevalence of low-frequency microsatellite instability (MSI) in tumors from heterozygous and homozygous/compound heterozygous MYH mutation carriers (P=.02); MSI status modified the CRC risk associated with heterozygous MYH mutations (P interaction<.001).Homozygous/compound heterozygous MYH mutations account for less than 1% of CRC cases. Heterozygous carriers are at increased risk of CRC. Further studies are needed to understand the possible interaction between the base excision repair and low-frequency MSI pathways.

    View details for DOI 10.1053/j.gastro.2008.12.050

    View details for Web of Science ID 000264716500026

    View details for PubMedID 19245865

  • Global DNA Hypomethyation (LINE-1) in the Normal Colon and Lifestyle Characteristics and Dietary and Genetic Factors CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Figueiredo, J. C., Grau, M. V., Wallace, K., Levine, A. J., Shen, L., Hamdan, R., Chen, X., Bresalier, R. S., McKeown-Eyssen, G., Haile, R. W., Baron, J. A., Issa, J. J. 2009; 18 (4): 1041-1049

    Abstract

    Global loss of methylated cytosines in DNA, thought to predispose to chromosomal instability and aneuploidy, has been associated with an increased risk of colorectal neoplasia. Little is known about the relationships between global hypomethylation and lifestyle, demographics, dietary measures, and genetic factors.Our data were collected as part of a randomized clinical trial testing the efficacy of aspirin and folic acid for the prevention of colorectal adenomas. At a surveillance colonoscopy approximately 3 years after the qualifying exam, we obtained two biopsies of the normal-appearing mucosa from the right colon and two biopsies from the left colon. Specimens were assayed for global hypomethylation using a pyrosequencing assay for LINE-1 (long interspersed nucleotide elements) repeats.The analysis included data from 388 subjects. There was relatively little variability in LINE methylation overall. Mean LINE-1 methylation levels in normal mucosa from the right bowel were significantly lower than those on the left side (P < 0.0001). No significant associations were found between LINE-1 methylation and folate treatment, age, sex, body mass index, smoking status, alcohol use, dietary intake, or circulating levels of B vitamins, homocysteine, or selected genotypes. Race, dietary folic acid, and plasma B(6) showed associations with global methylation that differed between the right and the left bowel. The effect of folic acid on risk of adenomas did not differ according to extent of LINE-1 methylation, and we found no association between LINE-1 methylation and risk of adenomas.LINE-1 methylation is not influenced by folic acid supplementation but differs by colon subsite.

    View details for DOI 10.1158/1055-9965.EPI-08-0926

    View details for Web of Science ID 000265125000004

    View details for PubMedID 19336559

  • Folic Acid and Risk of Prostate Cancer: Results From a Randomized Clinical Trial JOURNAL OF THE NATIONAL CANCER INSTITUTE Figueiredo, J. C., Grau, M. V., Haile, R. W., Sandler, R. S., Summers, R. W., Bresalier, R. S., Burke, C. A., McKeown-Eyssen, G. E., Baron, J. A. 2009; 101 (6): 432-435

    Abstract

    Data regarding the association between folate status and risk of prostate cancer are sparse and conflicting. We studied prostate cancer occurrence in the Aspirin/Folate Polyp Prevention Study, a placebo-controlled randomized trial of aspirin and folic acid supplementation for the chemoprevention of colorectal adenomas conducted between July 6, 1994, and December 31, 2006. Participants were followed for up to 10.8 (median = 7.0, interquartile range = 6.0-7.8) years and asked periodically to report all illnesses and hospitalizations. Aspirin alone had no statistically significant effect on prostate cancer incidence, but there were marked differences according to folic acid treatment. Among the 643 men who were randomly assigned to placebo or supplementation with folic acid, the estimated probability of being diagnosed with prostate cancer over a 10-year period was 9.7% (95% confidence interval [CI] = 6.5% to 14.5%) in the folic acid group and 3.3% (95% CI = 1.7% to 6.4%) in the placebo group (age-adjusted hazard ratio = 2.63, 95% CI = 1.23 to 5.65, Wald test P = .01). In contrast, baseline dietary folate intake and plasma folate in nonmultivitamin users were inversely associated with risk of prostate cancer, although these associations did not attain statistical significance in adjusted analyses. These findings highlight the potential complex role of folate in prostate cancer and the possibly different effects of folic acid-containing supplements vs natural sources of folate.

    View details for DOI 10.1093/jnci/djp019

    View details for Web of Science ID 000264393100011

    View details for PubMedID 19276452

  • Red meat and poultry intake, polymorphisms in the nucleotide excision repair and mismatch repair pathways and colorectal cancer risk CARCINOGENESIS Joshi, A. D., Corral, R., Siegmund, K. D., Haile, R. W., Le Marchand, L., Martinez, M. E., Ahnen, D. J., Sandler, R. S., Lance, P., Stern, M. C. 2009; 30 (3): 472-479

    Abstract

    Diets high in red meat have been consistently associated with colorectal cancer (CRC) risk and may result in exposure to carcinogens that cause DNA damage [i.e polycyclic aromatic hydrocarbons, heterocyclic amines (HCAs) and N-nitroso compounds]. Using a family-based study, we investigated whether polymorphisms in the nucleotide excision repair (NER) (ERCC1 3' untranslated region (UTR) G/T, XPD Asp312Asn and Lys751Gln, XPC intron 11 C/A, XPA 5' UTR C/T, XPF Arg415Gln and XPG Asp1104His) and mismatch repair (MLH1 Ile219Val and MSH2 Gly322Asp) pathways modified the association with red meat and poultry intake. We tested for gene-environment interactions using case-only analyses (n = 577) and compared the results using case-unaffected sibling comparisons (n = 307 sibships). Increased risk of CRC was observed for intake of more than or equal to three servings per week of red meat [odds ratio (OR) = 1.8, 95% confidence interval (CI) = 1.3-2.5)] or high-temperature cooked red meat (OR = 1.6, 95% CI = 1.1-2.2). Intake of red meat heavily brown on the outside or inside increased CRC risk only among subjects who carried the XPD codon 751 Lys/Lys genotype (case-only interaction P = 0.006 and P = 0.001, respectively, for doneness outside or inside) or the XPD codon 312 Asp/Asp genotype (case-only interaction P = 0.090 and P < 0.001, respectively). These interactions were stronger for rectal cancer cases (heterogeneity test P = 0.002 for XPD Asp312Asn and P = 0.03 for XPD Lys751Gln) and remained statistically significant after accounting for multiple testing. Case-unaffected sibling analyses were generally supportive of the case-only results. These findings highlight the possible contribution of diets high in red meat to the formation of lesions that elicit the NER pathway, such as carcinogen-induced bulky adducts.

    View details for DOI 10.1093/carcin/bgn260

    View details for Web of Science ID 000263944500012

    View details for PubMedID 19029193

  • The Association of Tumor Microsatellite Instability Phenotype with Family History of Colorectal Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bapat, B., Lindor, N. M., Baron, J., Siegmund, K., Li, L., Zheng, Y., Haile, R., Gallinger, S., Jass, J. R., Young, J. P., Cotterchio, M., Jenkins, M., Grove, J., Casey, G., Thibodeau, S. N., Bishop, D. T., Hopper, J. L., Ahnen, D., Newcomb, P. A., Le Marchand, L., Potter, J. D., Seminara, D. 2009; 18 (3): 967-975

    Abstract

    Family history is a strong predictor of colorectal cancer risk; however, a diagnosis of colorectal cancer among first-degree relatives has not been systematically investigated as a function of the colorectal cancer molecular subtypes related to tumor microsatellite instability (MSI) status. We investigated whether the observable familial colorectal cancer risks differed according to tumor MSI subtypes, stratified as MSI-High (>30% instability), MSI-Low (<30% instability), and MSS (no instability). Data from 3,143 population-based colorectal cancer cases from five institutions were assessed for family history according to the Amsterdam criteria and the Bethesda guidelines, age at diagnosis, sex, tumor location, and MSI status. The distribution of patient characteristics by MSI status was compared using polytomous logistic regression. Overall, 2.8% colorectal cancer cases met the Amsterdam criteria and 37% met the Bethesda guidelines. There were 14% MSI-High, 13% MSI-Low, and 73% MSS colorectal cancers. MSI-High (P<0.0001) and MSI-Low tumors (P=0.01) were more proximally located than MSS tumors. MSI-High tumors were more common among females (P<0.001). The highest proportion of MSI-High tumors occurred in cases<40 years of age whereas the age-dependent distribution of MSI-Low tumors was unchanged. MSI-High tumors showed a statistically significant association with increasing numbers of first-degree relatives with colorectal cancer (P=0.002); this association disappeared, however, when MSI-High cases meeting Amsterdam criteria were removed from the analysis. MSI-Low tumors did not show a similar association with family history of colorectal cancer. Familial risk associated with MSI-High tumors is primarily driven by the Amsterdam-criteria patients. MSI-Low tumors may represent a distinct subtype of colorectal cancer with respect to certain epidemiologic variables studied here.

    View details for DOI 10.1158/1055-9965.EPI-08-0878

    View details for Web of Science ID 000264226100037

    View details for PubMedID 19258475

  • Nonsteroidal Anti-inflammatory Drug Use After 3 Years of Aspirin Use and Colorectal Adenoma Risk: Observational Follow-up of a Randomized Study JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Grau, M. V., Sandler, R. S., McKeown-Eyssen, G., Bresalier, R. S., Haile, R. W., Barry, E. L., Ahnen, D. J., Gui, J., Summers, R. W., Baron, J. A. 2009; 101 (4): 267-276

    Abstract

    Frequent use of nonsteroidal anti-inflammatory drugs (NSAIDs) has been shown to reduce the risk of colorectal adenomas in randomized trials. We examined the persistence of the protective effect after the cessation of randomized aspirin treatment and whether it is affected by the duration and frequency of subsequent NSAID use.We used data from the Aspirin/Folate Polyp Prevention Study (AFPPS), in which 1121 subjects were randomly assigned to receive placebo or aspirin (81 or 325 mg/d) for 3 years. After the end of treatment and a follow-up colonoscopy, AFPPS participants were invited to remain under follow-up until their next surveillance colonoscopies, scheduled 3-5 years later. Information regarding use of NSAIDs during posttreatment follow-up was gathered periodically via questionnaires. Average weekly NSAID use was classified as sporadic (<2 days per week), moderate (2 to <4 days per week), or frequent (>or=4 days per week). The analysis was stratified according to randomized aspirin groups and posttreatment NSAID use; placebo subjects who later were sporadic NSAID users formed the reference group. The primary outcomes were all adenomas and advanced lesions. Adjusted relative risks and 95% confidence intervals were computed with generalized linear models. All statistical tests were two-sided.A total of 850 subjects underwent a posttreatment colonoscopy, on average 4 years after the end of study treatment. The protective effect of 81 mg of aspirin for colorectal adenomas persisted with continued posttreatment NSAID use. The risk of any adenoma among frequent NSAID users was 26.8% vs 39.9% among placebo subjects who later used NSAIDs sporadically (adjusted relative risk = 0.62, 95% confidence interval [CI] = 0.39 to 0.98; P(trend) with NSAID use frequency = .03). The unadjusted absolute risk reduction was 13.1 percentage points (95% CI = -0.3 to 26.5 percentage points) (P = .07). Results for 325 mg of aspirin were similar, although not statistically significant. For advanced lesions, small numbers of endpoints limited the analysis, but findings among subjects randomly assigned to 81 mg of aspirin suggested a protective association regardless of posttreatment NSAID use.Long-term and frequent use of NSAIDs may enhance the chemopreventive effect of aspirin against colorectal neoplasia.

    View details for DOI 10.1093/jnci/djn484

    View details for Web of Science ID 000274802600013

    View details for PubMedID 19211442

  • DOSE TO THE CONTRALATERAL BREAST FROM RADIOTHERAPY AND RISK OF SECOND PRIMARY BREAST CANCER IN THE WECARE STUDY INTERNATIONAL JOURNAL OF RADIATION ONCOLOGY BIOLOGY PHYSICS Stovall, M., Smith, S. A., Langholz, B. M., Boice, J. D., Shore, R. E., Andersson, M., Buchholz, T. A., Capanu, M., Bernstein, L., Lynch, C. F., Malone, K. E., Anton-Culver, H., Haile, R. W., Rosenstein, B. S., Reiner, A. S., Thomas, D. C., Bernstein, J. L. 2008; 72 (4): 1021-1030

    Abstract

    To quantify the risk of second primary breast cancer in the contralateral breast (CB) after radiotherapy (RT) for first breast cancer.The study population included participants in the Women's Environmental, Cancer, and Radiation Epidemiology study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were <55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals (CI) were calculated using multivariable-adjusted conditional logistic regression models.Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women <40 years of age who received >1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR = 2.5, 95% CI 1.4-4.5). No excess risk was observed in women >40 years of age. Women <40 years of age with follow-up periods >5 years had a RR of 3.0 (95% CI 1.1-8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI 0.1-3.0).Women <40 years of age who received a radiation dose >1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.

    View details for DOI 10.1016/j.ijrobp.2008.02.040

    View details for Web of Science ID 000260592600010

    View details for PubMedID 18556141

  • Molecular Characterization of MSI-H Colorectal Cancer by MLH1 Promoter Methylation, Immunohistochemistry, and Mismatch Repair Germline Mutation Screening CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Poynter, J. N., Siegmund, K. D., Weisenberger, D. J., Long, T. I., Thibodeau, S. N., Lindor, N., Young, J., Jenkins, M. A., Hopper, J. L., Baron, J. A., Buchanan, D., Casey, G., Levine, A. J., Le Marchand, L., Gallinger, S., Bapat, B., Potter, J. D., Newcomb, P. A., Haile, R. W., Laird, P. W. 2008; 17 (11): 3208-3215

    Abstract

    Microsatellite instability (MSI) occurs in 10% to 20% of colorectal cancers (CRC) and has been attributed to both MLH1 promoter hypermethylation and germline mutation in the mismatch repair (MMR) genes. We present results from a large population- and clinic-based study of MLH1 methylation, immunohistochemistry, and MMR germline mutations that enabled us to (a) estimate the prevalence of MMR germline mutations and MLH1 methylation among MSI-H cases and help us understand if all MSI-H CRC is explained by these mechanisms and (b) estimate the associations between MLH1 methylation and sex, age, and tumor location within the colon. MLH1 methylation was measured in 1,061 population-based and 172 clinic-based cases of CRC. Overall, we observed MLH1 methylation in 60% of population-based MSI-H cases and in 13% of clinic-based MSI-H cases. Within the population-based cases with MMR mutation screening and conclusive immunohistochemistry results, we identified a molecular event in MMR in 91% of MSI-H cases: 54% had MLH1 methylation, 14% had a germline mutation in a MMR gene, and 23% had immunohistochemistry evidence for loss of a MMR protein. We observed a striking age difference, with the prevalence of a MMR germline mutation more than 4-fold lower and the prevalence of MLH1 methylation more than 4-fold higher in cases diagnosed after the age of 50 years than in cases diagnosed before that age. We also determined that female sex is an independent predictor of MLH1 methylation within the MSI-H subgroup. These results reinforce the importance of distinguishing between the underlying causes of MSI in studies of etiology and prognosis.

    View details for DOI 10.1158/1055-9965.EPI-08-0512

    View details for Web of Science ID 000260896500041

    View details for PubMedID 18990764

  • Common Familial Colorectal Cancer Linked to Chromosome 7q31: A Genome-Wide Analysis CANCER RESEARCH Neklason, D. W., Kerber, R. A., Nilson, D. B., Anton-Culver, H., Schwartz, A. G., Griffin, C. A., Lowery, J. T., Schildkraut, J. M., Evans, J. P., Tomlinson, G. E., Strong, L. C., Miller, A. R., Stopfer, J. E., Finkelstein, D. M., Nadkarni, P. M., Kasten, C. H., Mineau, G. P., Burt, R. W. 2008; 68 (21): 8993-8997

    Abstract

    Present investigations suggest that approximately 30% of colorectal cancer cases arise on the basis of inherited factors. We hypothesize that the majority of inherited factors are moderately penetrant genes, common in the population. We use an affected sibling pair approach to identify genetic regions that are coinherited by siblings with colorectal cancer. Individuals from families with at least two siblings diagnosed with colorectal adenocarcinoma or high-grade dysplasia were enrolled. Known familial colorectal cancer syndromes were excluded. A genome-wide scan on 151 DNA samples from 70 kindreds was completed using deCODE 1100 short tandem repeat marker set at an average 4-cM density. Fine mapping on a total of 184 DNAs from 83 kindreds was done in regions suggesting linkage. Linkage analysis was accomplished with Merlin analysis package. Nonparametric linkage analysis revealed three genetic regions with logarithm of the odds (LOD) scores >or=2.0: Ch. 3q29, LOD 2.61 (P = 0.0003); Ch. 4q31.3, LOD 2.13 (P = 0.0009); and Ch. 7q31.31, LOD 3.08 (P = 0.00008). Affected siblings with increased sharing at the 7q31 locus have a 3.8-year (+/- 3.5) earlier age of colorectal cancer onset although this is not statistically significant (P = 0.11). No significant linkage was found near genes causing known syndromes or regions previously reported (8q24, 9q22, and 11q23). The chromosome 3q21-q24 region reported to be linked in colorectal cancer relative pairs is supported by our study, albeit a minor peak (LOD 0.9; P = 0.02). No known familial cancer genes reside in the 7q31 locus, and thus the identified region may contain a novel susceptibility gene responsible for common familial colorectal cancer.

    View details for DOI 10.1158/0008-5472.CAN-08-1376

    View details for Web of Science ID 000260698900042

    View details for PubMedID 18974144

  • Colorectal adenomas in a randomized folate trial: The role of baseline dietary and circulating folate levels CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Figueiredo, J. C., Levine, A. J., Grau, M. V., Barry, E. L., Ueland, P. M., Ahnen, D. J., Byers, T., Bresalier, R. S., Summers, R. W., Bond, J., McKeown-Eyssen, G. E., Sandler, R. S., Haile, R. W., Baron, J. A. 2008; 17 (10): 2625-2631

    Abstract

    The Aspirin/Folate Polyp Prevention Study is a randomized, placebo-controlled trial of aspirin use and folic acid supplementation and incidence of colorectal adenomas in individuals with a history of these lesions. The trial showed that folic acid supplementation does not prevent the occurrence of new adenomas and may increase risk. We extend these results by investigating whether the effect of folic acid treatment differed by baseline dietary and circulating folate levels. Diet and supplement use were ascertained at baseline through a food-frequency questionnaire; a blood sample was used to determine plasma and RBC folate levels. Individuals were followed for 3 years (first follow-up) and subsequently for an additional 3 to 5 years (second follow up). We used generalized linear regression to estimate risk ratios and 95% confidence limits as measures of association. There was little evidence that baseline dietary and total folate intake, and plasma and RBC folate modified the association between folic acid treatment and risk of any adenomas or advanced lesions. However, there was a protective association of the highest tertile of dietary and total intake as well as circulating folate with risk of any adenomas among those in the placebo group but no association among individuals in the folic acid group. Our findings support the idea that although moderate doses of folate may be protective compared with deficiency, at some point of sufficiency, supplementation provides no additional benefit.

    View details for DOI 10.1158/1055-9965.EPI-08-0382

    View details for Web of Science ID 000260051000015

    View details for PubMedID 18843003

  • MTHFR genotype and colorectal adenoma recurrence: Data from a double-blind placebo-controlled clinical trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Levine, A. J., Wallace, K., Tsang, S., Haile, R. W., Saibil, F., Ahnen, D., Cole, B. F., Barry, E. L., Munroe, D. J., Ali, I. U., Ueland, P., Baron, J. A. 2008; 17 (9): 2409-2415

    Abstract

    Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme in folate metabolism. We assessed the association between two common MTHFR variants, 677C>T and 1298A>C, and adenoma recurrence in the context of a randomized double- blind clinical trial of aspirin use and folate supplementation. We used generalized linear regression to estimate risk ratios and 95% confidence intervals (95% CI) for recurrence, adjusting for age, sex, clinical center, follow-up time, and treatment status. Neither MTHFR polymorphism was associated with overall or advanced adenoma recurrence. Compared with those with two wild-type alleles, the relative risk for advanced adenoma was 0.75 (95% CI, 0.36-1.55) for the MTHFR 677 TT genotype and 1.16 (95% CI, 0.58-2.33) for the MTHFR 1298 CC genotype. The effect of folate supplementation on recurrence risk did not differ by genotype. Our findings indicate that the MTHFR genotype does not change adenoma risk in a manner similar to its effect on colorectal cancer, and does not modify the effect of folate supplementation on metachronous adenoma risk.

    View details for DOI 10.1158/1055-9965.EPI-07-2670

    View details for Web of Science ID 000259211400032

    View details for PubMedID 18768511

  • Variants in the ATM gene associated with a reduced risk of contralateral breast cancer CANCER RESEARCH Concannon, P., Haile, R. W., Borresen-Dale, A., Rosenstein, B. S., Gatti, R. A., Teraoka, S. N., Diep, A. T., Jansen, L., Atencio, D. P., Langholz, B., Capanu, M., Liang, X., Begg, C. B., Thomas, D. C., Bernstein, L., Olsen, J. H., Malone, K. E., Lynch, C. F., Anton-Culver, H., Bernstein, J. L. 2008; 68 (16): 6486-6491

    Abstract

    Between 5% and 10% of women who survive a first primary breast cancer will subsequently develop a second primary cancer in the contralateral breast. The Women's Environment, Cancer, and Radiation Epidemiology Study was designed to identify genetic and environmental determinants of contralateral breast cancer (CBC). In this study, 708 women with asynchronous CBC served as cases and 1,397 women with unilateral breast cancer served as controls. ATM, a serine-threonine kinase, controls the cellular response to DNA double-strand breaks, and has been implicated in breast cancer risk. Complete mutation screening of the ATM gene in all 2,105 study participants identified 240 distinct sequence variants; only 15 were observed in >1% of subjects. Among the rare variants, deleterious alleles resulting in loss of ATM function were associated with a nonsignificant increase in risk of CBC. In contrast, carriers of common variants had a statistically significant reduction in risk of CBC. Four of these 15 variants were individually associated with a significantly decreased risk of second primary breast cancer [c.1899-55T>G, rate ratio (RR), 0.5; 95% confidence interval (CI), 0.3-0.8; c.3161C>G, RR, 0.5; 95% CI, 0.3-0.9; c.5558A>T, RR, 0.2; 95% CI, 0.1-0.6; c.6348-54T>C RR, 0.2; 95% CI, 0.1-0.8]. These data suggest that some alleles of ATM may exert an antineoplastic effect, perhaps by altering the activity of ATM as an initiator of DNA damage responses or a regulator of p53.

    View details for DOI 10.1158/0008-5472.CAN-08-0134

    View details for Web of Science ID 000258548200003

    View details for PubMedID 18701470

  • Vitamins B-2, B-6, and B-12 and risk of new colorectal adenomas in a randomized trial of aspirin use and folic acid supplementation CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Figueiredo, J. C., Levine, A. J., Grau, M. V., Midttun, O., Ueland, P. M., Ahnen, D. J., Barry, E. L., Tsang, S., Munroe, D., Ali, I., Haile, R. W., Sandler, R. S., Baron, J. A. 2008; 17 (8): 2136-2145

    Abstract

    Folate, other vitamin B cofactors, and genes involved in folate-mediated one-carbon metabolism all may play important roles in colorectal neoplasia. In this study, we examined the associations between dietary and circulating plasma levels of vitamins B(2), B(6), and B(12) and risk colorectal adenomas.The Aspirin/Folate Polyp Prevention Study is a randomized clinical trial of folic acid supplementation and incidence of new colorectal adenomas in individuals with a history of adenomas (n = 1,084). Diet and supplement use were ascertained through a food frequency questionnaire administered at baseline. Blood collected at baseline was used to determine plasma B-vitamin levels. We used generalized linear regression to estimate risk ratios (RR) and 95% confidence intervals (95% CI) as measures of association.We found a borderline significant inverse association with plasma B(6) [pyridoxal 5'-phosphate (PLP)] and adenoma risk (adjusted RR Q4 versus Q1, 0.78; 95% CI, 0.61-1.00; P(trend) = 0.08). This association was not modified by folic acid supplementation or plasma folate. However, the protective association of PLP with adenoma risk was observed only among subjects who did not drink alcohol (P(interaction) = 0.03). Plasma B(2) (riboflavin) was inversely associated with risk of advanced lesions (adjusted RR Q4 versus Q1, 0.51; 95% CI, 0.26-0.99; P(trend) = 0.12). No significant associations were observed between adenoma risk and plasma vitamin B(12) or dietary intake of vitamin B(2) and B(6). When we examined specific gene-B-vitamin interactions, we observed a possible interaction between methylenetetrahydrofolate reductase -C677T and plasma B(2) on risk of all adenomas.Our results suggest that high levels of PLP and B(2) may protect against colorectal adenomas.

    View details for DOI 10.1158/1055-9965.EPI-07-2895

    View details for Web of Science ID 000258800800043

    View details for PubMedID 18708408

  • Predictors of multivisceral resection in patients with locally advanced colorectal cancer ANNALS OF SURGICAL ONCOLOGY Govindarajan, A., Fraser, N., Cranford, V., Wirtzfeld, D., Gallinger, S., Law, C. H., Smith, A. J., Gagliardi, A. R. 2008; 15 (7): 1923-1930

    Abstract

    Practice guidelines recommend en bloc multivisceral resection (MVR) for all involved organs in patients with locally advanced adherent colorectal cancer (LAACRC) to reduce local recurrence and improve survival. We found that MVR was performed in one-third of eligible American patients in the Surveillance, Epidemiology and End Results cancer registry but that study could not identify factors amenable to quality improvement. This study was conducted to examine rates, and predictors of MVR among Canadian patients with LAACRC.Rates of MVR were examined by observational study. Eligible patients were aged 20-74 years who had surgery for nonmetastatic LAACRC from July 1997 to December 2000. Patient, tumor, surgeon, and hospital characteristics were extracted from medical records. Summary statistics were compared by type of surgery (MVR, partial MVR, standard resection). To identify factors associated with MVR we analyzed operative notes and transcripts from interviews with general surgeons using standard qualitative methods.Factors associated with MVR included fewer years in practice, preoperative treatment planning, involvement of surgical consultants, and access to diagnostic imaging and systems to enable preoperative multidisciplinary planning. Judgments regarding the nature of peritumoral adhesions, resectability, and personal technical skill may mediate decision-making. Many surgeons would prefer to refer patients than undertake complicated, lengthy cases.Further research is required to validate these findings in larger studies and among patients undergoing surgery for conditions other than LAACRC, and evaluate strategies to improve rates of MVR through enhanced individual awareness and system capacity.

    View details for DOI 10.1245/s10434-008-9930-1

    View details for Web of Science ID 000257222900016

    View details for PubMedID 18473145

  • Oral contraceptives, postmenopausal hormones, and risk of asynchronous bilateral breast cancer: The WECARE study group JOURNAL OF CLINICAL ONCOLOGY Figueiredo, J. C., Bernstein, L., Capanu, M., Malone, K. E., Lynch, C. F., Anton-Culver, H., Stovall, M., Bertelsen, L., Haile, R. W., Bernstein, J. L. 2008; 26 (9): 1411-1418

    Abstract

    To investigate whether oral contraceptive (OC) use and postmenopausal hormones (PMH) are associated with an increased risk of developing asynchronous bilateral breast cancer among women diagnosed with breast cancer younger than 55 years.The WECARE (Women's Environment, Cancer, and Radiation Epidemiology) study is a population-based, multicenter, case-control study of 708 women with asynchronous bilateral breast cancer and 1,395 women with unilateral breast cancer. Risk factor information collected during a telephone interview focused on exposures before and after the first breast cancer diagnosis. Treatment and tumor characteristics were abstracted from medical records. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% CIs.OC use before the first breast cancer diagnosis was not associated with risk of asynchronous bilateral breast cancer (RR = 0.88; 95% CI, 0.67 to 1.16). OC use after breast cancer diagnosis was also not significantly associated with risk (RR = 1.56; 95% CI, 0.71 to 3.45). Risk did not increase with longer duration of use or among women who had begun using OCs at a younger age. No evidence of an increased risk of asynchronous bilateral breast cancer was observed with PMH use before (RR = 1.21; 95% CI, 0.90 to 1.61) or after breast cancer diagnosis (RR = 1.10; 95% CI, 0.67 to 1.77). Neither duration nor type of PMH were associated with risk. Age at and time since first breast cancer diagnosis did not substantially affect these results.This study provides no strong evidence that OC or PMH use increases the risk of a second cancer in the contralateral breast.

    View details for DOI 10.1200/JCO.2007.14.3081

    View details for Web of Science ID 000254178600006

    View details for PubMedID 18250348

  • Risk for contralateral breast cancer among carriers of the CHEK2*1100delC mutation in the WECARE Study BRITISH JOURNAL OF CANCER Mellemkjaer, L., Dahl, C., Olsen, J. H., Bertelsen, L., Guldberg, P., Christensen, J., Borresen-Dale, A., Stovall, M., Langholz, B., Bernstein, L., Lynch, C. F., Malone, K. E., Haile, R. W., Andersson, M., Thomas, D. C., Concannon, P., Capanu, M., Boice, J. D., Bernstein, J. L. 2008; 98 (4): 728-733

    Abstract

    The protein encoded by the CHEK2 gene is involved in cellular repair of DNA damage. The truncating mutation, CHEK2*1100delC, seems to increase the risk for breast cancer. We investigated whether the CHEK2*1100delC mutation carrier status increases the risk for asynchronous contralateral breast cancer (CBC) and whether it interacts with radiation therapy (RT) or chemotherapy in regard to CBC risk. The germline mutation frequency was assessed in 708 women with CBC and 1395 women with unilateral breast cancer (UBC) in the Women's Environment, Cancer and Radiation Epidemiology (WECARE) Study whose first primary breast cancer was diagnosed before age 55 years and during 1985--1999. Seven women with CBC (1.0%) and 10 women with UBC (0.7%) were CHEK2*1100delC variant carriers (rate ratio (RR)=1.8, 95% confidence interval (CI)=0.6-5.4 for CBC vs UBC). Carriers who received RT for their first breast cancer, compared with non-carriers not treated with RT, had an RR of developing CBC of 2.6 (95% CI=0.8-8.7). We found no significant associations between the CHEK2*1100delC mutation and CBC overall or among those treated with RT. However, the sampling variability was such that modest increases in risk could not be excluded. Nonetheless, because this is a rare mutation, it is unlikely to explain a major fraction of CBC in the population.

    View details for DOI 10.1038/sj.bjc.6604228

    View details for Web of Science ID 000253219700009

    View details for PubMedID 18253122

  • Variation of breast cancer risk among BRCA1/2 carriers JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Begg, C. B., Haile, R. W., Borg, A., Malone, K. E., Concannon, P., Thomas, D. C., Langholz, B., Bernstein, L., Olsen, J. H., Lynch, C. F., Anton-Culver, H., Capanu, M., Liang, X., Hummer, A. J., Sima, C., Bernstein, J. L. 2008; 299 (2): 194-201

    Abstract

    The risk of breast cancer in BRCA1 and BRCA2 mutation carriers has been examined in many studies, but relatively little attention has been paid to the degree to which the risk may vary among carriers.To determine the extent to which risks for BRCA1 and BRCA2 carriers vary with respect to observable and unobservable characteristics.Probands were identified from a population-based, case-control study (Women's Environmental Cancer and Radiation Epidemiology [WECARE]) of asynchronous contralateral breast cancer conducted during the period of January 2000 to July 2004. Participants previously diagnosed with contralateral breast cancer or unilateral breast cancer were genotyped for mutations in BRCA1 and BRCA2. All participants had their initial breast cancer diagnosed during the period of January 1985 to December 2000, before the age of 55 years.Incidence of breast cancer in first-degree female relatives of the probands was examined and compared on the basis of proband characteristics and on the basis of variation between families.Among the 1394 participants with unilateral breast cancer, 73 (5.2%) were identified as carriers of deleterious mutations (42 with BRCA1 and 31 with BRCA2). Among the 704 participants with contralateral breast cancer, 108 (15.3%) were identified as carriers of deleterious mutations (67 with BRCA1 and 41 with BRCA2). Among relatives of carriers, risk was significantly associated with younger age at diagnosis in the proband (P = .04), and there was a trend toward higher risk for relatives of contralateral breast cancer vs unilateral breast cancer participants (odds ratio, 1.4 [95% confidence interval, 0.8-2.4]; P = .28). In addition, there were significant differences in risk between carrier families after adjusting for these observed characteristics.There exists broad variation in breast cancer risk among carriers of BRCA1 and BRCA2 mutations.

    View details for Web of Science ID 000252182600019

    View details for PubMedID 18182601

  • Effect of systemic adjuvant treatment on risk for contralateral breast cancer in the women's environment, cancer and radiation epidemiology study JOURNAL OF THE NATIONAL CANCER INSTITUTE Bertelsen, L., Bernstein, L., Olsen, J. H., Mellemkjaer, L., Haile, R. W., Lynch, C. F., Malone, K. E., Anton-Culver, H., Christensen, J., Langholz, B., Thomas, D. C., Begg, C. B., Capanu, M., Ejlertsen, B., Stovall, M., Boice, J. D., Shore, R. E., Bernstein, J. L. 2008; 100 (1): 32-40

    Abstract

    Results from randomized trials indicate that treatment with tamoxifen or chemotherapy for primary breast cancer reduces the risk for contralateral breast cancer. However, less is known about how long the risk is reduced and the impact of factors such as age and menopausal status.The study included 634 women with contralateral breast cancer (case patients) and 1158 women with unilateral breast cancer (control subjects) from the Women's Environment, Cancer and Radiation Epidemiology Study. The women were younger than age 55 when they were first diagnosed with breast cancer during 1985-1999. Rate ratios (RRs) and 95% confidence intervals (CIs) for contralateral breast cancer after treatment with chemotherapy or tamoxifen were assessed by multivariable adjusted conditional logistic regression analyses.Chemotherapy was associated with a lower risk for contralateral breast cancer (RR = 0.57, 95% CI = 0.42 to 0.75) than no chemotherapy. A statistically significant association between chemotherapy and reduced risk for contralateral breast cancer persisted up to 10 years after the first breast cancer diagnosis and was stronger among women who became postmenopausal within 1 year of the first breast cancer diagnosis (RR = 0.28, 95% CI = 0.11 to 0.76). Tamoxifen use was also associated with reduced risk for contralateral breast cancer (RR = 0.66, 95% CI = 0.50 to 0.88) compared with no use, and the association was statistically significant for 5 years after the first diagnosis.The associations between chemotherapy and tamoxifen treatment and reduced risk for contralateral breast cancer appear to continue for 10 and 5 years, respectively, after the initial breast cancer is diagnosed. Ovarian suppression may have a role in the association between chemotherapy and reduced risk for contralateral breast cancer.

    View details for DOI 10.1093/jnci/djm267

    View details for Web of Science ID 000252603600010

    View details for PubMedID 18159070

  • Variants on 9p24 and 8q24 are associated with risk of colorectal cancer: Results from the colon cancer family registry CANCER RESEARCH Poynter, J. N., Figueiredo, J. C., Conti, D. V., Kennedy, K., Gallinger, S., Siegnumd, K. D., Casey, G., Thibodeau, S. N., Jenkins, M. A., Hopper, J. L., Byrnes, G. B., Baron, J. A., Goode, E. L., Tiirikainen, M., Lindor, N., Grove, J., Newcomb, P., Jass, J., Young, J., Potter, J. D., Haile, R. W., Duggan, D. J., Le Marchand, L. 2007; 67 (23): 11128-11132

    Abstract

    Recent publications have reported that common variants on 8q24 are associated with both prostate and colorectal cancers (CRC). In addition, one of these studies (the ARCTIC study) initially observed an association with a single nucleotide polymorphism (SNP) on 9p24 that was not confirmed in some of their validation data sets. In the research described here, we conducted a case-unaffected sibling analysis using population- and clinic-based discordant sibships (N = 1,567 sibships) from the Colon Cancer Family Registry (Colon CFR) to investigate the associations between common variants at 9p24 and 8q24 and risk of CRC. We also evaluated whether these associations differed by age, family history, and tumor characteristics, including microsatellite instability and tumor site. Associations were estimated using conditional logistic regression, treating sibship as the matching factor. Analyses were adjusted for age and sex, and stratified by ascertainment source (population versus clinic). We observed an association between a SNP on 9p24 (rs719725) and risk of CRC in the population-based series (AA versus CC: odds ratios, 1.46; 95% confidence interval, 1.06-2.02; AC versus CC: odds ratios, 1.50; 95% confidence interval, 1.14-1.98; P = 0.011 on 2 df). In the population-based series, we also detected statistically significant associations between two SNPs on 8q24, rs10505477 and rs6983267, and risk of CRC (P = 0.005 and P = 0.002, respectively). There was no evidence of statistically significant heterogeneity by age at diagnosis, family history of CRC, microsatellite instability, or tumor site at either locus and no evidence of interaction between SNPs on 8q24 and 9p24. These data suggest that common variants may play important roles in the risk of CRC.

    View details for DOI 10.1158/0008-5472.CAN-07-3239

    View details for Web of Science ID 000251444100008

    View details for PubMedID 18056436

  • Colon cancer family registry: An international resource for studies of the genetic epidemiology of colon cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Newcomb, P. A., Baron, J., Cotterchio, M., Gallinger, S., Grove, J., Haile, R., Hall, D., Hopper, J. L., Jass, J., Le Marchand, L., Limburg, P., Lindor, N., Potter, J. D., Templeton, A. S., Thibodeau, S., Seminara, D. 2007; 16 (11): 2331-2343

    Abstract

    Family studies have served as a cornerstone of genetic research on colorectal cancer.The Colorectal Cancer Family Registry (Colon CFR) is an international consortium of six centers in North America and Australia formed as a resource to support studies on the etiology, prevention, and clinical management of colorectal cancer. Differences in design and sampling schemes ensures a resource that covers the continuum of disease risk. Two separate recruitment strategies identified colorectal cancer cases: population-based (incident case probands identified by cancer registries; all six centers) and clinic-based (families with multiple cases of colorectal cancer presenting at cancer family clinics; three centers). At this time, the Colon CFR is in year 10 with the second phase of enrollment nearly complete. In phase I recruitment (1998-2002), population-based sampling ranged from all incident cases of colorectal cancer to a subsample based on age at diagnosis and/or family cancer history. During phase II (2002-2007), population-based recruitment targeted cases diagnosed before the age of 50 years are more likely attributable to genetic factors. Standardized protocols were used to collect information regarding family cancer history and colorectal cancer risk factors, and biospecimens were obtained to assess microsatellite instability (MSI) status, expression of mismatch repair proteins, and other molecular and genetic processes.Of the 8,369 case probands enrolled to date, 2,602 reported having one or more colorectal cancer-affected relatives and 799 met the Amsterdam I criteria for Lynch syndrome. A large number of affected (1,324) and unaffected (19,816) relatives were enrolled, as were population-based (4,108) and spouse (983) controls. To date, 91% of case probands provided blood (or, for a few, buccal cell) samples and 75% provided tumor tissue. For a selected sample of high-risk subjects, lymphocytes have been immortalized. Nearly 600 case probands had more than two affected colorectal cancer relatives, and 800 meeting the Amsterdam I criteria and 128, the Amsterdam II criteria. MSI testing for 10 markers was attempted on all obtained tumors. Of the 4,011 tumors collected in phase I that were successfully tested, 16% were MSI-high, 12% were MSI-low, and 72% were microsatellite stable. Tumor tissues from clinic-based cases were twice as likely as population-based cases to be MSI-high (34% versus 17%). Seventeen percent of phase I proband tumors and 24% of phase II proband tumors had some loss of mismatch repair protein, with the prevalence depending on sampling. Active follow-up to update personal and family histories, new neoplasms, and deaths in probands and relatives is nearly complete.The Colon CFR supports an evolving research program that is broad and interdisciplinary. The greater scientific community has access to this large and well-characterized resource for studies of colorectal cancer.

    View details for DOI 10.1158/1055-9965.EPI-07-0648

    View details for Web of Science ID 000251123500024

    View details for PubMedID 17982118

  • Accuracy of colorectal polyp self-reports: Findings from the colon cancer family registry CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Madlensky, L., Daftary, D., Burnett, T., Harmon, P., Jenkins, M., Maskiell, J., Nigon, S., Phillips, K., Templeton, A., Limburg, P. J., Haile, R. W., Potter, J. D., Gallinger, S., Baron, J. A. 2007; 16 (9): 1898-1901

    Abstract

    Colorectal adenomas and other types of polyps are commonly used as end points or risk factors in epidemiologic studies. However, it is not known how accurately patients are able to self-report the presence or absence of adenomas following colonoscopy.Participants in the Colon Cancer Family Registry provided self-reports of recent colorectal cancer (CRC) screening activity, and whether or not they had ever been told they had a polyp. Positive and negative predictive values for polyp self-report were calculated by comparing medical records with self-reports from 488 participants.The positive predictive value for self-reported polyp was 80.9%, and the negative predictive value was 85.8%. The predictive values did not differ by age group or sex, but participants with a previous diagnosis of CRC had a lower negative predictive value (76.2%) than participants with no personal history of CRC (89.0%; P = 0.04).Predictive values for self-reports of polyps are fairly high, but researchers needing accurate polyp data should obtain medical record confirmation. Pursuing medical records on only those participants self-reporting a polyp could result in an underestimation of the polyp prevalence in a study population.

    View details for DOI 10.1158/1055-9965.EPI-07-0151

    View details for Web of Science ID 000249643600030

    View details for PubMedID 17726139

  • Estrogen plus progestin use, microsatellite instability, and the risk of colorectal cancer in women CANCER RESEARCH Newcomb, P. A., Zheng, Y., Chia, V. M., Morimoto, L. M., Doria-Rose, V. P., Templeton, A., Thibodeau, S. N., Potter, J. D. 2007; 67 (15): 7534-7539

    Abstract

    Current users of postmenopausal hormones (PMH) have approximately 30% to 40% lower risk of colorectal cancer (CRC), although associations with specific types of hormones have been inconsistent. Further, it is not clear whether some tumor types have a different risk. We conducted a case-control study to examine the relationship between PMH and CRC. Cases (n = 1,004), ages 50 to 74 years, were identified from the Surveillance Epidemiology and End Results registry in Washington from 1998 to 2002; controls (n = 1,062) were randomly selected from population lists. Case tissue samples were obtained for microsatellite instability (MSI) analyses. Interviews collected risk-factor data for CRC, including detailed information on PMH. Multivariable logistic regression models estimated odds ratios (OR) and 95% confidence intervals (95% CI). Current use of any PMH was associated with a 20% reduction in CRC risk (95% CI 0.6-0.9). This reduction in risk was limited to women who had taken estrogen plus progestin (EP) preparations only (OR = 0.6, 95% CI 0.5-0.9); there was no association with estrogen-only (E alone) use (OR = 0.9, 95% CI 0.7-1.1). For women with MSI-low or MSI-stable tumors, there was a statistically significant 40% reduction in CRC risk associated with EP use (95% CI 0.4-0.9); there was no clear association with MSI-high tumors. EP use was associated with a decreased risk of CRC; however, there seemed to be no association with E alone data that are consistent with the recent Women's Health Initiative findings. Progestin may enhance the estrogenic effect of conjugated estrogen so the combination may be more biologically active in the colon than E alone.

    View details for DOI 10.1158/0008-5472.CAN-06-4275

    View details for Web of Science ID 000248529300058

    View details for PubMedID 17671225

  • Pathology features in Bethesda guidelines predict colorectal cancer microsatellite instability: A population-based study GASTROENTEROLOGY Jenkins, M. A., Hayashi, S., O'Shea, A., Burgart, L. J., Smyrk, T. C., Shimizu, D., Waring, P. M., Ruszkiewicz, A. R., Pollett, A. F., Redston, M., Barker, M. A., Baron, J. A., Casey, G. R., Dowty, J. G., Giles, G. G., Limburg, P., Newcomb, P., Young, J. P., Walsh, M. D., Thibodeau, S. N., Lindor, N. M., LeMarchand, L., Gallinger, S., Haile, R. W., Potter, J. D., Hopper, J. L., Jass, J. R. 2007; 133 (1): 48-56

    Abstract

    The revised Bethesda guidelines for Lynch syndrome recommend microsatellite instability (MSI) testing all colorectal cancers in patients diagnosed before age 50 years and colorectal cancers diagnosed in patients between ages 50 and 59 years with particular pathology features. Our aim was to identify pathology and other features that independently predict high MSI (MSI-H).Archival tissue from 1098 population-based colorectal cancers diagnosed before age 60 years was tested for MSI. Pathology features, site, and age at diagnosis were obtained. Multiple logistic regression was performed to determine the predictive value of each feature, as measured by an odds ratio (OR), from which a scoring system (MsPath) was developed to estimate the probability a colorectal cancer is MSI-H.Fifteen percent of tumors (162) were MSI-H. Independent predictors were tumor-infiltrating lymphocytes (OR, 9.1; 95% confidence interval [CI], 5.9-14.1), proximal subsite (OR, 4.7; 95% CI, 3.1-7.3), mucinous histology (OR, 2.8; 95% CI, 1.7-4.8), poor differentiation (OR, 1.9; 95% CI, 1.2-3.1), Crohn's-like reaction (OR, 1.9; 95% CI, 1.2-2.9), and diagnosis before age 50 years (OR, 1.9; 95% CI, 1.3-2.9). MsPath score >or=1.0 had a sensitivity of 93% and a specificity of 55% for MSI-H.The probability an individual colorectal cancer is MSI-H is predicted well by the MsPath score. There is little value in testing for DNA mismatch repair loss in tumors, or for germline mismatch repair mutations, for colorectal cancers diagnosed in patients before age 60 years with an MSPath score <1 (approximately 50%). Pathology can identify almost all MSI-H colorectal cancers diagnosed before age 60 years.

    View details for DOI 10.1053/j.gastro.2007.04.044

    View details for Web of Science ID 000248055400011

    View details for PubMedID 17631130

  • Folic acid for the prevention of colorectal adenomas - A randomized clinical trial JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Cole, B. F., Baron, J. A., Sandler, R. S., Haile, R. W., Ahnen, D. J., Bresalier, R. S., McKeown-Eyssen, G., Summers, R. W., Rothstein, R. I., Burke, C. A., Snover, D. C., Church, T. R., Allen, J. I., Robertson, D. J., Beck, G. J., Bond, J. H., Byers, T., Mandel, J. S., Mott, L. A., Pearson, L. H., Barry, E. L., Rees, J. R., Marcon, N., Saibil, F., Ueland, P. M., Greenberg, E. R. 2007; 297 (21): 2351-2359

    Abstract

    Laboratory and epidemiological data suggest that folic acid may have an antineoplastic effect in the large intestine.To assess the safety and efficacy of folic acid supplementation for preventing colorectal adenomas.A double-blind, placebo-controlled, 2-factor, phase 3, randomized clinical trial conducted at 9 clinical centers between July 6, 1994, and October 1, 2004. Participants included 1021 men and women with a recent history of colorectal adenomas and no previous invasive large intestine carcinoma.Participants were randomly assigned in a 1:1 ratio to receive 1 mg/d of folic acid (n = 516) or placebo (n = 505), and were separately randomized to receive aspirin (81 or 325 mg/d) or placebo. Follow-up consisted of 2 colonoscopic surveillance cycles (the first interval was at 3 years and the second at 3 or 5 years later).The primary outcome measure was occurrence of at least 1 colorectal adenoma. Secondary outcomes were the occurrence of advanced lesions (> or =25% villous features, high-grade dysplasia, size > or =1 cm, or invasive cancer) and adenoma multiplicity (0, 1-2, or > or =3 adenomas).During the first 3 years, 987 participants (96.7%) underwent colonoscopic follow-up, and the incidence of at least 1 colorectal adenoma was 44.1% for folic acid (n = 221) and 42.4% for placebo (n = 206) (unadjusted risk ratio [RR], 1.04; 95% confidence interval [CI], 0.90-1.20; P = .58). Incidence of at least 1 advanced lesion was 11.4% for folic acid (n = 57) and 8.6% for placebo (n = 42) (unadjusted RR, 1.32; 95% CI, 0.90-1.92; P = .15). A total of 607 participants (59.5%) underwent a second follow-up, and the incidence of at least 1 colorectal adenoma was 41.9% for folic acid (n = 127) and 37.2% for placebo (n = 113) (unadjusted RR, 1.13; 95% CI, 0.93-1.37; P = .23); and incidence of at least 1 advanced lesion was 11.6% for folic acid (n = 35) and 6.9% for placebo (n = 21) (unadjusted RR, 1.67; 95% CI, 1.00-2.80; P = .05). Folic acid was associated with higher risks of having 3 or more adenomas and of noncolorectal cancers. There was no significant effect modification by sex, age, smoking, alcohol use, body mass index, baseline plasma folate, or aspirin allocation.Folic acid at 1 mg/d does not reduce colorectal adenoma risk. Further research is needed to investigate the possibility that folic acid supplementation might increase the risk of colorectal neoplasia.clinicaltrials.gov Identifier: NCT00272324.

    View details for Web of Science ID 000247007200017

    View details for PubMedID 17551129

  • Reproductive history and risk of second primary breast cancer: The WECARE study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Largent, J. A., Capanu, M., Bernstein, L., Langholz, B., Mellemkjaer, L., Malone, K. E., Begg, C. B., Haile, R. W., Lynch, C. F., Anton-Culver, H., Wolitzer, A., Bernstein, J. L. 2007; 16 (5): 906-911

    Abstract

    Women with an initial breast cancer diagnosis are at elevated risk of developing subsequent cancer in the contralateral breast. Studies of reproductive factors and contralateral breast cancer (CBC) have provided inconsistent results.We employed a case-control study nested within five population-based cancer registries in the United States and Denmark to examine associations between reproductive history and CBC risk. Cases were women with asynchronous CBC who had their first primary invasive breast cancer before age 55 years. Two controls, who had only one primary breast cancer diagnosis, were individually matched to each case on age and year of diagnosis, race, and registry. A total of 694 case-control triplets and 11 case-control pairs were enrolled. Information regarding possible CBC risk factors was obtained via telephone interviews. Multivariable conditional logistic regression was used to estimate rate ratios (RR) and 95% confidence intervals (95% CI) associated with risk factors of interest.Increasing number of full-term pregnancies (FTP) was inversely associated with CBC risk (P trend, 0.001). Women who reported menarche before age 13 years had an increased risk of CBC (RR, 1.26; 95% CI, 1.01-1.58). Age at first FTP, breastfeeding history, and age at menopause were not significantly associated with CBC risk.These results suggest age at menarche and parity, which are established risk factors for first primary breast cancer, are associated with CBC, whereas other reproductive risk factors associated with first primary breast cancer, such as age at first FTP, are less important factors in the development of CBC.

    View details for DOI 10.1158/1055-9965.EPI-06-1003

    View details for Web of Science ID 000246649200011

    View details for PubMedID 17507614

  • Prolonged effect of calcium supplementation on risk of colorectal adenomas in a randomized trial JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE Grau, M. V., Baron, J. A., Sandler, R. S., Wallace, K., Haile, R. W., Church, T. R., Beck, G. J., Summers, R. W., Barry, E. L., Cole, B. F., Snover, D. C., Rothstein, R., Mandel, J. S. 2007; 99 (2): 129-136

    Abstract

    Calcium supplementation has been shown to decrease the risk of recurrence of colorectal adenomas in randomized trials. However, the duration of this protective effect after cessation of active supplementation is not known.In the Calcium Polyp Prevention Study, 930 subjects with a previous colorectal adenoma were randomly assigned from November 1988 through April 1992 to receive placebo or 1200 mg of elemental calcium daily for 4 years. The Calcium Follow-up Study was an observational phase of the trial that tracked adenoma occurrence for an average of 7 years after the end of randomized treatment and gathered information regarding the use of medications, vitamins, and supplements during that time. We obtained follow-up information for 822 subjects, 597 of whom underwent at least one colonoscopy after the end of study treatment and are included in this analysis. Generalized linear models were used to compute relative risks (RRs) and 95% confidence intervals (CIs) for the effect of randomized calcium treatment on risk of adenoma recurrence during the first 5 years after study treatment ended and during the subsequent 5 years. Statistical tests were two-sided.During the first 5 years after randomized treatment ended, subjects in the calcium group still had a substantially and statistically significantly lower risk of any adenoma than those in the placebo group (31.5% versus 43.2%; adjusted RR = 0.63, 95% CI = 0.46 to 0.87, P = .005) and a smaller and not statistically significant reduction in risk of advanced adenomas (adjusted RR = 0.85, 95% CI = 0.43 to 1.69, P = .65). However, the randomized treatment was not associated with the risk of any type of polyp during the next 5 years. The findings were broadly similar when the analysis was restricted to subjects who did not report use of any calcium supplements after the treatment phase of the trial ended.The protective effect of calcium supplementation on risk of colorectal adenoma recurrence extends up to 5 years after cessation of active treatment, even in the absence of continued supplementation.

    View details for DOI 10.1093/jnci/dik016

    View details for Web of Science ID 000243528300009

    View details for PubMedID 17227996

  • Aspirin may be more effective in preventing colorectal adenomas in patients with higher BMI (United States) CANCER CAUSES & CONTROL Kim, S., Baron, J. A., Mott, L. A., Burke, C. A., Church, T. R., McKeown-Eyssen, G. E., Cole, B. F., Haile, R. W., Sandler, R. S. 2006; 17 (10): 1299-1304

    Abstract

    Obesity is a risk factor for colon cancer, possibly due to elevated levels of circulating cytokines derived from adipose tissue. Aspirin, which may affect the levels of these cytokines, has been shown in randomized controlled trials to decrease the risk of colorectal adenomas. We hypothesized that the chemopreventive effect of aspirin might be greater in individuals with higher body mass index (BMI). Data were available from the Aspirin/Folate Polyp Prevention Study, a randomized controlled trial of aspirin and folic acid to prevent recurrent colorectal adenomas. Obesity was defined as BMI > or = 30 (kg/m2), overweight as BMI of 25-29 (kg/m2) and normal weight as BMI <25 (kg/m2). For the analysis of the effect of aspirin on the recurrence of colorectal adenoma by BMI, we computed risk ratios for aspirin versus placebo within the three BMI strata using a modified Poisson model. Overall the risk reduction of adenomas with a daily dose of 325 mg aspirin was greater among subjects with higher BMI. Among obese subjects the risk ratio (RR) for advanced adenomas compared with placebo was 0.44 (95% CI 0.17-1.10), versus RR = 1.23 (95% CI 0.55-2.77) among those with normal weight. However, 81 mg aspirin daily did not interact with BMI to modify the risk of adenomas in such a fashion. The more pronounced effect of 325 mg aspirin in individuals with higher BMI suggests a possible protective role of anti-inflammatory aspirin against increased adipose-driven cytokines among obese subjects.

    View details for DOI 10.1007/s10552-006-0075-x

    View details for Web of Science ID 000242145700011

    View details for PubMedID 17111262

  • XRCC1, XRCC3, and XPD polymorphisms as modifiers of the effect of smoking and alcohol on colorectal adenoma risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Stern, M. C., Siegmund, K. D., Conti, D. V., Corral, R., Haile, R. W. 2006; 15 (12): 2384-2390

    Abstract

    Using a sigmoidoscopy-based case-control study (753 cases, 799 controls) in Los Angeles County, we investigated the potential modifier role in the effect of alcohol and smoking of single-nucleotide polymorphisms (SNP) in three DNA repair genes, XRCC1 (Arg194Trp and Arg399Gln), XRCC3 (Thr241Met), and XPD (Lys751Gln). We have previously reported an inverse association between the XRCC1 codon 399 SNP and adenoma risk among these subjects. We now report that subjects with the XPD Gln/Gln genotype were inversely associated with adenoma risk [odds ratio (OR), 0.7; 95% confidence interval (95% CI), 0.5-1.0] when compared with subjects with the Lys/Lys and Lys/Gln genotypes combined. This association differed between different ethnic groups (gene x race heterogeneity likelihood ratio test, P = 0.009), with a stronger inverse association among Latinos (OR, 0.1; 95% CI, 0.01-0.5) than among non-Latinos (OR, 0.9; 95% CI, 0.-1.3). We found no evidence of an XRCC3 x smoking or alcohol interaction or an XRCC1 x alcohol interaction. Instead, our data supported an XRCC1 x smoking interaction (P = 0.048). Whereas XPD did not modify the effect of smoking, our data suggested an XPD x alcohol interaction. Analyses ignoring XPD showed no association between alcohol intake and adenoma prevalence; however, among carriers of the codon 751 Gln/Gln genotype, we found a significant positive association (OR, 2.5; 95% CI, 1.2-5.2 for ever drinkers; test of interaction P = 0.04). Our data suggest that the effects of smoking and alcohol may vary depending on the genetic background of proteins that participate in the base excision repair and nucleotide excision repair pathways.

    View details for DOI 10.1158/1055-9965.EPI-06-0381

    View details for Web of Science ID 000242984400012

    View details for PubMedID 17164360

  • Ornithine decarboxylase polymorphism modification of response to aspirin treatment for colorectal adenoma prevention JOURNAL OF THE NATIONAL CANCER INSTITUTE Barry, E. L., Baron, J. A., Bhat, S., Grau, M. V., Burke, C. A., Sandler, R. S., Ahnen, D. J., Haile, R. W., O'Brien, T. G. 2006; 98 (20): 1494-1500

    Abstract

    Previous research suggests that the G315A single-nucleotide polymorphism in the ornithine decarboxylase (ODC) gene may be a genetic marker for risk of colorectal neoplasia and may also modify the association of aspirin use with risk.We tested these hypotheses among participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or to aspirin treatment (81 or 325 mg daily) and followed for 3 years for the occurrence of new adenomas. Genomic DNA from 973 subjects was analyzed for ODC genotype. Relative risks (RRs) and 95% confidence intervals (CIs) were calculated to test the association between ODC genotype and adenoma occurrence and interactions with aspirin treatment. All statistical tests were two-sided.Of the 973 subjects, 54% were homozygous wild-type (GG), 7% were homozygous variant (AA), and 39% were heterozygous individuals; the allele frequencies varied statistically significantly by race and ethnicity. Among these subjects, the absolute risk of any adenoma was 45% and the risk of an advanced lesion was 10%. Overall, no association was found between ODC genotype and the occurrence of new adenomas, but genotype did modify the effect of aspirin on adenoma risk. Although aspirin treatment had no protective effect among subjects with a GG genotype, among subjects with at least one A allele, it was associated with statistically significant reduced risks of any adenoma (RR = 0.77, 95% CI = 0.63 to 0.95; P = .02, P(interaction) = .04) and of advanced lesions (RR = 0.51, 95% CI = 0.29 to 0.90; P = .02, P(interaction) = .02). Among subjects with at least one A allele, 40.8% who took aspirin versus 52.9% who took placebo developed adenomas; 7.1% versus 14.0% developed advanced lesions.ODC genotype may modify the response to aspirin treatment for colorectal adenoma prevention.

    View details for DOI 10.1093/jnci/djj398

    View details for Web of Science ID 000241721400013

    View details for PubMedID 17047198

  • BRCA1 and BRCA2 mutation carriers, oral contraceptive use, and breast cancer before age 50 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Haile, R. W., Thomas, D. C., McGuire, V., Felberg, A., John, E. M., Milne, R. L., Hopper, J. L., Jenkins, M. A., Levine, A. J., Daly, M. M., Buys, S. S., Senie, R. T., Andrulis, I. L., Knight, J. A., Godwin, A. K., Southey, M., McCredie, M. R., Giles, G. G., Andrews, L., Tucker, K., Miron, A., Apicella, C., Tesoriero, A., Bane, A., Pike, M. C., Whittemore, A. S. 2006; 15 (10): 1863-1870

    Abstract

    Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice.We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years.For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77; 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (P(trend) = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62; 95% CI, 0.90-2.92); however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06; 95% CI, 1.08-3.94) and with duration of use (OR(trend) per year of use, 1.08; P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later.We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue.

    View details for DOI 10.1158/1055-9965.EPI-06-0258

    View details for Web of Science ID 000241616800019

    View details for PubMedID 17021353

  • No increased risk of breast cancer associated with alcohol consumption among carriers of BRCA1 and BRCA2 mutations ages < 50 years CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McGuire, V., John, E. M., Felberg, A., Haile, R. W., Boyd, N. F., Thomas, D. C., Jenkins, M. A., Milne, R. L., Daly, M. B., Ward, J., Terry, M. B., Andrulis, I. L., Knight, J. A., Godwin, A. K., Giles, G. G., Southey, M., West, D. W., Hopper, J. L., Whittemore, A. S. 2006; 15 (8): 1565-1567
  • CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer NATURE GENETICS Weisenberger, D. J., D Siegmund, K., Campan, M., Young, J., Long, T. I., Faasse, M. A., Kang, G. H., Widschwendter, M., Weener, D., Buchanan, D., Koh, H., Simms, L., Barker, M., Leggett, B., Levine, J., Kim, M., French, A. J., Thibodeau, S. N., Jass, J., Haile, R., Laird, P. W. 2006; 38 (7): 787-793

    Abstract

    Aberrant DNA methylation of CpG islands has been widely observed in human colorectal tumors and is associated with gene silencing when it occurs in promoter areas. A subset of colorectal tumors has an exceptionally high frequency of methylation of some CpG islands, leading to the suggestion of a distinct trait referred to as 'CpG island methylator phenotype', or 'CIMP'. However, the existence of CIMP has been challenged. To resolve this continuing controversy, we conducted a systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology, involving 295 primary human colorectal tumors and 16,785 separate quantitative analyses. We found that CIMP-positive (CIMP+) tumors convincingly represent a distinct subset, encompassing almost all cases of tumors with BRAF mutation (odds ratio = 203). Sporadic cases of mismatch repair deficiency occur almost exclusively as a consequence of CIMP-associated methylation of MLH1 . We propose a robust new marker panel to classify CIMP+ tumors.

    View details for DOI 10.1038/ng1834

    View details for Web of Science ID 000238669300014

    View details for PubMedID 16804544

  • K-ras mutations in incident sporadic colorectal adenomas CANCER Barry, E. L., Baron, J. A., Grau, M. V., Wallace, K., Haile, R. W. 2006; 106 (5): 1036-1040

    Abstract

    Although K-ras is the most frequently mutated protooncogene in colorectal carcinoma, the specific role and timing of K-ras mutations in colorectal carcinogenesis remains controversial. In the current study, the authors investigated associations with K-ras mutation in incident sporadic colorectal adenomas that occurred during a chemoprevention trial of calcium supplementation.K-ras genotyping was performed on 303 colorectal adenomas that were removed from 207 participants during the follow-up phase of the Calcium Polyp Prevention Study. Mutations in codons 12 or 13 of K-ras were detected by denaturing high-performance liquid chromatography and were confirmed by direct sequencing.The adenomas analyzed had a mean estimated size of 0.5 cm, and 3.0% were identified with mutations (95% confidence interval [95% CI], 1.3-4.4%). These mutations were more common in larger adenomas (risk ratio [RR], 12.7 for tumors that measured > 0.5 cm vs. < or = 0.5 cm; 95% CI, 2.7-59.7), in adenomas with more advanced histology (RR, 20.6 for tubulovillous/villous vs. tubular; 95% CI, 4.4-96.0), and in adenomas that were located in the rectum compared with the colon (RR, 8.4; 95% CI, 2.3-30.5).Compared with previous studies, the current analysis was novel, because it focused on incident adenomas that were diagnosed within a few years of a previous "clean" colonoscopy. The results provided evidence for a very low rate of K-ras mutation among these small, early adenomas and strong support for a role of K-ras mutations in adenoma progression.

    View details for DOI 10.1002/cncr.21721

    View details for Web of Science ID 000235822700008

    View details for PubMedID 16456810

  • Genome-wide associations of gene expression variation in humans PLOS GENETICS Stranger, B. E., Forrest, M. S., Clark, A. G., Minichiello, M. J., Deutsch, S., Lyle, R., Hunt, S., Kahl, B., Antonarakis, S. E., Tavare, S., Deloukas, P., Dermitzakis, E. T. 2005; 1 (6): 695-704

    Abstract

    The exploration of quantitative variation in human populations has become one of the major priorities for medical genetics. The successful identification of variants that contribute to complex traits is highly dependent on reliable assays and genetic maps. We have performed a genome-wide quantitative trait analysis of 630 genes in 60 unrelated Utah residents with ancestry from Northern and Western Europe using the publicly available phase I data of the International HapMap project. The genes are located in regions of the human genome with elevated functional annotation and disease interest including the ENCODE regions spanning 1% of the genome, Chromosome 21 and Chromosome 20q12-13.2. We apply three different methods of multiple test correction, including Bonferroni, false discovery rate, and permutations. For the 374 expressed genes, we find many regions with statistically significant association of single nucleotide polymorphisms (SNPs) with expression variation in lymphoblastoid cell lines after correcting for multiple tests. Based on our analyses, the signal proximal (cis-) to the genes of interest is more abundant and more stable than distal and trans across statistical methodologies. Our results suggest that regulatory polymorphism is widespread in the human genome and show that the 5-kb (phase I) HapMap has sufficient density to enable linkage disequilibrium mapping in humans. Such studies will significantly enhance our ability to annotate the non-coding part of the genome and interpret functional variation. In addition, we demonstrate that the HapMap cell lines themselves may serve as a useful resource for quantitative measurements at the cellular level.

    View details for DOI 10.1371/journal.pgen.0010078

    View details for Web of Science ID 000234900800009

    View details for PubMedID 16362079

  • Role of lipid peroxidation in the epidemiology and prevention of breast cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Gago-Dominguez, M., Castelao, J. E., Pike, M. C., Sevanian, A., Haile, R. W. 2005; 14 (12): 2829-2839

    Abstract

    We have recently proposed a common mechanistic pathway by which obesity and hypertension lead to increased renal cell cancer risk. Our hypothesis posits lipid peroxidation, which is a principal mechanism in rodent renal carcinogenesis, as an intermediate step that leads to a final common pathway shared by numerous observed risks (including obesity, hypertension, smoking, oophorectomy/hysterectomy, parity, preeclampsia, diabetes, and analgesics) or protective factors (including oral contraceptive use and alcohol) for renal cell cancer [Cancer Causes Control 2002;13:287-93]. During this exercise, we have noticed how certain risk factors for renal cell carcinoma are protective for breast cancer and how certain protective factors for renal cell carcinoma increase risk for breast cancer. Parity and oophorectomy, for example, are positively associated with renal cell carcinoma but are negatively associated with breast cancer. Similarly, obesity and hypertension are positively associated with renal cell carcinoma, but obesity is negatively associated with breast cancer in premenopausal women and hypertension during pregnancy is negatively associated with breast cancer. Furthermore, alcohol intake, negatively associated with renal cell carcinoma, is also positively associated with breast cancer. We propose here the possibility that lipid peroxidation may represent a protective mechanism in breast cancer. Although this runs counter to the conventional view that lipid peroxidation is a process that is harmful and carcinogenic, we present here the chemical and biological rationale, based on epidemiologic and biochemical data, which may deserve further consideration and investigation.

    View details for DOI 10.1158/1055-9965.EPI-05-0015

    View details for Web of Science ID 000234055600003

    View details for PubMedID 16364997

  • Fat, fiber, meat and the risk of colorectal adenomas AMERICAN JOURNAL OF GASTROENTEROLOGY Robertson, D. J., Sandler, R. S., Haile, R., Tosteson, T. D., Greenberg, E. R., Grau, M., Baron, J. A. 2005; 100 (12): 2789-2795

    Abstract

    The aim of this study was to determine the relationship between fat, fiber, and meat intake, and risk of colorectal adenoma recurrence.We determined adenoma recurrence and dietary intake for 1,520 participants in two randomized trials: The Antioxidant Polyp Prevention Study and Calcium Polyp Prevention Study. Subjects underwent baseline colonoscopy with removal of all adenomas, and dietary intake was estimated with a validated semiquantitative food frequency questionnaire. Follow-up colonoscopy was performed 1 and 4 yr later. Pooled risk ratios for adenoma recurrence were obtained by generalized linear regression, with adjustment for age, sex, clinical center, treatment category, study, and duration of observation.In the total colorectum, fiber intake was weakly and nonsignificantly associated with a risk for all adenomas (RR quartile 4 vs quartile 1=0.85, 95% CI 0.69-1.05) and advanced adenomas (RR=0.88, 95% CI 0.54-1.44). Associations were stronger for adenomas in the proximal colon (RR=0.73, 95% CI 0.56-0.97) and some fiber subtypes (fruit and vegetable, grain). There was no association between fat or total red meat intake and risk of adenoma or advanced adenoma recurrence. However, when considering other meats, risk (quartile 4 vs quartile 1) for advanced adenoma was increased for processed meat (RR=1.75, 95% CI 1.02-2.99) and decreased for chicken (RR=0.61, 95% CI 0.38-0.98).The inverse associations between fiber intake and risk of adenoma recurrence we observed are weak, and not statistically significant. Our data indicate that intake of specific meats may have different effects on risk.

    View details for DOI 10.1111/j.1572-0241.2005.00336.x

    View details for Web of Science ID 000233627400031

    View details for PubMedID 16393237

  • Molecular predictors of lymph node metastasis in colon cancer: Increased risk with decreased thymidylate synthase expression JOURNAL OF GASTROINTESTINAL SURGERY Artinyan, A., Essani, R., Lake, J., Kaiser, A. M., Vukasin, P., Danenberg, P., Danenberg, K., Haile, R., Beart, R. W. 2005; 9 (9): 1216-1221

    Abstract

    TNM staging in colon cancer has several limitations. Prognostic molecular markers are now being developed to address these limitations. The aim of this study was to identify a combination of genes and markers whose expression is predictive of nodal status and outcome in colon cancer. The expression of 12 genetic markers were examined in 66 node-positive and 65 node-negative T3 colon cancers. Gene expression was quantified using real-time polymerase chain reaction. Microsatellite instability status was available through the registry. Association with lymph node status was examined using univariate and multivariate logistic regression. Thymidylate synthase expression was statistically significantly associated with lymph node status (odds ratio 0.36; 95% confidence interval: 0.16-0.81). Microsatellite instability and the other genes were not associated with nodal status. Multiple logistic regression did not identify a significant multivariate predictive model. Decreased expression of thymidylate synthase is associated with a higher risk of lymph node metastasis in patients with T3 colon cancers. Microsatellite instability and the expression of other genes are not predictive of nodal status in this population. Thymidylate synthase gene expression may help identify patients at greater risk for progression of disease.

    View details for DOI 10.1016/j.gassur.2005.06.028

    View details for Web of Science ID 000234336100005

    View details for PubMedID 16332476

  • Interaction of calcium supplementation and nonsteroidal anti-inflammatory drugs and the risk of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Grau, M. V., Baron, J. A., Barry, E. L., Sandler, R. S., Haile, R. W., Mandel, J. S., Cole, B. F. 2005; 14 (10): 2353-2358

    Abstract

    Calcium and aspirin have both been found to be chemopreventive against colorectal neoplasia. However, the joint effect of the two agents has not been well investigated.To explore the separate and joint effects of calcium and aspirin/nonsteroidal anti-inflammatory drugs (NSAID), we used data from two large randomized clinical trials among patients with a recent history of colorectal adenomas. In the Calcium Polyp Prevention Study, 930 eligible subjects were randomized to receive placebo or 1,200 mg of elemental calcium daily for 4 years. In the Aspirin/Folate Polyp Prevention Study, 1,121 eligible subjects were assigned to take placebo, 81 mg of aspirin, or 325 mg of aspirin daily for 3 years. In each study, subjects completed a validated food frequency questionnaire at enrollment and were asked periodically about medications and supplements used. Recurrent adenomas and advanced adenomas were the end points considered. We used generalized linear models to assess the separate and combined effects of aspirin (or NSAIDs) and calcium supplementation (or dietary calcium) and the interactions between these exposures.In the Calcium Trial, subjects randomized to calcium who also were frequent users of NSAIDs had a reduction of risk for advanced adenomas of 65% [adjusted risk ratio (RR), 0.35; 95% confidence interval (95% CI), 0.13-0.96], and there was a highly significant statistical interaction between calcium treatment and frequent NSAID use (P(interaction) = 0.01). Similarly, in the Aspirin Trial, 81 mg aspirin and calcium supplement use together conferred a risk reduction of 80% for advanced adenomas (adjusted RR, 0.20; 95% CI, 0.05-0.81); there was a borderline significant statistical interaction between the two treatments (P(interaction) = 0.09). In this trial, we found similar trends when we considered baseline dietary calcium intake instead of calcium supplements. For all adenomas considered together, the interactive patterns were not consistent.Data from two different randomized clinical trials suggest that calcium and NSAIDs may act synergistically to lower the risk of advanced colorectal neoplastic polyps.

    View details for DOI 10.1158/1055-9965.EPI-05-0003

    View details for Web of Science ID 000232473400012

    View details for PubMedID 16214916

  • Recent developments in genomewide association scans: A workshop summary and review AMERICAN JOURNAL OF HUMAN GENETICS Thomas, D. C., Haile, R. W., Duggan, D. 2005; 77 (3): 337-345

    Abstract

    With the imminent availability of ultra-high-volume genotyping platforms (on the order of 100,000-1,000,000 genotypes per sample) at a manageable cost, there is growing interest in the possibility of conducting genomewide association studies for a variety of diseases but, so far, little consensus on methods to design and analyze them. In April 2005, an international group of >100 investigators convened at the University of Southern California over the course of 2 days to compare notes on planned or ongoing studies and to debate alternative technologies, study designs, and statistical methods. This report summarizes these discussions in the context of the relevant literature. A broad consensus emerged that the time was now ripe for launching such studies, and several common themes were identified--most notably the considerable efficiency gains of multistage sampling design, specifically those made by testing only a portion of the subjects with a high-density genomewide technology, followed by testing additional subjects and/or additional SNPs at regions identified by this initial scan.

    View details for Web of Science ID 000231314100001

    View details for PubMedID 16080110

  • Colorectal cancer in patients under close colonoscopic surveillance GASTROENTEROLOGY Robertson, D. J., Greenberg, E. R., Beach, M., Sandler, R. S., Ahnen, D., Haile, R. W., Burke, C. A., Snover, D. C., Bresalier, R. S., McKeown-Eyssen, G., Mandel, J. S., Bond, J. H., van Stolk, R. U., Summers, R. W., Rothstein, R., Church, T. R., Cole, B. F., Byers, T., Mott, L., Baron, J. A. 2005; 129 (1): 34-41

    Abstract

    Colonoscopic polypectomy is considered effective for preventing colorectal cancer (CRC), but the incidence of cancer in patients under colonoscopic surveillance has rarely been investigated. We determined the incidence of CRC in patients under colonoscopic surveillance and examined the circumstances and risk factors for CRC and adenoma with high-grade dysplasia.Patients were drawn from 3 adenoma chemoprevention trials. All underwent baseline colonoscopy with removal of at least one adenoma and were deemed free of remaining lesions. We identified patients subsequently diagnosed with invasive cancer or adenoma with high-grade dysplasia. The timing, location, and outcome of all cases of cancer and high-grade dysplasia identified are described and risks associated with their development explored.CRC was diagnosed in 19 of the 2915 patients over a mean follow-up of 3.7 years (incidence, 1.74 cancers/1000 person-years). The cancers were located in all regions of the colon; 10 were at or proximal to the hepatic flexure. Although most of the cancers (84%) were of early stage, 2 participants died of CRC. Seven patients were diagnosed with adenoma with high-grade dysplasia during follow-up. Older patients and those with a history of more adenomas were at higher risk of being diagnosed with invasive cancer or adenoma with high-grade dysplasia.CRC is diagnosed in a clinically important proportion of patients following complete colonoscopy and polypectomy. More precise and representative estimates of CRC incidence and death among patients undergoing surveillance examinations are needed.

    View details for DOI 10.1053/j.gastro.2005.05.012

    View details for Web of Science ID 000230423100007

    View details for PubMedID 16012932

  • Lower cancer incidence in Amsterdam-I criteria families without mismatch repair deficiency - Familial colorectal cancer type X JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Lindor, N. M., Rabe, K., Petersen, G. M., Haile, R., Casey, G., Baron, J., Gallinger, S., Bapat, B., Aronson, M., Hopper, J., Jass, J., LeMarchand, L., Grove, J., Potter, J., Newcomb, P., Terdiman, J. P., Conrad, P., Moslein, G., Goldberg, R., Ziogas, A., Anton-Culver, H., de Andrade, M., Siegmund, K., Thibodeau, S. N., Boardman, L. A., Seminara, D. 2005; 293 (16): 1979-1985

    Abstract

    Approximately 60% of families that meet the Amsterdam-I criteria (AC-I) for hereditary nonpolyposis colorectal cancer (HNPCC) have a hereditary abnormality in a DNA mismatch repair (MMR) gene. Cancer incidence in AC-I families with MMR gene mutations is reported to be very high, but cancer incidence for individuals in AC-I families with no evidence of an MMR defect is unknown.To determine if cancer risks in AC-I families with no apparent deficiency in DNA MMR are different from cancer risks in AC-I families with DNA MMR abnormalities.Identification (1997-2001) of 161 AC-I pedigrees from multiple population- and clinic-based sources in North America and Germany, with families grouped into those with (group A) or without (group B) MMR deficiency by tumor testing. A total of 3422 relatives were included in the analyses.Cancer incidence in groups A and B (excluding the 3 affected members used to define each pedigree as AC-I) and computed age- and sex-adjusted standardized incidence ratios (SIRs) using Surveillance, Epidemiology, and End Results data.Group A families from both population- and clinic-based series showed increased incidence of the HNPCC-related cancers. Group B families showed increased incidence only for colorectal cancer (SIR, 2.3; 95% confidence interval, 1.7-3.0) and to a lesser extent than group A (SIR, 6.1; 95% confidence interval, 5.2-7.2) (P<.001).Families who fulfill AC-I criteria but who have no evidence of a DNA MMR defect do not share the same cancer incidence as families with HNPCC-Lynch syndrome (ie, hereditary MMR deficiency). Relatives in such families have a lower incidence of colorectal cancer than those in families with HNPCC-Lynch syndrome, and incidence may not be increased for other cancers. These families should not be described or counseled as having HNPCC-Lynch syndrome. To facilitate distinguishing these entities, the designation of "familial colorectal cancer type X" is suggested to describe this type of familial aggregation of colorectal cancer.

    View details for Web of Science ID 000228651500023

    View details for PubMedID 15855431

  • A molecular/epidemiologic analysis of expression of cyclooxygenases 1 and 2, use of nonsteroidal antiinflammatory drugs, and risk of colorectal adenoma. Clinical colorectal cancer Haile, R. W., Yochim, J. M., Cortessis, V. K., Lin, J., Levine, A. J., Diep, A., Danenberg, K., Danenberg, P. 2005; 4 (6): 390-395

    Abstract

    Nonsteroidal antiinflammatory drugs (NSAIDs) are postulated to protect against colorectal cancer and adenomas at least in part by a cyclooxygenase (COX-mediated mechanism. The results reported herein address the questions of what factors are associated with expression (relative messenger RNA levels) of COX-1 and COX-2 in colorectal adenomas and whether there is heterogeneity in the protective effect of NSAIDs by levels of COX expression. Paraffin-embedded tissue samples and data describing selected risk factors were obtained from cases enrolled in a case-control study of colorectal adenomatous polyps. RNA was isolated from paraffin-embedded specimens. Samples of complementary DNA were quantified using a fluorescence-based real-time detection method. We tested for differences in levels of COX expression among selected subgroups of cases using a standard Student t test. Odds ratios for the effects of NSAID variables were calculated using unconditional logistic regression in order to make use of all available data on COX expression. Results suggest that use of NSAIDs is associated with lower levels of COX-2 expression and that the protective effect of NSAIDs on polyp occurrence is stronger in the subgroup of cases with higher expression of COX-2 and a higher COX-2/COX-1 ratio. The results suggest that at least part of the protective effect of NSAIDs on the risk of colorectal adenoma involves a COX-mediated pathway.

    View details for PubMedID 15807932

  • Meat intake, cooking-related mutagens and risk of colorectal adenoma in a sigmoidoscopy-based case-control study CARCINOGENESIS Gunter, M. J., Probst-Hensch, N. M., Cortessis, V. K., Kulldorff, M., Haile, R. W., Sinha, R. 2005; 26 (3): 637-642

    Abstract

    Reported habits of red meat consumption, particularly red meat that has been cooked to the degree termed 'well-done', is a positive risk factor for colorectal cancer. Under high, pyrolytic temperatures, heterocyclic amines (HCA) and benzo[a]pyrene (BP) molecules can form inside and on the surface of red meat, respectively. These compounds are precursors that are metabolically converted to compounds known to act as mutagens and carcinogens in animal models, yet their role in human colorectal carcinogenesis remains to be clarified. We investigated whether intake of these compounds is associated with risk of colorectal adenoma in the context of a polyp-screening study conducted in Southern California. Using a database of individual HCAs and BP in meats of various types and subjected to specified methods and degrees of cooking, we estimated nanogram consumption of 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine, 2-amino-3,4,8-trimethylimidazo[4,5-f] quinoxaline, 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline and benzo[a]pyrene (BP). We observed a 6% increased risk of large (>1 cm) adenoma per 10 ng/day consumption of BP [OR = 1.06 (95% CI, 1.00-1.12), P (trend) = 0.04]. A major source of BP is red meat exposed to a naked flame, as occurs during the barbecuing process. Consistent with this finding an incremental increase of 10 g of barbecued red meat per day was associated with a 29% increased risk of large adenoma [OR = 1.29 (95% CI, 1.02-1.63), P (trend) = 0.04]. Individuals in the top quintile of barbecued red meat intake were at increased risk of large adenoma [OR = 1.90 (95% CI, 1.04-3.45)], compared with never consuming barbecued red meat. The consumption of oven-broiled red meat was inversely related to adenoma risk compared with non-consumers [OR = 0.49 (95% CI, 0.28-0.85)]. We did not identify any association with consumption of individual HCAs and colorectal adenoma risk. These results support the hypothesis that BP contributes to colorectal carcinogenesis.

    View details for DOI 10.1093/carcin/bgh350

    View details for Web of Science ID 000227242400016

    View details for PubMedID 15579480

  • XRCC1 and XRCC3 polymorphisms and their role as effect modifiers of unsaturated fatty acids and antioxidant intake on colorectal adenomas risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Stern, M. C., Siegmund, K. D., Corral, R., Haile, R. W. 2005; 14 (3): 609-615

    Abstract

    Whereas animal and in vitro studies support a role of unsaturated fatty acids in colon carcinogenesis, the epidemiologic evidence is inconclusive. Using a large sigmoidoscopy-based case-control study (753 cases and 799 controls) in Los Angeles County, we investigated possible associations between single-nucleotide polymorphisms in the XRCC1 (codons 194 Arg/Trp and codon 399 Arg/Gln) and XRCC3 (codon 241 Thr/Met) genes and colorectal adenoma risk and their possible role as modifiers of the effect of monounsaturated fatty acid, the ratio of omega-6/omega-3 polyunsaturated fatty acids, and antioxidant intake. We found no evidence of associations between the XRCC1 codon 194 Arg/Trp or Trp/Trp genotypes and the XRCC3 codon 241 Thr/Met or Met/Met genotypes. Subjects with the XRCC1 Gln/Gln genotype were inversely associated with adenoma risk (odds ratio, 0.6; 95% confidence interval, 0.4-0.9; P = 0.01) when compared with subjects with Arg/Arg and Arg/Gln genotypes combined. We found no evidence of gene-dietary fat interactions for the XRCC3 codon 241 polymorphism. However, our data suggest an XRCC1-unsaturated fat interaction. High monounsaturated fatty acid intake was associated with adenoma risk only among subjects with the XRCC1 codon 194 Arg/Arg and codon 399 Gln/Gln combined genotypes (P for interaction = 0.018). High omega-6/omega-3 polyunsaturated fatty acid ratios were associated with adenoma risk among subjects with the XRCC1 codon 194 Arg/Arg and codon 399 Gln/Gln or the codon 194 Arg/Trp or Trp/Trp and codon 399 Arg/Arg or Arg/Gln combined genotypes (P for interaction = 0.026). These interactions were not modified by antioxidant intake. However, low antioxidant intake was associated with an inverse association only among subjects with the XRCC1 codon 194 Arg/Trp or Trp/Trp and codon 399 Arg/Arg or Arg/Gln combined genotypes (P for interaction = 0.022), which was independent of unsaturated fat intake. Our data suggest that the XRCC1 codon 194 and codon 399 single nucleotide polymorphisms may modify the effect of unsaturated fatty acid and antioxidant intake and that this XRCC1 effect modification may explain, in part, previously reported inconsistencies on the role of unsaturated fatty acids and adenoma risk.

    View details for Web of Science ID 000227545900013

    View details for PubMedID 15767338

  • Conversion analysis for mutation detection in MLH1 and MSH2 in patients with colorectal cancer JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Casey, G., Lindor, N. M., Papadopoulos, N., Thibodeau, S. N., Moskow, J., Steelman, S., Buzin, C. H., SOMMER, S. S., Collins, C. E., Butz, M., Aronson, M., Gallinger, S., Barker, M. A., Young, J. P., JASS, J. R., Hopper, J. L., Diep, A., Bapat, B., Salem, M., Seminara, D., Haile, R. 2005; 293 (7): 799-809

    Abstract

    The accurate identification and interpretation of germline mutations in mismatch repair genes in colorectal cancer cases is critical for clinical management. Current data suggest that mismatch repair mutations are highly heterogeneous and that many mutations are not detected when conventional DNA sequencing alone is used.To evaluate the potential of conversion analysis compared with DNA sequencing alone to detect heterogeneous germline mutations in MLH1, MSH2, and MSH6 in colorectal cancer patients.Multicenter study with patients who participate in the Colon Cancer Family Registry. Mutation analyses were performed in participant samples determined to have a high probability of carrying mismatch repair germline mutations. Samples from a total of 64 hereditary nonpolyposis colorectal cancer cases, 8 hereditary nonpolyposis colorectal cancer-like cases, and 17 cases diagnosed prior to age 50 years were analyzed from June 2002 to June 2003.Classification of family members as carriers or noncarriers of germline mutations in MLH1, MSH2, or MSH6; mutation data from conversion analysis compared with genomic DNA sequencing.Genomic DNA sequencing identified 28 likely deleterious exon mutations, 4 in-frame deletion mutations, 16 missense changes, and 22 putative splice site mutations. Conversion analysis identified all mutations detected by genomic DNA sequencing--plus an additional exon mutation, 12 large genomic deletions, and 1 exon duplication mutation--yielding an increase of 33% (14/42) in diagnostic yield of deleterious mutations. Conversion analysis also showed that 4 of 16 missense changes resulted in exon skipping in transcripts and that 17 of 22 putative splice site mutations affected splicing or mRNA transcript stability. Conversion analysis provided an increase of 56% (35/63) in the diagnostic yield of genetic testing compared with genomic DNA sequencing alone.The data confirm the heterogeneity of mismatch repair mutations and reveal that many mutations in colorectal cancer cases would be missed using conventional genomic DNA sequencing alone. Conversion analysis substantially increases the diagnostic yield of genetic testing for mismatch repair mutations in patients diagnosed as having colorectal cancer.

    View details for Web of Science ID 000226984600021

    View details for PubMedID 15713769

  • Breast cancer risks for BRCA1/2 carriers SCIENCE Easton, D. F., Hopper, J. L., Thomas, D. C., Antoniou, A., Pharoah, P. D., Whittemore, A. S., Haile, R. W. 2004; 306 (5705): 2187-2188

    View details for Web of Science ID 000225950000015

    View details for PubMedID 15622557

  • Effect of calcium supplementation on the risk of large bowel polyps JOURNAL OF THE NATIONAL CANCER INSTITUTE Wallace, K., Baron, J. A., Cole, B. F., Sandler, R. S., Karagas, M. R., Beach, M. A., Haile, R. W., Burke, C. A., Pearson, L. H., Mandel, J. S., Rothstein, R., Snover, D. C. 2004; 96 (12): 921-925

    Abstract

    Clinical trials have shown that calcium supplementation modestly decreases the risk of colorectal adenomas. However, few studies have examined the effect of calcium on the risk of different types of colorectal lesions or dietary determinants of this effect.Our analysis used patients from the Calcium Polyp Prevention Study, a randomized, double-blind, placebo-controlled chemoprevention trial among patients with a recent colorectal adenoma. Nine hundred thirty patients were randomly assigned to calcium carbonate (1200 mg/day) or placebo. Follow-up colonoscopies were conducted approximately 1 and 4 years after the qualifying examination. We used general estimating equation (GEE) and generalized linear regression analyses to compute risk ratios and 95% confidence intervals (CIs) to assess the effect of calcium treatment versus placebo on the risk of hyperplastic polyps, tubular adenomas, and more advanced lesions. Additionally, we used GEE analyses to compare the calcium treatment effects for various types of polyps with that for tubular adenomas. We also examined the interaction between calcium treatment and baseline intake of dietary calcium, fat, and fiber. All P values were obtained using Wald tests based on the corresponding models. All tests of statistical significance were two-sided.The calcium risk ratio for hyperplastic polyps was 0.82 (95% CI = 0.67 to 1.00), that for tubular adenomas was 0.89 (95% CI = 0.77 to 1.03), and that for histologically advanced neoplasms was 0.65 (95% CI = 0.46 to 0.93) compared with patients assigned to placebo. There were no statistically significant differences between the risk ratio for tubular adenomas and that for other types of polyps. The effect of calcium supplementation on adenoma risk was most pronounced among individuals with high dietary intakes of calcium and fiber and with low intake of fat, but the interactions were not statistically significant.Our results suggest that calcium supplementation may have a more pronounced antineoplastic effect on advanced colorectal lesions than on other types of polyps.

    View details for DOI 10.1093/jnci/djh165

    View details for Web of Science ID 000222340900011

    View details for PubMedID 15199111

  • Study design: Evaluating gene-environment interactions in the etiology of breast cancer - the WECARE study BREAST CANCER RESEARCH Bernstein, J. L., Langholz, B., Haile, R. W., Bernstein, L., Thomas, D. C., Stovall, M., Malone, K. E., Lynch, C. F., Olsen, J. H., Anton-Culver, H., Shore, R. E., Boice, J. D., Berkowitz, G. S., GATTI, R. A., Teitelbaum, S. L., Smith, S. A., Rosenstein, B. S., Borresen-Dale, A. L., Concannon, P. 2004; 6 (3): R199-R214

    Abstract

    Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.Our study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhanced our ability to detect radiation-genotype interactions.

    View details for DOI 10.1186/bcr771

    View details for Web of Science ID 000221068500015

    View details for PubMedID 15084244

  • Vitamin D, calcium supplementation, and colorectal adenomas: Results of a randomized trial JOURNAL OF THE NATIONAL CANCER INSTITUTE Grau, M. V., Baron, J. A., Sandler, R. S., Haile, R. W., Beach, M. L., Church, T. R., Heber, D. 2003; 95 (23): 1765-1771

    Abstract

    Calcium and vitamin D both appear to have antineoplastic effects in the large bowel. Although these nutrients are inter-related metabolically in bone and in the normal intestine, their potential interactions in large-bowel carcinogenesis are not well understood.We assessed independent and joint effects of calcium supplementation and vitamin D status on adenoma recurrence in 803 subjects in a multi-center, placebo-controlled randomized clinical trial of calcium supplementation for the prevention of colorectal adenoma recurrence. Serum levels of 25-hydroxy [25-(OH)] vitamin D and 1,25-dihydroxy [1,25-(OH)2] vitamin D levels were determined, and the Taq I and Fok I polymorphisms in the vitamin D receptor (VDR) gene were analyzed by polymerase chain reaction. Risk ratios (RRs) for any adenoma recurrence were computed for calcium supplementation within groups defined by serum vitamin D levels and for serum vitamin D levels within treatment groups. Associations of VDR polymorphisms with recurrence risk were also evaluated. All statistical tests were two-sided.Among subjects with baseline 25-(OH) vitamin D levels at or below the median (29.1 ng/mL), calcium supplementation was not associated with adenoma recurrence, whereas among those with levels above the median, calcium supplementation was associated with a reduced risk (RR = 0.71, 95 % confidence interval [CI] = 0.57 to 0.89, P for interaction =.012). Conversely, serum 25-(OH) vitamin D levels were associated with a reduced risk only among subjects receiving calcium supplements (RR per 12 ng/mL increase of vitamin D = 0.88, 95% CI = 0.77 to 0.99, P for interaction =.006). VDR polymorphisms were not related to adenoma recurrence and did not modify the associations with vitamin D or calcium.Calcium supplementation and vitamin D status appear to act largely together, not separately, to reduce the risk of colorectal adenoma recurrence. VDR genotype does not appear to be associated with risk.

    View details for DOI 10.1093/jnci/djg110

    View details for Web of Science ID 000187080700010

    View details for PubMedID 14652238

  • ATM variants 7271T > G and IVS10-6T > G among women with unilateral and bilateral breast cancer BRITISH JOURNAL OF CANCER Bernstein, J. L., Bernstein, L., Thompson, W. D., Lynch, C. F., Malone, K. E., Teitelbaum, S. L., Olsen, J. H., Anton-Culver, H., Boice, J. D., Rosenstein, B. S., Borresen-Dale, A. L., GATTI, R. A., Concannon, P., Haile, R. W. 2003; 89 (8): 1513-1516

    Abstract

    Recent reports suggest that two ATM gene mutations, 7271T>G and IVS10-6T>G, are associated with a high risk of breast cancer among multiple-case families. To assess the importance of these two mutations in another 'high-risk' group, young women (under age 51) with multiple primaries, we screened a large population-based series of young women with bilateral breast cancer and compared the frequency of these mutations among similar women diagnosed with unilateral breast cancer. The 1149 women included were enrolled in an ongoing population-based case-control study of the genetic factors that contribute to bilateral breast cancer; they were not selected on the basis of family history of cancer. Screening for 7271T>G and IVS10-6T>G ATM gene mutations was conducted using DHPLC followed by direct sequencing. The 7271T>G mutation was detected in one out of 638 (0.2%) women with unilateral breast cancer and in none of the bilateral cases, and the IVS10-6T>G mutation in one out of 511 (0.2%) bilateral and in eight out of 638 (1.3%) unilateral breast cancer cases. Carriers of either mutation were not limited to women with a family history. Given the likelihood that young women with bilateral breast cancer have a genetic predisposition, the observed mutation distribution is contrary to that expected if these two mutations were to play an important role in breast carcinogenesis among individuals at high risk.

    View details for DOI 10.1038/sj.bjc.6601289

    View details for Web of Science ID 000186189300023

    View details for PubMedID 14562025

  • Neoplastic and antineoplastic effects of beta-carotene on colorectal adenoma recurrence: Results of a randomized trial JOURNAL OF THE NATIONAL CANCER INSTITUTE Baron, J. A., Cole, B. F., Mott, L., Haile, R., Grau, M., Church, T. R., Beck, G. J., Greenberg, E. R. 2003; 95 (10): 717-722

    Abstract

    In two large, randomized prevention trials, supplementation with beta-carotene increased the risk of lung cancer. Subjects in these studies were predominantly cigarette smokers, and the adverse effects were concentrated among those who also drank alcohol. Although beta-carotene supplementation appeared not to increase the risk of cancer generally, it is not clear if smoking and/or alcohol use alters the effect of beta-carotene on carcinogenesis at sites outside the lung.We studied the effect of beta-carotene supplementation on colorectal adenoma recurrence among subjects in a multicenter double-blind, placebo-controlled clinical trial of antioxidants for the prevention of colorectal adenomas. A total of 864 subjects who had had an adenoma removed and were polyp-free were randomly assigned (in a factorial design) to receive beta-carotene (25 mg or placebo) and/or vitamins C and E in combination (1000 mg and 400 mg, respectively, or placebo), and were followed with colonoscopy for adenoma recurrence 1 year and 4 years after the qualifying endoscopy. A total of 707 subjects had two follow-up examinations and provided smoking and alcohol use data. Adjusted multivariate risk ratios (RRs) and 95% confidence intervals (CIs) were used to assess the effects of beta-carotene on adenoma recurrence.Among subjects who neither smoked cigarettes nor drank alcohol, beta-carotene was associated with a marked decrease in the risk of one or more recurrent adenomas (RR = 0.56, 95% CI = 0.35 to 0.89), but beta-carotene supplementation conferred a modest increase in the risk of recurrence among those who smoked (RR = 1.36, 95% CI = 0.70 to 2.62) or drank (RR = 1.13, 95% CI = 0.89 to 1.43). For participants who smoked cigarettes and also drank more than one alcoholic drink per day, beta-carotene doubled the risk of adenoma recurrence (RR = 2.07, 95% CI = 1.39 to 3.08; P for difference from nonsmoker/nondrinker RR <.001).Alcohol intake and cigarette smoking appear to modify the effect of beta-carotene supplementation on the risk of colorectal adenoma recurrence.

    View details for Web of Science ID 000183040500008

    View details for PubMedID 12759389

  • Designing and implementing quality control for multi-center screening of mutations in the ATM gene among women with breast cancer HUMAN MUTATION Bernstein, J. L., Teraoka, S., Haile, R. W., Borresen-Dale, A. L., Rosenstein, B. S., GATTI, R. A., Diep, A. T., Jansen, L., Atencio, D. R., Olsen, J. H., Bernstein, L., Teitelbaum, S. L., Thompson, W. D., Concannon, P. 2003; 21 (5): 542-550

    Abstract

    Epidemiologic studies of breast and other cancers are increasingly turning toward large, multi-center designs in order to obtain adequate power to detect low-penetrance susceptibility alleles. The size of such studies often makes it necessary to distribute the genetic screening efforts to multiple sites. Careful standardization of screening methodology and quality control across sites is required for such multi-center screening designs to be efficient. In this report, we illustrate our approach to these challenges in the context of the WECARE (Women's Environment, Cancer and Radiation Epidemiology) Study, a multi-center population-based genetic epidemiologic study of women with unilateral and bilateral breast cancer. We provide optimized conditions for screening the ataxia-telangiectasia gene (ATM) for variation by denaturing high-performance liquid chromatography (DHPLC) and describe the results of two independent quality control studies at four international centers employing these conditions. Finally, we report novel mutations in the ATM gene identified both in patients with ataxia-telangiectasia and in patients with unilateral or bilateral breast cancer.

    View details for DOI 10.1002/humu.10206

    View details for Web of Science ID 000182557500011

    View details for PubMedID 12673797

  • A randomized trial of aspirin to prevent colorectal adenomas NEW ENGLAND JOURNAL OF MEDICINE Baron, J. A., Cole, B. F., Sandler, R. S., Haile, R. W., Ahnen, D., Bresalier, R., McKeown-Eyssen, G., Summers, R. W., Rothstein, R., Burke, C. A., Snover, D. C., Church, T. R., Allen, J. I., Beach, M., Beck, G. J., Bond, J. H., Byers, T., Greenberg, E. R., Mandel, J. S., Marcon, N., Mott, L. A., Pearson, L., Saibil, F., van Stolk, R. U. 2003; 348 (10): 891-899

    Abstract

    Laboratory and epidemiologic data suggest that aspirin has an antineoplastic effect in the large bowel.We performed a randomized, double-blind trial of aspirin as a chemopreventive agent against colorectal adenomas. We randomly assigned 1121 patients with a recent history of histologically documented adenomas to receive placebo (372 patients), 81 mg of aspirin (377 patients), or 325 mg of aspirin (372 patients) daily. According to the protocol, follow-up colonoscopy was to be performed approximately three years after the qualifying endoscopy. We compared the groups with respect to the risk of one or more neoplasms (adenomas or colorectal cancer) at least one year after randomization using generalized linear models to compute risk ratios and 95 percent confidence intervals.Reported adherence to study medications and avoidance of nonsteroidal antiinflammatory drugs were excellent. Follow-up colonoscopy was performed at least one year after randomization in 1084 patients (97 percent). The incidence of one or more adenomas was 47 percent in the placebo group, 38 percent in the group given 81 mg of aspirin per day, and 45 percent in the group given 325 mg of aspirin per day (global P=0.04). Unadjusted relative risks of any adenoma (as compared with the placebo group) were 0.81 in the 81-mg group (95 percent confidence interval, 0.69 to 0.96) and 0.96 in the 325-mg group (95 percent confidence interval, 0.81 to 1.13). For advanced neoplasms (adenomas measuring at least 1 cm in diameter or with tubulovillous or villous features, severe dysplasia, or invasive cancer), the respective relative risks were 0.59 (95 percent confidence interval, 0.38 to 0.92) and 0.83 (95 percent confidence interval, 0.55 to 1.23).Low-dose aspirin has a moderate chemopreventive effect on adenomas in the large bowel.

    View details for Web of Science ID 000181341100004

    View details for PubMedID 12621133

  • Alcohol, tobacco and breast cancer - collaborative reanalysis of individual data from 53 epidemiological studies, including 58515 women with breast cancer and 95067 women without the disease BRITISH JOURNAL OF CANCER Beral, V., Hamajima, N., Hirose, K., Rohan, T., Calle, E. E., Heath, C. W., Coates, R. J., Liff, J. M., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Morabia, A., Schuman, L., Stewart, W., Szklo, M., Bain, C., Schofield, F., Siskind, V., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Kolonel, L. M., Nomura, A. M., Hu, J., Johnson, K. C., Mao, Y., De Sanjose, S., Lee, N., Marchbanks, P., Ory, H. W., Peterson, H. B., Wilson, H. G., Wingo, P. A., Ebeling, K., Kunde, D., Nishan, P., Hopper, J. L., Colditz, G., Gajalakshmi, V., Martin, N., PARDTHAISONG, T., Solpisornkosol, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., Ewertz, M., Adami, H. O., Bergkvist, L., Magnusson, C., Persson, I., Chang-Claude, J., Paul, C., Skegg, D. C., Spears, G. F., Boyle, P., Evstifeeva, T., Daling, J. R., Hutchinson, W. B., Malone, K., NOONAN, E. A., Stanford, J. L., Thomas, D. B., Weiss, N. S., White, E., Andrieu, N., Bremond, A., Clavel, F., Gairard, B., Lansac, J., Piana, L., Renaud, R., Izquierdo, A., Viladiu, P., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., Arsitizabal, N., Cuadros, A., Tryggvadottir, L., Tulinius, H., Bachelot, A., Le, M. G., Peto, J., Franceschi, S., Lubin, F., Modan, B., Ron, E., Wax, Y., Friedman, G. D., Hiatt, R. A., Levi, F., Bishop, T., Kosmelj, K., Primic-Zakelj, M., Ravnihar, B., Stare, J., Beeson, W. L., Fraser, G., Bulbrook, R. D., Cuzick, J., Duffy, S. W., Fentiman, I. S., Hayward, J. L., Wang, D. Y., McMichael, A. J., McPherson, K., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. O., Weinstein, A. L., Moller, T. R., Olsson, H., Ranstam, J., Goldbohm, R. A., van den Brandt, P. A., APELO, R. A., BAENS, J., de la Cruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., La Vecchia, C., Negri, E., Marubini, E., Ferraroni, M., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Hoover, R., Schairer, C., Spirtas, R., Lee, H. P., Rookus, M. A., van Leeuwen, F. E., Schoenberg, J. A., McCredie, M., Gammon, M. D., Clarke, E. A., Jones, L., Neil, A., Vessey, M., Yeates, D., Appleby, P., Banks, E., Bull, D., Crossley, B., Goodill, A., Green, J., Hermon, C., Key, T., Langston, N., Lewis, C., Reeves, G., Collins, R., DOLL, R., Peto, R., Mabuchi, K., Preston, D., Hannaford, P., Kay, C., Rosero-Bixby, L., Gao, Y. T., Jin, F., Yuan, J. M., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., Cooper Booth, J., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., WANG, Q. S., Baines, C. J., Miller, A. B., WALL, C., Lund, E., Stalsberg, H., Shu, X. O., Zheng, W., Katsouyanni, K., Trichopoulou, A., Trichopoulos, D., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, X. E., Anderson, K., Folsom, A. R., Hulka, B. S., Bernstein, L., Enger, S., Haile, R. W., Paganini-Hill, A., Pike, M. C., Ross, R. K., Ursin, G., Yu, M. C., Longnecker, M. P., Newcomb, P., Bergkvist, L., Kalache, A., Farley, T. M., Holck, S., MEIRIK, O. 2002; 87 (11): 1234-1245

    Abstract

    Alcohol and tobacco consumption are closely correlated and published results on their association with breast cancer have not always allowed adequately for confounding between these exposures. Over 80% of the relevant information worldwide on alcohol and tobacco consumption and breast cancer were collated, checked and analysed centrally. Analyses included 58,515 women with invasive breast cancer and 95,067 controls from 53 studies. Relative risks of breast cancer were estimated, after stratifying by study, age, parity and, where appropriate, women's age when their first child was born and consumption of alcohol and tobacco. The average consumption of alcohol reported by controls from developed countries was 6.0 g per day, i.e. about half a unit/drink of alcohol per day, and was greater in ever-smokers than never-smokers, (8.4 g per day and 5.0 g per day, respectively). Compared with women who reported drinking no alcohol, the relative risk of breast cancer was 1.32 (1.19-1.45, P<0.00001) for an intake of 35-44 g per day alcohol, and 1.46 (1.33-1.61, P<0.00001) for >/=45 g per day alcohol. The relative risk of breast cancer increased by 7.1% (95% CI 5.5-8.7%; P<0.00001) for each additional 10 g per day intake of alcohol, i.e. for each extra unit or drink of alcohol consumed on a daily basis. This increase was the same in ever-smokers and never-smokers (7.1% per 10 g per day, P<0.00001, in each group). By contrast, the relationship between smoking and breast cancer was substantially confounded by the effect of alcohol. When analyses were restricted to 22 255 women with breast cancer and 40 832 controls who reported drinking no alcohol, smoking was not associated with breast cancer (compared to never-smokers, relative risk for ever-smokers=1.03, 95% CI 0.98-1.07, and for current smokers=0.99, 0.92-1.05). The results for alcohol and for tobacco did not vary substantially across studies, study designs, or according to 15 personal characteristics of the women; nor were the findings materially confounded by any of these factors. If the observed relationship for alcohol is causal, these results suggest that about 4% of the breast cancers in developed countries are attributable to alcohol. In developing countries, where alcohol consumption among controls averaged only 0.4 g per day, alcohol would have a negligible effect on the incidence of breast cancer. In conclusion, smoking has little or no independent effect on the risk of developing breast cancer; the effect of alcohol on breast cancer needs to be interpreted in the context of its beneficial effects, in moderation, on cardiovascular disease and its harmful effects on cirrhosis and cancers of the mouth, larynx, oesophagus and liver.

    View details for DOI 10.1038/sj.bjc.6600596

    View details for Web of Science ID 000179819900009

    View details for PubMedID 12439712

  • Prostaglandin H synthase 2 variant (Va1511Ala) in African Americans may reduce the risk for colorectal neoplasia CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lin, H. J., Lakkides, K. M., Keku, T. O., Reddy, S. T., Louie, A. D., Kau, I. H., Zhou, H. Y., Gim, J. S., Ma, H. L., Matthies, C. F., Dai, A. H., Huang, H. F., Materi, A. M., Lin, J. H., Frankl, H. D., Lee, E. R., Hardy, S. I., Herschman, H. R., Henderson, B. E., Kolonel, L. N., Le Marchand, L., Garavito, R. M., Sandler, R. S., Haile, R. W., Smith, W. L. 2002; 11 (11): 1305-1315

    Abstract

    Prostaglandin H synthase 2 (also known as cyclooxygenase-2) is thought to play a role in the prevention of colon cancer by aspirin, an inhibitor of the enzyme. We used DNA heteroduplex analysis to screen the prostaglandin H synthase 2 gene, to search for naturally occurring enzyme variants that may simulate the effects of aspirin. We found among African-Americans a single-nucleotide polymorphism that changes valine to alanine at residue 511 (V511A; GTT>GCT; g.5939T>C; allele frequency 0.045). The polymorphism was also seen among Asian-Indians (allele frequency, 0.03) but not among Chinese, Filipinos, Hispanics, Japanese, Koreans, Samoans, and Caucasians. The amino acid change is predicted to open a 53 cubic angstrom cavity near the active site of the enzyme, but no change in V(max), K(m), or thermal stability was observed for the variant enzyme in COS-1 cell transfection assays. Case-control analysis of African-Americans from two different study populations showed a 0.56 odds ratio for colorectal adenomas among polymorphism carriers (95% confidence interval, 0.25-1.27; 161 cases and 219 controls). A similar analysis of African-Americans nested in the Multiethnic Cohort Study showed a 0.67 odds ratio for colorectal cancer (95% confidence interval, 0.28-1.56; 138 cases and 258 controls). Consistency of the results across all three of the studies is potentially compatible with a protective effect of the polymorphism, mimicking aspirin.

    View details for Web of Science ID 000179270300005

    View details for PubMedID 12433707

  • The MnSOD A16V mitochondrial targeting sequence polymorphism is not associated with increased risk of distal colorectal adenomas: Data from a sigmoidoscopy-based case control study CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Levine, A. J., Elkhouly, E., Diep, A. T., Lee, E. R., Frankl, H., Haile, R. W. 2002; 11 (10): 1140-1141

    View details for Web of Science ID 000178634100033

    View details for PubMedID 12376525

  • Comparison of techniques for the successful detection of BRCA1 mutations in fixed paraffin-embedded tissue CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bernstein, J. L., Thompson, W. D., Casey, G., DiCioccio, R. A., Whittemore, A. S., Diep, A. T., Thakore, S. S., Vaziri, S., Xue, S. Y., Haile, R. W. 2002; 11 (9): 809-814

    Abstract

    Genomic DNA isolated from archived paraffin-embedded tissues (PETs) has important applicability in genetic epidemiological studies. To determine the accuracy of the sequence data, using DNA derived from PET among patients with known mutations characterized from blood, we conducted a blinded factorial experiment to simultaneously examine the influence of mutation type, age of the PET, PCR product type, and Taq DNA polymerase on BRCA1 gene mutation detection. The probability of detecting sequencing artifacts was also investigated. We found that: (a) gene detection was most accurate for newer PET; (b) high fidelity Taq with shorter PCR amplicon length yielded the highest mutation detection success rate and lowest artifact rate; and (c) base substitutions were more often correctly identified than frameshift mutations or wild-type sequences. We concluded that DNA derived from PET that archived for less than 18 years can be used successfully for detecting BRCA1 gene mutations if quality control is strictly maintained.

    View details for Web of Science ID 000177967900003

    View details for PubMedID 12223423

  • Risk factors for advanced colorectal adenomas: A pooled analysis CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Terry, M. B., Neugut, A. I., Bostick, R. M., Sandler, R. S., Haile, R. W., Jacobson, J. S., Fenoglio-Preiser, C. M., Potter, J. D. 2002; 11 (7): 622-629

    Abstract

    Although most colorectal cancers arise from adenomatous polyps, most adenomas do not progress to invasive cancer. Understanding the epidemiology of advanced adenomas, specifically those with severe dysplasia, carcinoma in situ, or intramucosal carcinoma, is crucial to uncovering why some adenomas progress and some do not. Using data from four colonoscopy-based adenoma case-control studies, we compared two case groups: subjects with advanced adenomas (those with severe dysplasia, carcinoma in situ, or intramucosal carcinoma; n = 119) and subjects with nonadvanced adenomas (those with none, mild, or moderate dysplasia; n = 441) to a polyp-free control group (n = 1866) in regard to frequently studied risk factors for colorectal neoplasia. All of the cases were newly diagnosed and had no prior history of adenomas. We used an unordered polytomous logistic model to calculate multivariate odds ratios for advanced and nonadvanced adenoma cases relative to polyp-free controls. Among women, ever use of hormone replacement therapy was more strongly associated with reduced risk of advanced adenomas relative to polyp-free controls [odds ratio (OR), 0.4; 95% confidence interval (CI), 0.2-0.9] than with reduced risk of nonadvanced adenomas (OR, 0.7; 95% CI, 0.4-1.0). Among men, increased physical activity (>or=2 h/week) was more strongly associated with reduced risk for advanced adenomas (OR, 0.4; 95% CI, 0.2-1.0) than with reduced risk for nonadvanced adenomas (OR, 0.8; 95% CI, 0.5-1.2). Apart from these differences, most other risk factors, including body size and cigarette smoking were similar in their association with advanced and nonadvanced adenomas, suggesting that many risk factors for colorectal neoplasia may be important to adenoma formation but not to dysplasia per se.

    View details for Web of Science ID 000176751000005

    View details for PubMedID 12101109

  • Reliability in the classification of advanced colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Terry, M. B., Neugut, A. I., Bostick, R. M., Potter, J. D., Haile, R. W., Fenoglio-Preiser, C. M. 2002; 11 (7): 660-663

    Abstract

    In conjunction with a pooled analysis of risk factors for advanced adenomas [adenomas with severe dysplasia, carcinoma in situ (CIS), and intramucosal carcinoma], we undertook a reliability study on the pathological diagnosis of advanced adenomas. We assessed intraobserver agreement (using Kappa (kappa) as the measure of agreement) across two time periods 10 years apart with a single pathologist and interobserver agreement (using Kappa) between two pathologists rating the same slides concurrently. The study pathologists were blinded to the original case classification. We used the slides of 190 colorectal adenomatous polyp cases (104 originally diagnosed as advanced adenomas, 86 adenomas without advanced lesions) from a colonoscopy-based case-control study conducted in New York City between 1986 and 1988. We also assessed conditional agreement for 71 slides of advanced adenomas from four adenoma case-control studies conducted in different geographic regions of the United States in the 1990s. Intra- and interobserver agreement was only fair to moderate on the classification of both histological type (villous, tubulovillous, and tubular: intraobserver kappa = 0.28; 95% confidence interval (CI), 0.17-0.39; interobserver kappa = 0.48; 95% CI, 0.33-0.62) and degree of dysplasia (none/mild, moderate, severe, CIS, and intramucosal: intraobserver kappa = 0.20; 95% CI, 0.12-0.28; interobserver kappa = 0.42; 95% CI, 0.29-0.55). Using broader, rather than finer, classifications for degree of dysplasia substantially improved the reliability (interobserver agreement for high-grade dysplasia (including severe dysplasia, CIS, and intramucosal carcinoma) versus low-grade dysplasia: kappa = 0.69; 95% CI, 0.55-0.83). These findings suggest that future epidemiological studies of advanced adenomas should use broad categories, such as high-grade versus low-grade dysplasia, include central review of all slides, and take measurement error into account in sample size calculations.

    View details for Web of Science ID 000176751000010

    View details for PubMedID 12101114

  • Glutathione transferase GSTT1, broccoli, and prevalence of colorectal adenomas PHARMACOGENETICS Lin, H. J., Zhou, H. Y., Dai, A. H., Huang, H. F., Lin, J. H., Frankl, H. D., Lee, E. R., Haile, R. W. 2002; 12 (2): 175-179

    View details for Web of Science ID 000174947200011

    View details for PubMedID 11875371

  • Workshop on The Epidemiology of the ATM Gene: Impact on Breast Cancer Risk and Treatment, Present Status and Future Focus, Lillehammer, Norway, 29 June 2002. Breast cancer research Bernstein, J. L., Seminara, D., Børresen-Dale, A. 2002; 4 (6): 249-252

    Abstract

    The role of ataxia-telangiectasia mutated (ATM) heterozygosity in cancer is uncertain. In vitro studies of cells from ATM heterozygotes provide strong evidence of radiation sensitivity. Some, but not all, clinical studies suggest an increased risk of breast cancer among ATM gene carriers, and this risk may be greater among those exposed to radiation. This possible excess risk of breast cancer associated with ATM heterozygosity constitutes the basis for several genetic epidemiological studies designed to clarify the role that the ATM gene plays in the etiology of breast and other cancers. The primary focus of this international, multidisciplinary, National Cancer Institute-sponsored workshop was to discuss ongoing and planned epidemiologic studies aimed at understanding the complexities of the ATM gene and its role in carcinogenesis. The invited participants were from diverse disciplines including molecular and clinical genetics, radiation biology and physics, epidemiology, biostatistics, pathology, and medicine. In the present meeting report, the aims of each project are described.

    View details for PubMedID 12473172

  • An association between genetic polymorphisms in the ileal sodium-dependent bile acid transporter gene and the risk of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Wang, W., Xue, S. Y., Ingles, S. A., Chen, Q. X., Diep, A. T., Frankl, H. D., Stolz, A., Haile, R. W. 2001; 10 (9): 931-936

    Abstract

    Epidemiological and experimental studies have implicated bile acids (particularly secondary bile acids) as important factors in the development of colorectal cancer. The ileal sodium-dependent bile acid transporter (ISBT) is a crucial player in the enterohepatic circulation of bile acids. Genetic defects in ISBT may result in malabsorption of bile acids and a loss of bile acids into the large intestine, with a resultant increase in the cytotoxic secondary bile acids in the colon. In a case-control study, we investigated the association between two sequence variations in SLC10A2, the gene encoding ISBT, and colorectal adenomas, a precursor lesion of colorectal cancer. The frequency of the missense mutation in codon 171 of exon 3 (a nucleotide transversion from G to T resulting in an alanine to serine substitution) was not significantly different between cases and controls. However, we found a 2-fold higher risk of colorectal adenomas associated with a C-->T nucleotide transition in codon 169 of exon 3 (odds ratio = 2.06; 95% confidence interval: 1.10-3.83). Logistic regression analysis using A171S/169 C-->T haplotypes as the allelic markers showed that among AA wild-type homozygotes for A171S mutation, this C-->T nucleotide transition in codon 169 was associated with a 2.42 times increased risk (odds ratio = 2.42; 95% confidence interval: 1.26-4.63). This initial observation of an association between a polymorphism in the SLC10A2 gene and the risk of colorectal adenomatous polyps would, if confirmed by other studies, support the role of bile acids in the carcinogenesis of colorectal cancer.

    View details for Web of Science ID 000170899000003

    View details for PubMedID 11535543

  • Vitamin D receptor polymorphisms and risk of colorectal adenomas (United States) CANCER CAUSES & CONTROL Ingles, S. A., Wang, J., Coetzee, G. A., Lee, E. R., Frankl, H. D., Haile, R. W. 2001; 12 (7): 607-614

    Abstract

    The purpose of this study was to determine whether vitamin D receptor (VDR) gene polymorphisms influence risk of colorectal adenoma.Polymorphisms in the 5' and 3' ends of the VDR gene were genotyped for 373 colorectal adenoma cases and 394 controls.Overall, there was no significant association between the 5' (FokI) or the 3' (BsmI) polymorphisms and adenoma risk. However, risk of large (>1 cm) adenomas decreased with increasing copies of the FokI f allele (p = 0.04). Compared to the FF genotype, odds ratios for the Ff and ff genotypes were 0.79 (95% CI 0.44-1.41) and 0.32 (95% CI 0.11-0.91), respectively. FokI genotype was more strongly related to large adenoma risk among subjects with low dietary calcium intake (ORFf=0.48; 95% CI 0.17-1.3; ORff=0.21: 95% CI 0.04-1.3), low dietary vitamin D intake (ORFf=0.25; 95% CI 0.09-0.69; ORff= 0.22; 95% CI 0.04-1.2), or dark skin color (ORFf=0.66; 95% CI 0.27-1.6; ORff=0.10; 95% CI 0.01-1.0).These results suggest that VDR FokI genotype influences development of colorectal adenomas. and that the effect may be modified by calcium and vitamin D status.

    View details for Web of Science ID 000170160400004

    View details for PubMedID 11552708

  • A case-control study of microsomal epoxide hydrolase, smoking, meat consumption, glutathione S-transferase M3, and risk of colorectal adenomas CANCER RESEARCH Cortessis, V., Siegmund, K., Chen, Q. X., Zhou, N. M., Diep, A., Frankl, H., Lee, E., Zhu, Q. S., Haile, R., Levy, D. 2001; 61 (6): 2381-2385

    Abstract

    We estimated associations between polymorphisms in the gene encoding microsomal epoxide hydrolase (mEH) among 464 cases diagnosed with first occurrence of colorectal adenoma and 510 matched controls. In an analysis controlling only for the matching variables, we found little or no association between adenoma and mEH genotypes defined by polymorphisms at either codon 113 and 139 or mEH activity predicted by both polymorphisms. However, in subsequent analyses, high predicted mEH activity was significantly associated with adenoma among certain subgroups defined by smoking history [odds ratio (OR), 4.27; 95% confidence interval (CI), 1.68-10.81 among current smokers; interaction, P = 0.11], meat consumption (OR, 2.47; CI, 0.99-6.19 among individuals who regularly eat well-done meat; interaction, P = 0.03), and genotypes for the *A/*B polymorphism in the gene encoding glutatione S-transferase M3 (OR, 2.60; CI, 1.28-5.28 among individuals with *A*A genotype; interaction, P = 0.03). These findings are consistent with causal roles for environmental polycyclic aromatic hydrocarbons and genetically encoded variants in enzymes whose actions lead to the production of activated polycyclic aromatic hydrocarbon metabolites.

    View details for Web of Science ID 000167697500007

    View details for PubMedID 11289100

  • Glutathione transferases, broccoli, and colon adenomas CHEMICO-BIOLOGICAL INTERACTIONS Lin, H. J., Zhou, H. Y., Dai, A. H., Huang, H. F., Lin, J., Frankl, H. D., Lee, E. R., Haile, R. W. 2001; 133 (1-3): 81-83
  • Rectal mucosal proliferation and risk of colorectal adenomas: Results from a randomized controlled trial CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sandler, R. S., Baron, J. A., Tosteson, T. D., Mandel, J. S., Haile, R. W. 2000; 9 (7): 653-656

    Abstract

    Although rectal mucosal labeling index is thought to be a useful surrogate biomarker for colorectal cancer, the ability of the index to predict future neoplasia is unclear. We obtained rectal mucosal biopsies from 333 participants of a randomized controlled chemoprevention trial of calcium supplementation to determine whether labeling index was correlated with concurrent or future colorectal neoplasms. Labeling index was measured using proliferating cell nuclear antigen immunohistochemistry. Adenomas were enumerated at the time of the biopsies (cross-sectional) and 3 years later (prospective). We used logistic regression to test for an association of adenoma occurrence with overall labeling index, the mean proliferative height, and labeling index in the upper 40% of colon crypts. In the cross-sectional analysis, we found indications that higher proliferation was associated with an increase in the prevalence of adenomas. The overall adjusted odds ratios (OR) (95% confidence interval) were 1.14 (0.90-1.45) per % crypt labeling index, OR 1.08 (0.99-1.19) for upper crypt proliferation, and OR 1.07 (1.03-1.12) for proliferative height. In contrast, individuals with higher labeling index at baseline were actually less likely to have adenomas in the prospective analyses: OR 0.80 (0.62-1.02) per % crypt labeling index, OR 0.86 (0.73-1.00) for upper crypt index, and OR 0.97 (0.93-1.01) for proliferative height. Proliferative index does not predict future colorectal neoplasia, although it may be weakly associated with the presence of current adenomas. These results have important implications for the design of future intervention studies. Although it may be attractive to include the measurement of intermediate markers in large controlled trials, until we have more confidence in their performance, we should rely on better proven and more reliable intermediates, such as adenomas.

    View details for Web of Science ID 000088217100004

    View details for PubMedID 10919733

  • The methylenetetrahydrofolate reductase 677C -> T polymorphism and distal colorectal adenoma risk CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Levine, A. J., Siegmund, K. D., Ervin, C. M., Diep, A., Lee, E. R., Frankl, H. D., Haile, R. W. 2000; 9 (7): 657-663

    Abstract

    A common polymorphism in the methylenetetrahydrofolate reductase (MTHFR) gene, where a cytosine at nucleotide 677 is replaced by a thymine (677C-->T), is associated with enzyme thermolability and a reduction in the conversion of 5,10-methyltetrahydrofolate (5,10-MTHF) into 5-methyltetrahydrofolate. We assessed the association between homozygosity for the MTHFR 677CT genotype (TT) and colorectal adenoma risk in a large sigmoidoscopy-based case-control study of members of a prepaid health plan in Los Angeles. MTHFR genotype was determined for 471 cases and 510 age-, sex-, clinic-, and sigmoidoscopy-date-matched controls. Information on RBC and plasma folate levels were analyzed for 331 cases and 350 controls. When compared with the presence of at least one wild-type allele (CT/CC), the odds ratio (OR) for the TT genotype was 1.19 [95% confidence interval (CI), 0.77-1.76] after adjusting for race and the matching factors. Compared with those in the lowest quartiles of RBC and plasma folate and a wild-type allele, adenoma risk was increased for TT homozygotes in the lowest folate quartiles (genotype: OR, 2.04 and 95% CI, 0.6-7.0; OR, 1.84 and 95% CI, 0.6-7.0 for RBCs and plasma folate, respectively) and decreased in TT homozygotes in the highest quartiles (genotype: OR, 0.82 and 95% CI, 0.32-2.10; OR, 0.65 and 95% CI, 0.22-1.95, respectively). There was also a significant interaction between TT genotype and the increased adenoma risk associated with alcohol. These data are consistent with an interaction between MTHFR genotype and folate availability.

    View details for Web of Science ID 000088217100005

    View details for PubMedID 10919734

  • Serum ferritin concentration and recurrence of colorectal adenoma CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Tseng, M., Greenberg, E. R., Sandler, R. S., Baron, J. A., Haile, R. W., Blumberg, B. S., McGlynn, K. A. 2000; 9 (6): 625-630

    Abstract

    Both body iron stores and dietary iron intake have been reported to increase risk of colorectal neoplasms. We assessed whether serum ferritin concentration was associated with recurrence of colorectal adenomas among 733 individuals with baseline determinations of ferritin as part of a multicenter clinical trial of antioxidant supplements for adenoma prevention. All study participants had at least one adenoma removed within 3 months before enrollment, and 269 of them developed one or more adenomas between follow-up colonoscopies conducted 1 and 4 years after enrollment. Baseline serum ferritin concentrations were analyzed both as a log-transformed continuous variable and as a categorical variable, defined as whether iron stores were nonreplete and low (ferritin < or =30 microg/liter), nonreplete and borderline (31-70 microg/liter), replete and adequate (71-160 microg/liter), or replete and high (>160 microg/liter). Analyses were based on multiple logistic regression models, including age, sex, study center, energy, alcohol, fiber, folate, and total fat intake, number of months between colonoscopic examinations, smoking status, and aspirin use. Overall, there was no statistically significant linear association between log ferritin concentration and adenoma recurrence (P = 0.33). Risk of adenoma recurrence was modestly increased among participants with ferritin concentrations >70 microg/liter relative to those with lower ferritin (odds ratio, 1.39; 95% confidence interval, 0.96-2.02). This result seemed more pronounced among women than men. Dietary intake of iron and red meat was inversely associated with adenoma recurrence among participants with replete iron stores but not consistently associated among those with nonreplete stores. Our findings suggest that any role of iron stores and dietary iron in influencing risk of colorectal adenoma recurrence is likely complex.

    View details for Web of Science ID 000087634300015

    View details for PubMedID 10868699

  • Cancer risk estimates for family members of a population-based family registry for breast and ovarian cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ziogas, A., Gildea, M., Cohen, P., Bringman, D., Taylor, T. H., Seminara, D., Barker, D., Casey, G., Haile, R., Liao, S. Y., Thomas, D., Noble, B., Kurosaki, T., Anton-Culver, H. 2000; 9 (1): 103-111

    Abstract

    Population-based breast and ovarian cancer family registries can facilitate studies to evaluate genetic and environmental factors in the etiology of these malignancies. The purpose of this study is to describe what is, as far as we know, the first population-based breast and ovarian cancer family registry and to estimate breast and ovarian cancer risk in relatives of breast and ovarian cancer probands. Population-based consecutive incident cases of breast and ovarian cancer were invited to participate in the University of California, Irvine breast and ovarian family registry. In this study, we report data on 1567 breast cancer and 328 ovarian cancer probands. The operational components of this family registry include enrollment of probands, family history interviewing, confidentiality, pathology, verification and review, biospecimen bank, statistical/genetic analysis, and special studies on positional cloning of known genes. All of the components are tracked through the University of California, Irvine Genetic Research Information System. In non-Hispanic-white breast cancer probands, relative risk (RR) of breast cancer in mothers and sisters is significantly elevated [RR = 1.7 and 95% confidence interval (CI) = 1.4-2.0 and RR = 2.8 and 95% CI = 2.3-3.3, respectively]. In families of ovarian cancer probands, mothers are at increased risk of ovarian cancer (RR = 4.6; 95% CI, 2.1-8.7). RR of breast cancer in mothers of Hispanic breast cancer probands is significantly elevated (RR = 4.9; 95% CI, 2.6-8.5). No elevation of breast or ovarian cancer risk was observed among relatives of Asian probands. In general, there is a decrease in RR among mothers and sisters with increase in age of onset of probands. In second-degree relatives and first cousins, the breast cancer hazards ratios increase with increase in the number of affected first-degree relatives and decrease with increase in age at onset of the proband.

    View details for Web of Science ID 000085056400012

    View details for PubMedID 10667470

  • Vitamin D receptor genotype and breast cancer in Latinas (United States) CANCER CAUSES & CONTROL Ingles, S. A., Garcia, D. G., Wang, W., Nieters, A., Henderson, B. E., Kolonel, L. N., Haile, R. W., Coetzee, G. A. 2000; 11 (1): 25-30

    Abstract

    Polymorphism in the vitamin D receptor (VDR) gene has been associated with variation in bone mineral density and with prostate cancer risk. The purpose of this study was to determine whether polymorphism in the VDR gene may also influence breast cancer risk.Polymorphisms in the 5' and 3' ends of the VDR gene were genotyped for 143 Latina women with breast cancer and 300 cohort controls.Both the BsmI and poly-A polymorphisms in the 3' end of the VDR gene were associated with breast cancer risk, with a trend for increasing risk with increasing number of BsmI B alleles or short (S) poly-A alleles. Compared to subjects having two long poly-A alleles (genotype LL), odds ratios (and 95% confidence intervals) were 1.5 (1.0 2.3) and 3.2 (1.5-6.9) for subjects having genotypes SL and SS, respectively. Compared to BsmI genotype bb, odds ratios (and 95% confidence intervals) were 1.6 (1.1-2.5) and 2.2 (1.0-4.7) for genotypes Bb and BB respectively. The start codon polymorphism, FokI, was not associated with breast cancer risk.These results suggest that polymorphic variation in or near the 3' end of the VDR gene influences breast cancer risk in Latina women.

    View details for Web of Science ID 000083814400003

    View details for PubMedID 10680726

  • Colorectal hyperplastic polyps and risk of recurrence of adenomas and hyperplastic polyps LANCET Bensen, S. P., Cole, B. F., Mott, L. A., Baron, J. A., Sandler, R. S., Haile, R. 1999; 354 (9193): 1873-1874

    Abstract

    We examined data from two large colorectal chemoprevention trials for possible associations of hyperplastic polyps and adenomas with subsequent development of these lesions. Hyperplastic polyps do not predict metachronous adenomas.

    View details for Web of Science ID 000083909100015

    View details for PubMedID 10584726

  • Correspondence re: H. J. Lin et al., Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas. Cancer Epidemiol., Biomark, Prev., 7 : 647-652, 1998 CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Acquavella, J., Cullen, M. R. 1999; 8 (10): 947-947

    View details for Web of Science ID 000083352400016

    View details for PubMedID 10548326

  • Linkage analysis and loss of heterozygosity for chromosome arm Ip in familial breast cancer GENES CHROMOSOMES & CANCER Millikan, R. C., Ingles, S. A., Diep, A. T., Xue, S. Y., Zhou, N. M., Florentine, B. D., Sparkes, R. S., Haile, R. W. 1999; 25 (4): 354-361

    Abstract

    We conducted linkage analysis of 64 multiple-case families with early-onset bilateral breast cancer using DNA markers on chromosome band 1p36. Evidence against tight linkage was obtained using a dominant model for transmission (summary LOD scores at recombination fraction theta = 0.000001 were -4.71 for D1S160 and -2.70 for D1S170). Similar results were obtained after excluding 20 families that were potentially attributable to BRCA1 or BRCA2. We also investigated loss of heterozygosity for a panel of markers on chromosome arm 1p using breast tumors from affected family members. The most common regions of allele loss were 1p36 (32% for D1S160, 35% for D1S243) and 1p32 (51% for MYCL). The frequency and location of 1p allele loss did not differ substantially from previous studies of sporadic breast cancer. We conclude that 1p36 probably does not contain a locus of susceptibility for a large proportion of breast cancer families, but a variety of loci on 1p may contribute to progression of familial and sporadic disease. Genes Chromosomes Cancer 25:354-361, 1999.

    View details for Web of Science ID 000081358100007

    View details for PubMedID 10398429

  • A case-control study of colorectal adenomatous polyps and consumption of foods containing partially hydrogenated oils CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION McKelvey, W., Greenland, S., Chen, M. J., Longnecker, M. P., Frankl, H. D., Lee, E. R., Haile, R. W. 1999; 8 (6): 519-524

    Abstract

    The trans fatty acids produced by partially hydrogenating vegetable oils may cause colorectal neoplasia by interfering with cell membrane function or eicosanoid synthesis. This possibility provides a rationale for looking at the relation between colorectal adenomatous polyps and consumption of foods containing partially hydrogenated vegetable oils (PHVOs). A total of 516 cases and 551 controls who underwent screening sigmoidoscopy from 1991-1993 were recruited from a prepaid Los Angeles health plan. Subjects were interviewed and given a self-administered food frequency questionnaire. Food items containing PHVOs were divided into four groups characterized by principal ingredients and preparation methods: sweetened baked goods, candy bars, oils and condiments, and french fries and chips. After adjusting for age, sex, physical activity, body mass index, smoking, total energy, and red meat and vegetable intake, there was a positive association between polyps and sweetened baked goods [350+ versus <50 kcal/day (odds ratio, 2.1; 95% confidence interval, 1.3-3.5)]. No association was found with the other food groups after adjustment for dietary and nondietary covariates. Neither was total dietary trans fatty acid associated with adenomas after adjustment for sweetened baked goods and other covariates. These results do not support the hypothesis that eating foods containing PHVOs increases the risk of colorectal adenomas, but they are consistent with the hypothesis that foods high in fat and sugar and low in fiber and correlated micronutrients increase the risk of adenomas.

    View details for Web of Science ID 000080780100006

    View details for PubMedID 10385142

  • Aromatase and breast cancer susceptibility ENDOCRINE-RELATED CANCER Probst-Hensch, N. M., Ingles, S. A., Diep, A. T., Haile, R. W., Stanczyk, F. Z., Kolonel, L. N., Henderson, B. E. 1999; 6 (2): 165-173

    Abstract

    Based on experimental and epidemiological evidence it is hypothesized that estrogen increases breast cancer risk by increasing mitotic activity in breast epithelial cells. Aromatase is crucial to the biosynthesis of estrogens and may therefore play a role in breast cancer development. Supporting data for an etiological role of aromatase in breast tumor biology are several-fold. First, the association between weight and postmenopausal breast cancer risk may be mediated by aromatase. Secondly, a pilot study found a higher aromatase expression in normal breast adipose tissue from breast cancer cases as opposed to healthy women. Thirdly, experimental data in animals suggest that aromatase activity predisposes mammary tissue to preneoplastic and neoplastic changes. In a multiethnic cohort study conducted in Los Angeles and on Hawaii we investigated (i) whether the plasma estrone to androstenedione (E1/A) ratio in different ethnic groups was associated with ethnic differences in breast cancer incidence, and (ii) whether genetic variation in the CYP19 gene encoding the P450 aromatase protein was associated with breast cancer risk. The age- and weight-adjusted ethnic specific E1/A ratios x 100 among women without oophorectomy were 7.92 in African-Americans, 8.22 in Japanese, 10.73 in Latinas and 9.29 in non-Latina Whites (P=0.09). The high E1/A ratio in Latina women was not associated with a high breast cancer incidence; in fact Latina women had the lowest breast cancer incidence in the cohort observed so far. We found no consistent association of an intronic (TTTA)n repeat polymorphism with breast cancer risk in different ethnic groups. This polymorphism was not associated with differences in the plasma E1/A ratio in a way that would predict its functional relevance. We describe a newly identified TTC deletion in intron 5 of the CYP19 gene that is associated with the (TTTA)n repeat polymorphism. Neither this polymorphism, nor a polymorphism at codon 264 in exon VII of the CYP19 gene, was associated with breast cancer. We did not identify any genetic variation in exon VIII in 54 African-American subjects. We identified rare genetic variants of unknown functional relevance in the promoter 1.4 of the CYP19 gene in 3 out of 24 Latina women. Further investigation into the role of aromatase in breast cancer etiology is important, given that the potential use of aromatase inhibitors as breast cancer chemopreventives depends on these results.

    View details for Web of Science ID 000080466300006

    View details for PubMedID 10731105

  • Germline BRCA1 alterations in a population-based series of ovarian cancer cases HUMAN MOLECULAR GENETICS Janezic, S. A., Ziogas, A., Krumroy, L. M., Krasner, M., Plummer, S. J., Cohen, P., Gildea, M., Barker, D., Haile, R., Casey, G., Anton-Culver, H. 1999; 8 (5): 889-897

    Abstract

    The objective of this study was to provide more accurate frequency estimates of breast cancer susceptibility gene 1 ( BRCA1 ) germline alterations in the ovarian cancer population. To achieve this, we determined the prevalence of BRCA1 alterations in a population-based series of consecutive ovarian cancer cases. This is the first population-based ovarian cancer study reporting BRCA1 alterations derived from a comprehensive screen of the entire coding region. One hundred and seven ovarian cancer cases were analyzed for BRCA1 alterations using the RNase mismatch cleavage assay followed by direct sequencing. Two truncating mutations, 962del4 and 3600del11, were identified. Both patients had a family history of breast or ovarian cancer. Several novel as well as previously reported uncharacterized variants were also identified, some of which were associated with a family history of cancer. The frequency distribution of common polymorphisms was determined in the 91 Caucasian cancer cases in this series and 24 sister controls using allele-specific amplification. The rare form of the Q356R polymorphism was significantly ( P = 0.03) associated with a family history of ovarian cancer, suggesting that this polymorphism may influence ovarian cancer risk. In summary, our data suggest a role for some uncharacterized variants and rare forms of polymorphisms in determining ovarian cancer risk, and highlight the necessity to screen for missense alterations as well as truncating mutations in this population.

    View details for Web of Science ID 000080109200019

    View details for PubMedID 10196379

  • Vitamin D receptor 3 '-untranslated region polymorphisms: lack of effect on mRNA stability BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE Durrin, L. K., Haile, R. W., Ingles, S. A., Coetzee, G. A. 1999; 1453 (3): 311-320

    Abstract

    Allelic variation at the 3'-end of the vitamin D receptor (VDR) gene has been associated with a 3-5-fold increased risk of developing prostate cancer and with differences in bone mineralization. This genetic diversity does not alter the VDR protein structurally, but instead may be a marker(s) of other, nearby polymorphisms that influence message stability or translation. The work reported here was instigated to identify additional VDR 3'-UTR polymorphisms that may have functional significance and to then test whether these genetic variants alter message stability. Initially, four novel, frequently occurring sequence variants were identified that associated with two common haplotypes that were described previously. These common sequence variants were not found within three message-destabilizing elements that we mapped within the 3'-UTR of the vitamin D receptor mRNA. Furthermore, the two VDR 3'-UTR haplotypes conferred an identical half-life on a heterologous beta-globin reporter gene, in an in vitro assay. We therefore conclude that common polymorphisms within the VDR 3'-UTR do not influence message stability.

    View details for Web of Science ID 000079649200001

    View details for PubMedID 10101249

  • The family history component of cancer genetic risk counseling CANCER NURSING Loescher, L. J. 1999; 22 (1): 96-102

    Abstract

    Family history is an important risk factor for inherited cancers. Obtaining a family history is therefore a key component of cancer genetic risk counseling (CGRC). Many oncology nurses do not have training in cancer genetic risk counseling. However, every nurse is capable of obtaining a basic family history. The family history can help in identifying patterns of cancer transmission in families. Nurses can then refer families with a strong history of cancer to nurse geneticists, genetic counselors, or others qualified to make a further assessment of risk. If those resources are unavailable locally, the Internet can be of assistance. This article summarizes genetic and clinical characteristics of inherited cancers, the significance of family history, interview approaches, questions to ask about personal and family history of cancer, what a pedigree is and how to draw one, what to do with family information including risk analysis and documentation, and available resources on the Internet.

    View details for Web of Science ID 000079242100017

    View details for PubMedID 9990765

  • Calcium supplements for the prevention of colorectal adenomas NEW ENGLAND JOURNAL OF MEDICINE Baron, J. A., Beach, M., Mandel, J. S., van Stolk, R. U., Haile, R. W., Sandler, R. S., Rothstein, R., Summers, R. W., Snover, D. C., Beck, G. J., Bond, J. H., Greenberg, E. R. 1999; 340 (2): 101-107

    Abstract

    Laboratory, clinical, and epidemiologic evidence suggests that calcium may help prevent colorectal adenomas. We conducted a randomized, double-blind trial of the effect of supplementation with calcium carbonate on the recurrence of colorectal adenomas. We randomly assigned 930 subjects (mean age, 61 years; 72 percent men) with a recent history of colorectal adenomas to receive either calcium carbonate (3 g [1200 mg of elemental calcium] daily) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The primary end point was the proportion of subjects in whom at least one adenoma was detected after the first follow-up endoscopy but up to (and including) the second follow-up examination. Risk ratios for the recurrence of adenomas were adjusted for age, sex, lifetime number of adenomas before the study, clinical center, and length of the surveillance period.The subjects in the calcium group had a lower risk of recurrent adenomas. Among the 913 subjects who underwent at least one study colonoscopy, the adjusted risk ratio for any recurrence of adenoma with calcium as compared with placebo was 0.85 (95 percent confidence interval, 0.74 to 0.98; P=0.03). The main analysis was based on the 832 subjects (409 in the calcium group and 423 in the placebo group) who completed both follow-up examinations. At least one adenoma was diagnosed between the first and second follow-up endoscopies in 127 subjects in the calcium group (31 percent) and 159 subjects in the placebo group (38 percent); the adjusted risk ratio was 0.81 (95 percent confidence interval, 0.67 to 0.99; P=0.04). The adjusted ratio of the average number of adenomas in the calcium group to that in the placebo group was 0.76 (95 percent confidence interval, 0.60 to 0.96; P=0.02). The effect of calcium was independent of initial dietary fat and calcium intake.Calcium supplementation is associated with a significant - though moderate - reduction in the risk of recurrent colorectal adenomas.

    View details for Web of Science ID 000078016200004

    View details for PubMedID 9887161

  • Calcium supplements and colorectal adenomas. Polyp Prevention Study Group. Annals of the New York Academy of Sciences Baron, J. A., Beach, M., Mandel, J. S., van Stolk, R. U., Haile, R. W., Sandler, R. S., Rothstein, R., Summers, R. W., Snover, D. C., Beck, G. J., Frankl, H., Pearson, L., Bond, J. H., Greenberg, E. R. 1999; 889: 138-145

    Abstract

    Experimental and observational findings suggest that calcium intake may protect against colorectal neoplasia. To investigate this hypothesis, we conducted a randomized, double-blind trial of colorectal adenoma recurrence. Nine hundred thirty patients with a recent history of colorectal adenomas were randomly given calcium carbonate (3 gm daily; 1200 mg elemental calcium) or placebo, with follow-up colonoscopies one and four years after the qualifying examination. The main analysis focused on new adenomas found after the first follow-up endoscopy, up to (and including) the second follow-up examination. Risk ratios of at least one recurrent adenoma and ratios of the average numbers of adenomas were calculated as measures of calcium effect. There was a lower risk of recurrent adenomas in subjects assigned calcium. Eight hundred thirty-two patients had two follow-up examinations and were included in the main analysis; the adjusted risk ratio of one or more adenomas was 0.81 (95% CI 0.67 to 0.99); the adjusted ratio of the average numbers of adenomas was 0.76 (95% CI 0.60 to 0.96). Among subjects who had at least one follow-up colonoscopy, the adjusted risk ratio of one or more recurrent adenomas was 0.85 (95% CI 0.74 to 0.98). The effect of calcium seemed independent of initial dietary fat and calcium intake. No toxicity was associated with supplementation. These findings indicate that calcium supplementation has a modest protective effect against colorectal adenomas, precursors of most colorectal cancers.

    View details for PubMedID 10668490

  • Calcium supplements and colorectal adenomas CANCER PREVENTION: NOVEL NUTRIENT AND PHARMACEUTICAL DEVELOPMENTS Baron, J. A., Beach, M., Mandel, J. S., van Stolk, R. U., Haile, R. W., Sandler, R. S., Rothstein, R., Summers, R. W., Snover, D. C., Beck, G. J., Frankl, H., Pearson, L., Bond, J. H., Greenberg, E. R. 1999; 889: 138-145
  • Study-design issues in the development of the University of Southern California Consortium's Colorectal Cancer Family Registry. Journal of the National Cancer Institute. Monographs Haile, R. W., Siegmund, K. D., Gauderman, W. J., Thomas, D. C. 1999: 89-93

    Abstract

    The University of Southern California Consortium is a participating center in the National Cancer Institute's Collaborative Family Registry for Colorectal Cancer Studies (CFRCCS). Because data collection takes time, money, and effort, all of which are in short supply, we first defined our research objectives and then attempted to design our registry to enable us to address these objectives in an efficient manner. We decided on a family-based design, and our objectives are to characterize cloned genes that are generally accepted causes of colorectal cancer, to assess putative candidate genes, to map new genes, and to conduct prevention trials in high-risk subjects. For the gene characterization objectives, our primary aim is to estimate gene frequency and penetrance, with a secondary aim to investigate factors that may affect penetrance (allele-specific effects plus gene-gene and gene-environment interactions). We describe a multiple-stage design to select families into the registry. After a family is selected into the registry, we collect questionnaire data and blood samples on selected subjects only, and we tailor data collection decisions to each family (given who is affected and who is available) to optimize power per unit effort and cost. We also discuss practical decisions faced by our registry, including 1) defining a reference period for use in questionnaires; 2) deciding whether or not to establish cell lines and, if so, on whom; and 3) determining which cases should be tested for microsatellite instability. Finally, we address the appropriate use of data derived from high-risk clinics, within more broadly defined, population-based research.

    View details for PubMedID 10854491

  • Glutathione transferase null genotype, broccoli, and lower prevalence of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Lin, H. J., Probst-Hensch, N. M., Louie, A., Kau, I. H., Witte, J. S., Ingles, S. A., Frankl, H. D., Lee, E. R., Haile, R. W. 1998; 7 (8): 647-652

    Abstract

    Cruciferous vegetables, especially broccoli, may prevent cancer through anticarcinogenic compounds. For example, broccoli contains isothiocyanates that induce carcinogen-detoxifying enzymes. Glutathione transferase enzymes conjugate isothiocyanates, leading to excretion. We hypothesized that broccoli consumption in combination with the glutathione transferase M1 (GSTM1) null genotype would be associated with a lower prevalence of colorectal adenomas because of higher isothiocyanate levels. We used a case-control study of mainly asymptomatic subjects aged 50-74 years who underwent a screening sigmoidoscopy at either of two Southern California Kaiser Permanente Medical Centers during 1991-1993. Cases (n = 459) had a first-time diagnosis of histologically confirmed adenomas detected by flexible sigmoidoscopy. Controls (n = 507) had no polyp detected. Subjects had a 45-min in-person interview for information on various risk factors and basic demographic data and completed a 126-item, semiquantitative food frequency questionnaire. Blood samples were used for GSTM1 genotyping. Subjects with the highest quartile of broccoli intake (an average of 3.7 servings per week) had an odds ratio of 0.47 (95% confidence interval, 0.30-0.73) for colorectal adenomas, compared with subjects who reportedly never ate broccoli. When stratified by GSTM1 genotype, a protective effect of broccoli was observed only among subjects with the GSTM1 null genotype (P for trend, 0.001; P for interaction, 0.01). The observed broccoli-GSTM1 interaction is compatible with an isothiocyanate mechanism.

    View details for Web of Science ID 000075283700002

    View details for PubMedID 9718215

  • Adenoma characteristics at first colonoscopy as predictors of adenoma recurrence and characteristics at follow-up GASTROENTEROLOGY van Stolk, R. U., Beck, G. J., Baron, J. A., Haile, R., Summers, R. 1998; 115 (1): 13-18

    Abstract

    All patients with colorectal adenomas may not require identical follow-up. We aimed to determine if adenoma characteristics at initial colonoscopy could predict adenoma recurrence or characteristics at follow-up.The number of adenomas and the size, type, and degree of atypia in 479 patients in a polyp prevention trial were evaluated as predictors of the same characteristics at follow-up using odds ratios (ORs) with 95% confidence intervals (CIs). Multiple logistic regression analysis was performed to determine if several baseline characteristics were simultaneously associated with outcome.Although several characteristics were significant predictors of recurrence univariately, by multivariate analysis, multiple adenomas at follow-up were more likely when patients had > or = 3 baseline adenomas (OR, 2.25; 95% CI, 1.20-4.21) or at least 1 tubulovillous adenoma (OR, 2.12; 95% CI, 1.12-4.02). No specific characteristic was associated with recurrence of high-risk polyps (> or = 1 cm, villous, severe atypia). Seventy percent of patients with 1 or 2 baseline adenomas had no recurrence, and only 3.3% had any adenomas of clinical concern.Number and type of baseline adenomas predict recurrent adenomas, but the recurrence is rarely of clinical concern. Patients with 1 or 2 tubular adenomas constitute a low-risk group for whom follow-up might be extended beyond 3 years.

    View details for Web of Science ID 000074434500006

    View details for PubMedID 9649453

  • Variants of N-acetyltransferase NAT1 and a case-control study of colorectal adenomas PHARMACOGENETICS Lin, H. J., Probst-Hensch, N. M., Hughes, N. C., Sakamoto, G. T., Louie, A. D., Kau, I. H., Lin, B. K., Lee, D. B., Lin, J., Frankl, H. D., Lee, E. R., Hardy, S., Grant, D. M., Haile, R. W. 1998; 8 (3): 269-281

    Abstract

    N-acetyltransferase NAT1, together with enzymes CYP1A2 and NAT2, helps convert heterocyclic amines to mutagens. Epidemiologic studies of the association of variants of these enzymes with colorectal cancer may provide indirect support for a heterocyclic amine mechanism. We used single strand conformation polymorphism and heteroduplex analysis to screen fro mutations in the NAT1 coding region in a case-control study (n = 932) of colorectal adenomas, which are precursors to cancer. Thirteen different single-base mutations were found: C97T, C190T, T402C, G445A-G459A-T640G ( a combination of three mutations), C559T, G560A, A613G, A752T, T777C, G781A, and A787G. Function of novel mutations was tested by bacterial production of enzymes and measurements of Km, Vmax, and stability. However, on 24-control individuals and 18 cases carried an inactivating NAT1 mutation. When combined with our data on the NAT2 acetylation polymorphism, we saw no evidence for an association between N-acetyltransferases and prevalence of adenomas. Larger sample sizes are required for further evaluation.

    View details for Web of Science ID 000074405300009

    View details for PubMedID 9682272

  • Protective effect of cigarette smoking on breast cancer risk in women with BRCA1 or BRCA2 mutations??? JOURNAL OF THE NATIONAL CANCER INSTITUTE Baron, J. A., Haile, R. W. 1998; 90 (10): 726-727

    View details for Web of Science ID 000073696700002

    View details for PubMedID 9605638

  • Association of prostate cancer with vitamin D receptor haplotypes in African-Americans CANCER RESEARCH Ingles, S. A., Coetzee, G. A., Ross, R. K., Henderson, B. E., Kolonel, L. N., Crocitto, L., Wang, W., Haile, R. W. 1998; 58 (8): 1620-1623

    Abstract

    In previous studies, allelic variation in the 3' end of the vitamin D receptor gene was associated with increased risk of prostate cancer in white men. Several polymorphisms, including a BsmI restriction site and a poly(A) microsatellite, can be used interchangeably to mark the unidentified locus in whites. In African-Americans, however, these markers are not interchangeable, due to weaker linkage disequilibrium in this genomic region in this population. Here, we genotyped both the BsmI and poly(A) markers for 151 African-American prostate cancer cases (102 localized and 49 advanced) and 174 African-American male controls from a large epidemiological cohort. A direct haplotyping procedure was devised to determine BsmI/poly(A) haplotypes for double heterozygotes so that haplotypes could be used as allelic markers in standard logistic regression analyses. Using BsmI alone, b alleles were associated with a 2-fold decrease in risk of advanced prostate cancer. The association was, however, confined to haplotypes carrying a long (L) allele of the poly(A) microsatellite. BL and bL haplotypes were associated with increased and decreased risk, respectively, whereas neither BS nor bS haplotypes were associated with prostate cancer risk. An allelic variant that confers increased risk of advanced prostate cancer appears to be associated with the BsmI/poly(A) BL haplotype in African-Americans.

    View details for Web of Science ID 000073132600009

    View details for PubMedID 9563471

  • Dietary and supplemental calcium and the recurrence of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Hyman, J., Baron, J. A., Dain, B. J., Sandler, R. S., Haile, R. W., Mandel, J. S., Mott, L. A., Greenberg, E. R. 1998; 7 (4): 291-295

    Abstract

    The association between calcium intake and the risk of colorectal neoplasia remains controversial. This analysis prospectively investigated the association between dietary and supplemental calcium intake and recurrent colorectal adenomas. Participants were part of a multicenter, randomized clinical trial of antioxidant vitamins. The study endpoints were adenomas detected between surveillance colonoscopies conducted at approximately 1 year and 4 years after study entry. Baseline intake of energy-adjusted calcium derived from a food frequency questionnaire was used as the main exposure of interest. Calcium supplement use was assessed by semiannual questionnaires. Logistic regression was used to compute odds ratios and 95% confidence limits, and Poisson regression was used to estimate rate ratios. Subjects in the fifth quintile of dietary calcium had an adjusted odds ratio of 0.72 (95% confidence interval, 0.43-1.22) compared to those in the lowest quintile. Investigation of the numbers of adenomas yielded stronger findings: the rate ratio for the fifth quintile versus the first was 0.63 (95% confidence interval, 0.39-1.02). Dietary calcium seemed to have a greater effect among individuals with a high-fat diet than among those with a low-fat diet; however, the interaction was not statistically significant. Use of calcium supplements was not related to adenoma recurrence. These results suggest that a high calcium intake may be associated with a reduction in risk of recurrent adenomas, especially among individuals on a high-fat diet.

    View details for Web of Science ID 000073015500004

    View details for PubMedID 9568783

  • Obesity, weight gain, large weight changes, and adenomatous polyps of the left colon and rectum AMERICAN JOURNAL OF EPIDEMIOLOGY Bird, C. L., Frankl, H. D., Lee, E. R., Haile, R. W. 1998; 147 (7): 670-680

    Abstract

    Epidemiologic studies of colorectal neoplasia have usually examined body mass index as a risk factor, but not other aspects of obesity. During 1991-1993, the authors obtained weight histories and comprehensive covariate data from men and women aged 50-75 years who underwent sigmoidoscopy at a health maintenance organization in southern California. Using 483 cases with adenomas and 483 controls, measures of obesity (body mass index), positive energy balance (net weight gain in the past 10 years), and weight variability (large weight changes) were each independently related to adenoma prevalence. Compared with subjects in the lowest quartile of body mass index, multivariate-adjusted odds ratios for subjects in increasingly higher quartiles were 2.1 (95% confidence interval (CI) 1.4-2.3), 1.8 (1.1-2.9), and 1.7 (1.0-2.8), respectively. Compared with subjects who reported a net weight loss during the 10 years before sigmoidoscopy, subjects with net weight gains of 1.5-4.5 kg or > or = 4.5 kg had adjusted odds ratios (95% CI) of 2.5 (1.2-5.6) and 1.8 (0.7-4.4), respectively. Compared with subjects who had no large weight changes during adulthood, subjects with 1-2, 3, or > or = 4 changes had adjusted odds ratios (95% CI) of 2.0 (1.0-3.9), 2.5 (1.2-5.5), and 1.5 (0.6-3.6), respectively. Obesity, weight gain, and unstable adult weight may be independently associated with colorectal carcinogenesis.

    View details for Web of Science ID 000072853800008

    View details for PubMedID 9554606

  • Recent use of hormone replacement therapy and the prevalence of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Chen, M. J., Longnecker, M. P., Morgenstern, H., Lee, E. R., Frankl, H. D., Haile, R. W. 1998; 7 (3): 227-230

    Abstract

    The etiological role of hormone replacement therapy (HRT) (including estrogen only, combined estrogen-progesterone, and progesterone only) in colorectal neoplasia remains unclear. Several large studies have reported a reduced risk of colorectal cancer among HRT users; however, other studies have given inconsistent results. We examined the association between HRT and colorectal adenomatous polyps, precursors of colorectal cancer, among female participants in a case-control study. Subjects were members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy in 1991-1993. Participants received an in-person interview and completed a food frequency questionnaire. A total of 187 histologically confirmed cases and 188 controls, ages 50-75 years, were included in the analysis. Compared with women who did not use HRT during the year before sigmoidoscopy, recent users had an adjusted odds ratio of 0.57 (95% confidence interval, 0.35-0.94). Duration of use was inversely related to the prevalence of colorectal adenomas, with a multivariate-adjusted odds ratio of 0.49 (95% confidence interval, 0.25-0.97) for use of 5 years or more. These results support a protective effect of HRT on colorectal adenomatous polyps.

    View details for Web of Science ID 000072384000010

    View details for PubMedID 9521438

  • Plasma tocopherol and prevalence of colorectal adenomas in a multiethnic population CANCER RESEARCH Ingles, S. A., Bird, C. L., Shikany, J. M., Frankl, H. D., Lee, E. R., Haile, R. W. 1998; 58 (4): 661-666

    Abstract

    Although vitamin E can block mutagenesis and cell transformation in vitro and can reduce the number of chemically induced colonic adenomas in mice, previous clinical trials have found no protective effect of vitamin E supplements against colorectal adenomas, and epidemiological studies have found only weak protective effects of dietary or plasma alpha-tocopherol against colorectal cancer. We previously examined first diagnosis of colorectal adenomas in a sigmoidoscopy screening population and failed to find a protective effect of dietary vitamin E. Because measurements of dietary intake may not be a good proxy of vitamin E status, we assayed plasma alpha- and gamma-tocopherol concentration for 332 subjects with colorectal adenomas and 363 control subjects from this previous sigmoidoscopy-based study. Increasing alpha-tocopherol and decreasing gamma-tocopherol levels were associated with decreased occurrence of large (> or = 1 cm) but not of small (<1 cm) adenomas; however, after adjustment for potential confounding variables, these trends were not statistically significant. A strong trend (P = 0.02) was observed by using the alpha-tocopherol:gamma-tocopherol ratio, which may be a more sensitive indicator of alpha-tocopherol intake. Subjects in the highest versus lowest quintile of alpha-tocopherol: gamma-tocopherol ratio had an odds ratio of 0.36 (95% confidence interval, 0.14-0.95) for large adenomas. The finding that a high alpha-tocopherol:gamma-tocopherol ratio is associated with decreased occurrence of large, but not of small, colorectal adenomas is consistent with previous findings that alpha-tocopherol may be protective against colon cancer. A high plasma alpha-tocopherol:gamma-tocopherol ratio may be a better predictor of decreased cancer risk than high plasma alpha-tocopherol alone.

    View details for Web of Science ID 000072025300019

    View details for PubMedID 9485018

  • Folate intake, alcohol consumption, cigarette smoking, and risk of colorectal adenomas JOURNAL OF THE NATIONAL CANCER INSTITUTE Baron, J. A., Sandler, R. S., Haile, R. W., Mandel, J. S., Mott, L. A., Greenberg, E. R. 1998; 90 (1): 57-62

    Abstract

    Recent evidence suggests that folic acid (and derivatives) could contribute to the protective effect of fruits and vegetables against the risk of large-bowel cancer. Other evidence indicates that alcohol drinking and cigarette smoking may impair the biologic actions of folate. We used data from an adenoma prevention trial to investigate the occurrence of colorectal adenomas (possible precursors of colorectal cancer) in association with folate intake, alcohol consumption, and cigarette smoking.Patients with at least one recent large-bowel adenoma were followed with colonoscopy 1 year and 4 years after their qualifying colon examinations. Adenomas detected after the year 1 examination were used as end points. A food-frequency questionnaire was administered at study entry and at study completion; nutrient intake at study entry was used in this analysis. All statistical tests were two-sided.After adjustment for caloric intake, dietary folate had a significant protective association with the risk of recurrence of large-bowel adenoma (P for trend = .04). However, this inverse association was attenuated by further adjustment for intake of dietary fiber and fat. Use of folate supplements was not associated with a reduction in risk. Alcohol intake (seven or more drinks/week) was associated with increased risk (odds ratio = 2.04; 95% confidence interval = 1.28-3.26). Cigarette smoking, even smoking for long duration, was not related to adenoma recurrence.These data provide only modest support for previous findings suggesting beneficial effects of folate on colorectal adenoma risk. We find no evidence that cigarette smoking increases risk. These findings do suggest a substantial increase in risk with alcohol consumption.

    View details for Web of Science ID 000072003600014

    View details for PubMedID 9428784

  • Dietary iron and recurrence of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Tseng, M., Sandler, R. S., Greenberg, E. R., Mandel, J. S., Haile, R. W., Baron, J. A. 1997; 6 (12): 1029-1032

    Abstract

    Previous research suggests that iron acts as a prooxidant to increase the risk of colorectal neoplasia. This study examined effects of dietary intake of iron on colorectal adenoma recurrence using data from an antioxidant clinical trial. All subjects were free of polyps at study entry but had at least one adenoma removed within the 3 months before enrollment. Follow-up colonoscopies were conducted after 1 and 4 years. Patients who developed one or more adenomatous polyps between years 1 and 4 were classified as cases; all others were controls. Dietary iron intake at baseline and at the end of the study was estimated from self-administered food frequency questionnaires and averaged together for each subject, energy-adjusted, and categorized into quartiles. Odds ratios were adjusted for age, center, sex, calories, treatment group, and alcohol, fiber, folate, and fat intakes in unconditional logistic regression analysis. Dietary iron was inversely associated with adenoma risk, although risk did not decrease monotonically with increasing intake. Odds ratios comparing second, third, and fourth quartiles to the lowest quartile were 0.61 [95% confidence interval (CI), 0.37-1.02], 0.80 (95% CI, 0.45-1.44), and 0.37 (95% CI, 0.19-0.73), respectively. A limited examination showed no clear evidence that use of iron supplements affected risk of recurrence in this study population. This study provides evidence against the hypothesis that recent dietary intake of iron increases risk for colorectal adenomas. However, these results may reflect the presence of other dietary factors found in combination with iron.

    View details for Web of Science ID 000071254300008

    View details for PubMedID 9419398

  • A sigmoidoscopy-based case-control study of polyps: Macronutrients, fiber and meat consumption INTERNATIONAL JOURNAL OF CANCER Haile, R. W., Witte, J. S., Longnecker, M. P., PROBSTHENSCH, N., Chen, M. J., Harper, J., Frankl, H. D., Lee, E. R. 1997; 73 (4): 497-502

    Abstract

    We conducted a large, sigmoidoscopy-based case-control study to examine the relation of intake of macronutrients, meat, and fiber to occurrence of adenomas of the large bowel. Cases were subjects diagnosed for the first time with one or more histologically confirmed adenomas. Controls had no polyps of any type at sigmoidoscopy, had no history of polyps, and were individually matched to cases by gender, age, date of sigmoidoscopy, and Kaiser Center. The response rate was 84% for cases and 82% for controls. Complete dietary data for 488 matched pairs were available. All odds ratios are from matched analyses adjusted for energy. We observed positive associations with risk of adenomas for calories, animal fat, saturated fat, red meat, and the ratio of red meat to poultry and fish. Protective effects were observed for vegetable protein, carbohydrates, and dietary fiber. The fiber effects diminished after adjusting for fruits and vegetables. Results after mutually adjusting for the effects of saturated fat, fiber and the ratio of red meat to chicken and fish suggest that each of these variables has an effect on risk of adenomas that is independent of the other 2 exposures.

    View details for Web of Science ID A1997YG99200007

    View details for PubMedID 9389562

  • Phenolphthalein-containing laxative use in relation to adenomatous colorectal polyps in three studies ENVIRONMENTAL HEALTH PERSPECTIVES Longnecker, M. P., Sandler, D. P., Haile, R. W., Sandler, R. S. 1997; 105 (11): 1210-1212

    Abstract

    Phenolphthalein, the active ingredient in many laxatives, was recently found to be a carcinogen in animal models. Human data suggest a laxative-colon cancer association, but few data specifically address the effects of phenolthalein-containing laxatives. We examined use of phenolphtalein-containing laxatives in relation to occurrence of adenomatous colorectal polyps in data from three case-control studies. The study conducted in Los Angeles, California (1991-1993), and the two studies conducted in North Carolina (1988-1990 and 1992-1995) altogether included 866 cases and 1,066 controls. The prevalence of using phenolphthalein-containing laxatives at least once a week in the recent past, however, was less than 5% among these subjects. The multivariate-adjusted odds ratios associated with recent use of phenolphthalein-containing laxatives once a week or more were 1.8 -95% confidence interval (CI), 0.5-6.2] in Los Angeles, 1.0 (CI, 0.4-2.2) in North Carolina (1988-1990), and 1.1 (CI, 0.2-5.7) in North Carolina (1992-1995). For use of other types of laxatives, the corresponding odds ratios were 1.3 (CI, 0.9-1.9) in Los Angeles, 1.0 (CI, 0.5-1.7) in North Carolina (1988-1990), and 0.9 (CI, 0.4-1.8) in North Carolina (1992-1995). Although the low prevalence of frequent use made for relatively wide confidence intervals, overall these data suggest that use of phenolphthalein-containing laxatives does not increase risk of adenomatous colorectal polyps.

    View details for Web of Science ID 000072815000014

    View details for PubMedID 9370521

  • Breast cancer and hormone replacement therapy: collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer and 108,411 women without breast cancer LANCET Beral, V., Bull, D., DOLL, R., Key, T., Peto, R., Reeves, G., Calle, E. E., Heath, C. W., Coates, R. J., Liff, J. M., Franceschi, S., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Morabia, A., Schuman, L., Stewart, W., Szklo, M., Bain, C., Schofield, F., Siskind, V., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Duffy, S. W., Kolonel, L. M., Nomura, A. M., Oberle, M. W., Ory, H. W., Peterson, H. B., Wilson, H. G., Wingo, P. A., Ebeling, K., Kunde, D., Nishan, P., Colditz, G., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., McMichael, A. J., Rohan, T., Ewertz, M., Adami, H. O., BERGKVIST, R., Persson, I., Paul, C., Skegg, D. C., Spears, G. F., Boyle, P., Evstifeeva, T., Daling, J. R., Hutchinson, W. B., Malone, K., NOONAN, E. A., Stanford, J. L., Thomas, D. B., Weiss, N. S., White, E., Andrieu, N., Bramond, A., Clavel, F., Gairard, B., Lansac, J., Piana, L., Renaud, R., Fine, S. R., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., ARISTIZABAL, N., Cuadros, A., BACHELOR, A., Le, M. G., Deacon, J., Peto, J., Taylor, C. N., Modan, B., Ron, E., Friedman, G. D., Hiatt, R. A., Levi, F., Bishop, T., Kosmelj, K., PRIMICZAKELJ, M., Ravnihar, B., Stare, J., Beeson, W. L., Fraser, G., Bulbrook, R. D., Cuzick, J., Fentiman, I. S., Hayward, J. L., Wang, D. Y., McPherson, K., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. O., Weinstein, A. L., Moller, T. R., Olsson, H., Ranstam, J., Goldbohm, R. A., VANDENBRANDT, P. A., APELO, R. A., BAENS, J., delaCruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., LAVECCHIA, C., Negri, E., Marubini, E., Ferraroni, M., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Hoover, R., Schairer, C., Spirtas, R., Lee, H. P., Rookus, M. A., VANLEEUWEN, F. E., Schoenberg, J. A., Gammon, M. D., Clarke, E. A., Jones, L., Neil, A., Vessey, M., Yeates, D., Crossley, B., Hermon, C., Jones, S., Lewis, C., Collins, R., Mabuchi, K., Preston, D., Hannaford, P., Kay, C., ROSEROBIXBY, L., Yuan, J. M., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., BOOTH, J. C., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., WANG, Q. S., Baines, C. J., Miller, A. B., WALL, C., Lund, E., Stalsberg, H., Katsouyanni, K., Trichopoulos, D., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, F. E., Folsom, A. R., Chilvers, C. E., Bernstein, L., Haile, R. W., PAGANINIHILL, A., Pike, M. C., Ross, R. K., Ursin, G., Yu, M. C., Longnecker, M. P., Newcomb, P., Bergkvist, L., Farley, T. M., Holck, S., MEIRIK, O. 1997; 350 (9084): 1047-1059
  • Does oral contraceptive use increase the risk of breast cancer in women with BRCA1/BRCA2 mutations more than in other women? CANCER RESEARCH Ursin, G., Henderson, B. E., Haile, R. W., Pike, M. C., Zhou, N. M., Diep, A., Bernstein, L. 1997; 57 (17): 3678-3681

    Abstract

    We conducted a study to determine whether the risk of breast cancer associated with oral contraceptive (OC) use is higher in women with BRCA1/BRCA2 mutations than in other women by examining whether breast cancer patients with these mutations were more likely than breast cancer patients without mutations in BRCA1/BRCA2 to have used OCs. We tested for BRCA1 185delAG and 5382insC and BRCA2 6174delT mutations in a population-based sample of 50 young Ashkenazi Jewish breast cancer patients. Nine patients (18%) had a BRCA1 mutation, and five patients (10%) had a BRCA2 mutation. Long-term OC use (>48 months) before a first full-term pregnancy was associated with an elevated risk of being classified as a mutBRCA carrier (odds ratio, 7.8; trend, P = 0.004). The results suggest that OC use may increase the risk of breast cancer more in mutBRCA carriers than in noncarriers; however, they must be interpreted with caution given the small sample size.

    View details for Web of Science ID A1997XU39600013

    View details for PubMedID 9288771

  • Hierarchical modeling of gene-environment interactions: Estimating NAT2* genotype-specific dietary effects on adenomatous polyps CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Aragaki, C. C., Greenland, S., PROBSTHENSCH, N., Haile, R. W. 1997; 6 (5): 307-314

    Abstract

    Data sparseness currently limits gene-environment interaction estimation. To improve effect estimates of gene-environment interactions, we give an overview of one approach, hierarchical modeling, and propose a two-stage hierarchical model. The first stage is a logistic model for the joint effects of the genetic and environmental factors. The second stage regresses the joint effects on genotype-specific enzymatic activity of the environmentally derived substrate. The model is illustrated using a case-control study of adenomas of the large bowel, for which NAT2 genotype and dietary data were collected. The first-stage interactions of dietary components and genotype were regressed on initial conversion rates of dietary heterocyclic amines to aryl nitrenium ions. We fit the hierarchical model by penalized likelihood. Compared to effect estimates from maximum-likelihood logistic regression, hierarchical results are more reasonable and precise. These results lend further support to previous observations that hierarchical regression is preferable to ordinary logistic regression when multiple factors and their interactions are being studied. We propose that hierarchical modeling can act as a bridge between molecular epidemiology studies and laboratory data, combining both efficiently.

    View details for Web of Science ID A1997WZ60300003

    View details for PubMedID 9149889

  • Plasma carotenoids and the prevalence of adenomatous polyps of the distal colon and rectum AMERICAN JOURNAL OF EPIDEMIOLOGY Shikany, J. M., Witte, J. S., Henning, S. M., Swendseid, M. E., Bird, C. L., Frankl, H. D., Lee, E. R., Haile, R. W. 1997; 145 (6): 552-557

    Abstract

    In a case-control study, the authors investigated relations between plasma carotenoid concentrations and the prevalence of colorectal adenomatous polyps (precursors to colorectal cancer) in residents of Los Angeles County and Orange County, California, from 1991 through 1993. Plasma concentrations of six carotenoids were compared in 472 asymptomatic cases with a first-time diagnosis of at least one adenomatous polyp of the distal colon or rectum and 502 matched controls. Odds ratios adjusted for age, sex, smoking, alcohol intake, and energy, saturated fat, and fruit and vegetable intake revealed no associations between any of the individual carotenoids and polyp prevalence or between total carotenoids and polyp prevalence.

    View details for Web of Science ID A1997WM32100012

    View details for PubMedID 9063346

  • Meat preparation and colorectal adenomas in a large sigmoidoscopy-based case-control study in California (United States) CANCER CAUSES & CONTROL PROBSTHENSCH, N. M., Sinha, R., Longnecker, M. P., Witte, J. S., Ingles, S. A., Frankl, H. D., Lee, E. R., Haile, R. W. 1997; 8 (2): 175-183

    Abstract

    The often observed association between red meat and colorectal cancer could be due in part to mutagens, such as heterocyclic amines (HCA), that are present in cooked meat. HCAs are highly mutagenic and cause intestinal tumors in animals. The hypothesis that HCAs are also carcinogenic to humans remains to be substantiated in epidemiologic studies. We determined the associations of meat preparation and frequency of intake (proxy variables for HCA exposure, since HCA concentration depends on the type of meat and the way it is cooked) with the prevalence of distal colorectal adenomas in a sigmoidoscopy-based case-control study of 488 matched pairs of subjects from two California (United States) Kaiser Permanente Medical Centers. A more than twofold difference in adenoma prevalence between subjects at extreme ends of estimated HCA intake was observed. For subjects who ate red meat more than once per week, fried it more than 10 percent of the time, and ate it with a darkly browned surface, compared with subjects who ate red meat one time or less per week, fried it 10 or less percent of the time, and ate it with a lightly browned surface, the odds ratio was 2.2 (95 percent confidence interval = 1.1-4.3). Adenoma prevalence also increased with frequency of frying red meat (P trend = 0.004). These results are consistent with a carcinogenic effect of HCA.

    View details for Web of Science ID A1997WU35100008

    View details for PubMedID 9134241

  • Diet and premenopausal bilateral breast cancer: A case-control study BREAST CANCER RESEARCH AND TREATMENT Witte, J. S., Ursin, G., Siemiatycki, J., Thompson, W. D., PAGANINIHILL, A., Haile, R. W. 1997; 42 (3): 243-251

    Abstract

    We investigated associations between diet and premenopausal bilateral breast cancer in a familial matched case-control study. We studied 140 cases from population-based registries in Los Angeles County (California) and Connecticut, and from the major hospitals in the southern parts of the Province of Quebec. Unaffected sisters of the cases served as matched controls (222 total). Dietary intake were assessed with a food frequency questionnaire. Total fat, monounsaturated fat, polyunsaturated fat, oleic acid, and linoleic acid intake was inversely associated with premenopausal bilateral breast cancer risk. Consumption of carbohydrates (and sweetened beverages) was associated with an increased risk. We observed no associations for dietary fiber, antioxidants, or major food groupings, but we did observe inverse associations for intake of low fat dairy products and tofu. These findings suggest that monounsaturated and polyunsaturated fats, as well as soy foods, might reduce the risk of premenopausal bilateral breast cancer.

    View details for Web of Science ID A1997WM10800006

    View details for PubMedID 9065608

  • Strength of linkage disequilibrium between two vitamin D receptor markers in five ethnic groups: Implications for association studies CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Ingles, S. A., Haile, R. W., Henderson, B. E., Kolonel, L. N., Nakaichi, G., Shi, C. Y., Yu, M. C., Ross, R. K., Coetzee, G. A. 1997; 6 (2): 93-98

    Abstract

    Markers in the 3' end of the vitamin D receptor gene have recently been associated with prostate cancer risk. To evaluate the adequacy of the commonly used BsmI restriction fragment length polymorphism as a marker of this locus, we genotyped 627 individuals from five ethnic groups for this marker, as well as for a polymorphic site in the 3' untranslated region of this gene. At the latter site, we identified 12 alleles, A13 to A24, of a poly(A) microsatellite. Allele size followed a bimodal distribution with distinct short (A13-A17) and long (A18-A24) allele populations. Poly(A) allele frequency differed by ethnicity, with the frequency of short alleles being highest in non-Hispanic whites (41%), intermediate in Hispanics and African-Americans (31 and 29%, respectively), and lowest in Japanese-Americans and Chinese (8 and 9%, respectively). In each of the ethnic groups, some degree of coupling was observed between BsmI B and short poly(A) alleles and between BsmI b and long poly(A) alleles. However, the strength of the linkage disequilibrium varied by ethnicity, with departures from complete disequilibrium producing disagreement between the BsmI and poly(A) genotypes. Genotypic disagreement was lowest in Japanese-Americans and non-Hispanic whites (6 and 7%, respectively), intermediate in Chinese and Hispanics (11 and 19%, respectively), and highest among African-Americans (37%), indicating that BsmI is not a good marker for the vitamin D receptor 3' untranslated region genotype in all populations. This finding may explain contradictory results from recent association studies using the BsmI marker.

    View details for Web of Science ID A1997WG44500004

    View details for PubMedID 9037559

  • Association of prostate cancer risk with genetic polymorphisms in vitamin D receptor and androgen receptor JOURNAL OF THE NATIONAL CANCER INSTITUTE Ingles, S. A., Ross, R. K., Yu, M. C., Irvine, R. A., LAPERA, G., Haile, R. W., Coetzee, G. A. 1997; 89 (2): 166-170

    Abstract

    Prostate cancer is an increasingly common disease for which there are few well-established risk factors. Family history data suggest a genetic component; however, the majority of prostate cancer cases cannot be explained by a single-gene model. Prostate cell division is influenced by two steroid hormones, testosterone and vitamin D, the action of each being mediated by its respective receptor. The genes for the two receptors are candidates in a multigenic model for prostate cancer susceptibility.We examined genetic polymorphisms in two steroid receptors, the androgen receptor (AR) and the vitamin D receptor (VDR), in a case-control pilot study of prostate cancer.Fifty-seven non-Hispanic white case patients with prostate cancer and 169 non-Hispanic white control subjects were genotyped for a previously described microsatellite (CAG repeats) in the AR gene and for a newly discovered poly-A microsatellite in the 3'-untranslated region (3'UTR) of the VDR gene. To compare genotypes with respect to prostate cancer risk, we estimated odds ratios (ORs) by using logistic regression. ORs were also estimated separately for advanced and localized cases of disease. All P values resulted from two-sided tests.Both the AR and the VDR polymorphisms were associated, individually and after mutual adjustment, with prostate cancer. Adjusted ORs (95% confidence intervals [CIs]) for prostate cancer were 2.10 (95% CI = 1.11-3.99) for individuals carrying an AR CAG allele with fewer than 20 repeats versus an allele with 20 or more repeats and 4.61 (95% CI = 1.34-15.82) for individuals carrying at least one long (A18 to A22) VDR poly-A allele versus two short (A14 to A17) poly-A alleles. For both the AR and VDR genes, the at-risk genotypes were more strongly associated with advanced disease than with localized disease.In this pilot study, genetic variation in both the VDR and the AR genes was associated with prostate cancer, and both genes appear to preferentially confer risk for advanced disease. These two genetic risk factors, if confirmed, are among the strongest risk factors yet identified for prostate cancer.These results are consistent with a multigenic model of prostate cancer susceptibility. On the basis of the joint effect of several genetic loci, one might ultimately be able to construct a risk profile to predict advanced disease, so that men whose disease is unlikely to progress to an advanced stage can possibly be spared aggressive treatment.

    View details for Web of Science ID A1997WB92500018

    View details for PubMedID 8998186

  • Resent and past physical activity and prevalence of colorectal adenomas BRITISH JOURNAL OF CANCER Enger, S. M., Longnecker, M. P., Lee, E. R., Frankl, H. D., Haile, R. W. 1997; 75 (5): 740-745

    Abstract

    Epidemiological evidence has generally supported a protective association of physical activity with large-bowel adenomas, but whether the protective effects are restricted to recent or past activity is uncertain. We determined whether recent and past recreational or total daily activity was associated with prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, aged 50-74 years, completed a 126-item semiquantitative food frequency questionnaire and were also interviewed regarding non-dietary risk factors in 1991-93. In the univariate analysis, all measures of recent recreational physical activity were associated with reduced prevalence of polyps. After adjustment for body mass index, smoking status, daily servings of fruit and vegetables, use of non-steroidal anti-inflammatory agents and intakes of calories, saturated fat and alcohol, the associations were weakened. For subjects engaging in high-intensity activities compared with subjects not engaging in vigorous activities, the multivariate odds ratio (OR) for recent recreational activity was 0.7 [95% confidence interval (CI) 0.4-1.1, trend P = 0.08]. Past recreational activity and past or recent total daily activity were not associated with prevalence of adenomas. These results support a modest association of recent recreational physical activity with prevalence of colorectal adenomas.

    View details for Web of Science ID A1997WK06600019

    View details for PubMedID 9043034

  • Coffee and tea and the risk of recurrent colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Baron, J. A., Greenberg, E. R., Haile, R., Mandel, J., Sandler, R. S., Mott, L. 1997; 6 (1): 7-10

    Abstract

    Consumption of coffee has been associated with a reduction in the risk of cancer of the colon, and (less consistently) drinking tea has been associated with a reduction in the risk of rectal cancer. The effect of these beverages on the risk of colorectal adenomas, however, has not been well investigated. We used data from an adenoma prevention trial to investigate these associations. Patients with at least one recent large bowel adenoma were followed with colonoscopy 1 and 4 years after their qualifying examinations. Adenomas detected at the year 4 colonoscopy were used as end points. A food frequency questionnaire was administered at study entry and study completion; average intake over the study period was used to estimate the exposures of interest. There was no apparent association between the intake of regular coffee, decaffeinated coffee, or tea and the risk of recurrent colorectal adenomas. The relative risks and 95% confidence intervals per cup daily were 0.96 (0.87-1.05) for regular coffee, 0.97 (0.84-1.12) for decaffeinated coffee, and 1.02 (0.83-1.25) for tea. These negative findings were present both overall and for adenomas of the right and left large bowel.

    View details for Web of Science ID A1997WB77200002

    View details for PubMedID 8993790

  • Relation of vegetable, fruit, and grain consumption to colorectal adenomatous polyps AMERICAN JOURNAL OF EPIDEMIOLOGY Witte, J. S., Longnecker, M. P., Bird, C. L., Lee, E. R., Frankl, H. D., Haile, R. W. 1996; 144 (11): 1015-1025

    Abstract

    Previous studies suggest that colorectal cancer risk decreases with higher intake of vegetables, fruits, and grains. Few studies, however, have examined these factors in relation to occurrence of colorectal polyps. The authors used case-control data from 488 matched pairs to evaluate associations of vegetables, fruits, and grains with polyps. Subjects were southern Californians aged 50-74 years who had a sigmoidoscopy in 1991-1993. Diet in the year before sigmoidoscopy was measured with a food frequency questionnaire. Frequent consumption of vegetables, fruits, and grains was associated with decreased polyp prevalence. Specifically, the adjusted odds ratio comparing the highest with the lowest quintile of intake for vegetables was 0.47 (95% confidence interval (CI) 0.29-0.76), for fruits was 0.65 (95% CI 0.40-1.05), and for grains was 0.55 (95% CI 0.33-0.91). The authors also found inverse associations for high carotenoid vegetables, cruciferae, high vitamin C fruits, garlic, and tofu (or soybeans). After further adjusting for potentially anticarcinogenic constituents of these foods, high carotenoid vegetables, cruciferous vegetables, garlic, and tofu (or soybeans) remained inversely associated with polyps. These findings support the hypothesis that high intake of vegetables, fruits, or grains decreases the risk of polyps and suggest that any protective effects might reflect unmeasured constituents in these foods.

    View details for Web of Science ID A1996VV53500002

    View details for PubMedID 8942431

  • Lack of association between the polyadenylation polymorphism in the NAT1 (acetyltransferase 1) gene and colorectal adenomas CARCINOGENESIS PROBSTHENSCH, N. M., Haile, R. W., Li, D. S., Sakamoto, G. T., Louie, A. D., Lin, B. K., Frankl, H. D., Lee, E. R., Lin, H. J. 1996; 17 (10): 2125-2129

    Abstract

    Smoking and a high intake of red meat are risk factors for colorectal tumors. These effects could be due to aromatic amine carcinogens. Individual susceptibility to aromatic amines has been related to acetylation phenotype, which plays a role in the bioactivation of arylamines. Polymorphisms in both N-acetyltransferase genes, NAT1 and NAT2, have been associated with an increased risk of colorectal tumors. We studied the NAT1*10 fast acetylator allele (1088 T-->A mutation) and distal adenomas in a sigmoidoscopy-based case-control study (441 cases, 484 controls). We found neither an increased adenoma prevalence in subjects homozygous or heterozygous for the NAT1*10 fast acetylator allele (odds ratio 1.04; 95% confidence interval 0.79-1.36), nor a gene-gene interaction between NA1 and NAT2 (P(interaction) = 0.59). Further NAT1 alleles must be considered for more conclusive results regarding the relevance of NAT1 activity to colorectal tumorigenesis.

    View details for Web of Science ID A1996VM80500004

    View details for PubMedID 8895478

  • Breast cancer and hormonal contraceptives: Further results CONTRACEPTION Calle, E. E., Heath, C. W., MIRACLEMCMAHILL, H. L., Coates, R. J., Liff, J. M., Franceschi, S., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Morabia, A., Schuman, I., Stewart, W., Szklo, M., Bain, C., Schofield, F., Siskind, V., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Duffy, S. W., Kolonel, L. M., Nomura, A. M., Oberle, M. W., Ory, H. W., Peterson, H. B., Wilson, H. G., Wingo, P. A., Ebeling, K., Kunde, D., Nishan, P., Colditz, G., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., McMichael, A. J., Rohan, T., Ewertz, M., Paul, C., Skegg, D. C., Spears, G. F., Boyle, P., Evstifeeva, T., Daling, J. R., Malone, K., NOONAN, E. A., Stanford, J. L., Thomas, D. B., Weiss, N. S., White, E., Andrieu, N., Bremond, A., Clavel, F., Gairard, B., Lansac, J., Piana, L., Renaud, R., Fine, S. R., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., Aristizabel, N., Cuadros, A., Bachelot, A., Le, M. G., Deacon, J., Peto, J., Taylor, C. N., Alfandary, E., Modan, B., Ron, E., Friedman, G. D., Hiatt, R. A., Bishop, T., Kosmelj, K., PRIMICZAKELJ, M., Ravnihar, B., Stare, J., Beeson, W. L., Fraser, G., Allen, D. S., Bulbrook, R. D., Cuzick, J., Fentiman, I. S., Hayward, J. L., Wang, D. Y., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. P., Weinstein, A. L., Moller, T. R., Olsson, H., Ranstam, J., Goldbohm, R. A., VANDENBRANDT, P. A., APELO, R. A., BAENS, J., delaCruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., LAVECCHIA, C., Negri, E., Marbuni, E., Ferraroni, M., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Hoover, R., Schairer, C., Spirtas, R., Lee, H. P., Rookus, M. A., VANLEEUWEN, F. E., Schoenberg, J. A., Gammon, M. D., Clarke, E. A., Jones, L., McPherson, K., Neil, A., Vessey, M., Yeates, D., Beral, V., Bull, D., Crossley, B., Hermon, C., Jones, S., Key, T., Lewis, C., Reeves, G., Smith, P., Collins, R., DOLL, R., Peto, R., Hannaford, P., Kay, C., ROSEROBIXBY, L., Yuan, J. M., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., BOOTH, J. C., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., WANG, Q. S., Baines, C. J., Miller, A. B., WALL, C., Lund, E., Stalsberg, H., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, F. E., Hulka, B. S., Chilvers, C. E., Bernstein, L., Haile, R. W., PAGANINIHILL, A., Pike, M. C., Ross, R. K., Ursin, G., Yu, M. C., Adami, H. O., Bergstrom, R., Longnecker, M. P., Newcomb, P., Farley, T. M., Holck, S., MEIRIK, O. 1996; 54 (3): S1-S106
  • Serum lipids and adenomas of the left colon and rectum CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bird, C. L., Ingles, S. A., Frankl, H. D., Lee, E. R., Longnecker, M. P., Haile, R. W. 1996; 5 (8): 607-612

    Abstract

    Levels of serum lipids are partially determined by several established risk factors for colorectal cancer and are themselves potential risk factors for the disease. However, evaluating serum lipids as risk factors has proved problematic because metabolic events associated with malignant transformation or progression appear to alter serum lipid concentrations. Serum lipid concentrations are less likely to have altered in individuals with precancerous lesions, such as colorectal adenomas. During 1991-1993, we collected fasting blood samples from and provided questionnaires to men and women 50-75 years old, who visited sigmoidoscopy clinics at a health maintenance organization. Serum lipid concentrations from 486 cases with adenomas and 520 controls were analyzed. Compared to subjects in the lowest quintile of serum triglyceride concentrations, subjects in the highest quintile had an adjusted odds ratio of 1.5 (95% confidence interval, 1.0-2.2). The corresponding odds ratio for total cholesterol was 1.3 (0.9-1.9); for high-density lipoprotein cholesterol, it was 1.1 (0.7-1.6); and for low-density lipoprotein cholesterol, it was 1.1 (0.7-1.6). Further adjustment for potential confounding did not alter these results substantively, although determinants of serum triglycerides and high-density lipoprotein cholesterol (e.g., obesity, physical activity, and refined carbohydrate and alcohol intake) in this and other studies may not be sufficiently well measured to avoid residual confounding. Higher levels of serum triglycerides are associated with an increased risk of adenomatous polyps. Consistent with previous studies, serum cholesterol was not inversely related to the risk of colorectal polyps.

    View details for Web of Science ID A1996VC07400004

    View details for PubMedID 8824362

  • Agreement in alcohol consumption levels as measured by two different questionnaires JOURNAL OF STUDIES ON ALCOHOL Witte, J. S., Haile, R. W. 1996; 57 (4): 406-409

    Abstract

    We evaluated the agreement in reported alcohol consumption between a standard food frequency questionnaire (FFQ) and a risk factor questionnaire (RFQ) developed for a genetic epidemiologic study of breast cancer.The FFQ measured intake of alcoholic beverages by asking which of nine levels were consumed during a single time period. In contrast, the RFQ used open-ended questions to measure intake of alcoholic beverages during numerous time periods. Subjects (N = 765) completed both questionnaires at home.Mean daily alcohol consumption levels were consistently higher in the FFQ than in the RFQ; for example, the mean alcohol consumption for all subjects was 7.0 g/day in the FFQ versus 5.3 g/day in the RFQ. Moreover, the RFQ overestimated the number of nondrinkers relative to the FFQ. Nonetheless, the Spearman correlation coefficients between daily alcohol consumption levels as measured by the two questionnaires were relatively high: total alcohol, r = 0.72; beer, r = 0.69; wine, r = 0.69; and distilled spirits, r = 0.54.The reasonable agreement between these questionnaires supports the validity of historical alcohol consumption levels measured by the RFQ.

    View details for Web of Science ID A1996UR80200011

    View details for PubMedID 8776682

  • Plasma ferritin, iron intake, and the risk of colorectal polyps AMERICAN JOURNAL OF EPIDEMIOLOGY Bird, C. L., Witte, J. S., Swendseid, M. E., Shikany, J. M., HUNT, I. F., Frankl, H. D., Lee, E. R., Longnecker, M. P., Haile, R. W. 1996; 144 (1): 34-41

    Abstract

    High iron exposure has been associated with colorectal neoplasia in several studies. The authors investigated plasma ferritin, an indicator of iron stores, and iron intake as risk factors for adenomatous polyps, intermediate markers for colorectal cancer. During 1991-1993, they collected fasting blood samples from and administered questionnaires to men and women 50-75 years old who visited free sigmoidoscopy clinics at a health maintenance organization. Data from 965 subjects (467 cases, 498 controls) were analyzed. Compared with those who had low-normal plasma ferritin concentrations (73-141 micrograms/liter), those with elevated concentrations ( > 289 micrograms/liter) had a multivariate-adjusted odds ratio of 1.5 (95% confidence interval (CI) 1.0-2.3) after excluding subjects with possible non-iron-related elevations in ferritin. Compared with subjects consuming an adequate amount of iron (11.6-13.6 mg/day), multivariate-adjusted odds ratios were 1.6 (95% CI 1.1-2.4) for < 11.6 mg/day and 1.4 (95% CI 0.9-2.0) for > 27.3 mg/day. These results provide further support for a weak positive association between iron exposure and colorectal polyps.

    View details for Web of Science ID A1996UT90600004

    View details for PubMedID 8659483

  • Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53297 women with breast cancer and 100239 women without breast cancer from 54 epidemiological studies LANCET Calle, E. E., Heath, C. W., MIRACLEMCMAHILL, H. L., Coates, R. J., Liff, J. M., Franceschi, S., Talamini, R., CHANTARAKUL, N., KOETSAWANG, S., RACHAWAT, D., Morabia, A., Schuman, L., Stewart, W., Szklo, M., Bain, C., Schofield, F., Siskind, V., Band, P., Coldman, A. J., Gallagher, R. P., Hislop, T. G., Yang, P., Duffy, S. W., Kolonel, L. M., Nomura, A. M., Oberle, M. W., Ory, H. W., Peterson, H. B., Wilson, H. G., Wingo, P. A., Ebeling, K., Kunde, D., Nishan, P., Colditz, G., Martin, N., PARDTHAISONG, T., SILPISORNKOSOL, S., Theetranont, C., BOOSIRI, B., CHUTIVONGSE, S., Jimakorn, P., Virutamasen, P., Wongsrichanalai, C., McMichael, A. J., Rohan, T., Ewertz, M., Paul, C., Skegg, D. C., Boyle, P., Evstifeeva, M., Daling, J. R., Malone, K., NOONAN, E. A., Stanford, J. L., Thomas, D. B., Weiss, N. S., White, E., Andrieu, N., Bremond, A., Clavel, F., Gairard, B., Lansac, J., Piana, L., Renaud, R., Cuevas, H. R., Ontiveros, P., PALET, A., Salazar, S. B., Aristizabel, N., Cuadros, A., Bachelot, A., Le, M. G., Deacon, J., Peto, J., Taylor, C. N., Alfandary, E., Modan, B., Ron, E., Friedman, G. D., Hiatt, R. A., Bishop, T., Kosmelj, J., PRIMICZAKELJ, M., Ravnihar, B., Stare, J., Beeson, W. L., Fraser, G., Allen, D. S., Bulbrook, R. D., Cuzick, J., Fentiman, I. S., Hayward, J. L., Wang, D. Y., Hanson, R. L., Leske, M. C., Mahoney, M. C., Nasca, P. C., Varma, A. O., Weinstein, A. L., Moller, T. R., Olsson, H., Ranstam, J., Goldbohm, R. A., VANDENBRANDT, P. A., APELO, R. A., BAENS, J., delaCruz, J. R., JAVIER, B., Lacaya, L. B., Ngelangel, C. A., LAVECCHIA, C., Negri, E., Marubini, E., Ferraroni, M., Gerber, M., Richardson, S., Segala, C., Gatei, D., Kenya, P., Kungu, A., Mati, J. G., Brinton, L. A., Hoover, R., Schairer, C., Spirtas, R., Lee, H. P., Rookus, M. A., VANLEEUWEN, F. E., Schoenberg, J. A., Gammon, M. D., Clarke, E. A., Jones, L., McPherson, K., Neil, A., Vessey, M., Yeates, D., Beral, V., Bull, D., Crossley, B., Hermon, C., Jones, S., Key, T., Lewis, C., Reeves, G., Smith, P., Collins, R., DOLL, R., Peto, R., Hannaford, P., Kay, C., ROSEROBIXBY, L., Gao, Y. T., Yuan, J. M., Wei, H. Y., Yun, T., Zhiheng, C., Berry, G., BOOTH, J. C., JELIHOVSKY, T., MACLENNAN, R., SHEARMAN, R., WANG, Q. S., Baines, C. J., Miller, A. B., WALL, C., Lund, E., Stalsberg, H., DABANCENS, A., Martinez, L., Molina, R., SALAS, O., Alexander, F. E., Hulka, B. S., Bernstein, L., Haile, R. W., PAGANINIHILL, A., Pike, M. C., Ross, R. K., Ursin, G., Yu, M. C., Adami, H. O., Bergstrom, R., Longnecker, M. P., Newcomb, P., Farley, T. M., Holck, S., MEIRIK, O. 1996; 347 (9017): 1713-1727
  • Alcohol and smoking in relation to the prevalence of adenomatous colorectal polyps detected at sigmoidoscopy EPIDEMIOLOGY Longnecker, M. P., Chen, M. J., PROBSTHENSCH, N. M., Harper, J. M., Lee, E. R., Frankl, H. D., Haile, R. W. 1996; 7 (3): 275-280

    Abstract

    Cigarette smoking has been associated with adenomatous polyps of the large bowel but not with increased risk of colorectal cancer. Giovannucci et al recently proposed a hypothesis to explain this inconsistency. A key testable aspect of the hypothesis is that smoking in the distant past increases the risk of large polyps. Questions also remain about the association between colorectal polyps and consumption of alcohol. To address these issues, we examined data from 488 cases with adenomatous polyps and 488 controls. Subjects were members of a prepaid health plan in Los Angeles who had a sigmoidoscopy in 1991-1993. As expected, the adjusted odds of polyps in current smokers compared with never-smokers was increased [odds ratio = 2.43; 95% confidence interval (CI) = 1.56-3.79]. For those who had smoked in the distant past (for example, 30 or more pack-years before 20 years ago), the adjusted odds of an adenoma > or = 1 cm, relative to nonsmokers, was 0.88 (95% CI = 0.23-3.42). The adjusted odds of polyps in those consuming > or = 46 gm per day of alcohol compared with nondrinkers was 1.50 (95% CI = 0.72-3.13). Although imprecise, these data do not support the hypothesis that past smoking increases the risk of large polyps, but our results indicate a weak association between alcohol use and risk of adenomatous polyps.

    View details for Web of Science ID A1996UG18400012

    View details for PubMedID 8728441

  • A seroprevalence and descriptive epidemiological study of malaria among Indian tribes of the Amazon basin of Brazil ANNALS OF TROPICAL MEDICINE AND PARASITOLOGY DEARRUDA, M. E., Aragaki, C., Gagliardi, F., Haile, R. W. 1996; 90 (2): 135-143

    Abstract

    Data on the seroprevalences of Plasmodium falciparum, P. vivax, and P. malariae in four isolated Indian tribes of the Amazon basin in Brazil, as determined by IFAT, were re-analysed. Age-, sex- and tribe-specific geometric mean antibody titres and externally standardized prevalence ratios were calculated for each parasite species. Correlation coefficients and prevalence odds ratios were also calculated for multiple infections with different combinations of the three Plasmodium species. Titres of all but one of the antibodies studied were similar in males and females; titres of antibodies to the blood stages of P. malariae were slightly higher in females than in males. Titres of antibodies to all three Plasmodium species increased with subject age, and this age effect was not confounded by sex or tribal differences. There were striking differences between tribes, with the Parakana tribe having relatively low titres of antibodies against P. falciparum and P. malariae; these tribal effects were not confounded by sex or age differences between tribes. The results indicate that conditions conductive to the transmission of P. malariae exist in this region of the Amazon. The potential for zoonotic transmission of P. brasilianum, a parasite of monkeys which is morphologically similar to P. malarie, and the generally high rates of seropositivity to all three species of Plasmodium indicate that control measures which are adequate and applicable to the region studied need to be developed.

    View details for Web of Science ID A1996UG28200004

    View details for PubMedID 8762403

  • Mortality associated with low plasma concentration of beta carotene and the effect of oral supplementation JAMA-JOURNAL OF THE AMERICAN MEDICAL ASSOCIATION Greenberg, E. R., Baron, J. A., Karagas, M. R., Stukel, T. A., Nierenberg, D. W., Stevens, M. M., Mandel, J. S., Haile, R. W. 1996; 275 (9): 699-703

    Abstract

    To examine the relationship between beta carotene plasma concentration and beta carotene supplementation and risk of death from major disease causes.Cohort study of plasma concentrations; randomized, controlled clinical trial of supplementation.Medical school-affiliated dermatology practices.A total of 1188 men and 532 women with mean age of 63.2 years, who had enrolled in a randomized clinical trial of beta carotene supplementation to prevent nonmelanoma skin cancer.Oral beta carotene, 50 mg per day for a median of 4.3 years.All-cause mortality and mortality from cardiovascular disease and cancer.During a median follow-up period of 8.2 years, there were 285 deaths. Persons whose initial plasma beta carotene concentrations were in the highest quartile (>0.52 micromol/L [27.7 microg/dL]) had a lower risk of death from all causes (adjusted relative rate [RR], 0.52; 95% confidence interval [CI] 0.44 to 0.87) and from cardiovascular diseases (adjusted RR, 0.57; 95% CI, 0.34 to 0.95) compared with persons with initial concentrations in the lowest quartile (<0.21 micromol/L [11.2 microg/dL]). Patients randomly assigned to beta carotene supplementation showed no reduction in relative mortality rates from all causes (adjusted RR, 1.03; 95% CI, 0.82 to 1.30) or from cardiovascular disease (adjusted RR, 1.16; 95% CI, 0.82 to 1.64). There was no evidence of lower mortality following supplementation among patients with initial beta carotene concentrations below the median for the study group.These analyses provide no support for a strong effect of supplemental beta carotene in reducing mortality from cardiovascular disease or other causes. Although the possibility exists that beta carotene supplementation produces benefits that are too small or too delayed to have been detected in this study, noncausal explanations should be sought for the association between plasma concentrations of beta carotene and diminished risk of death.

    View details for Web of Science ID A1996TX17400025

    View details for PubMedID 8594267

  • Dietary intake of specific carotenoids and vitamins A, C, and E, and prevalence of colorectal adenomas CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Enger, S. M., Longnecker, M. P., Chen, M. J., Harper, J. M., Lee, E. R., Frankl, H. D., Haile, R. W. 1996; 5 (3): 147-153

    Abstract

    We determined whether intakes of the main dietary carotenoids (alpha-carotene, beta-carotene, beta-cryptoxanthin, lutein plus zeaxanthin, and lycopene) and of vitamins A, C, and E were associated with the prevalence of colorectal adenomas among male and female members of a prepaid health plan in Los Angeles who underwent sigmoidoscopy (n = 488 matched pairs). Participants, ages 50-74 years, completed a 126-item semiquantitative food-frequency questionnaire and a non-dietary questionnaire from 1991 to 1993. In the univariate-matched analysis, alpha-carotene, beta-carotene (with and without supplements), beta-cryptoxanthin, lutein plus zeaxanthin, vitamin A (with and without supplements), and vitamin C (with and without supplements) were associated with a decreased prevalence of colorectal adenomas. After adjustment for intake of calories, saturated fat, folate, fiber, and alcohol, and for current smoking status, body mass index, race, physical activity, and use of nonsteroidal anti-inflammatory drugs, only beta-carotene including supplements was inversely associated with adenomas (odds ratio (OR), 0.6; 95% confidence interval (CI), 0.41.1; trend, P= 0.04; ORs compare highest to lowest quartiles0; vitamin C showed a weaker inverse association (OR, 0.8; 95% CI, 0.5-1.5; trend, P = 0.08); and the remaining compounds were no longer clearly associated with risk. After including beta-carotene with supplements and vitamin C simultaneously in the mutivariate model, the association of beta-carotene with supplements with adenomas was weakened (OR, 0.8; 95% CI, 0.5-1.3; trend P = 0.15), and vitamin C was no longer associated with risk. These data provide only modest support for a protective association of beta-carotene with colorectal adenomatous polyps.

    View details for Web of Science ID A1996TZ89100001

    View details for PubMedID 8833613

  • Leisure, home, and occupational physical activity and cardiovascular risk factors in postmenopausal women - The postmenopausal estrogens/progestins intervention (PEPI) study ARCHIVES OF INTERNAL MEDICINE Greendale, G. A., BodinDunn, L., Ingles, S., Haile, R., BARRETTCONNOR, E. 1996; 156 (4): 418-424

    Abstract

    To examine the associations between self-reported leisure, home, and occupational physical activity and selected cardiovascular risk factors.A cross-sectional analysis of baseline data from the Postmenopausal Estrogen/Progestins Intervention Trial was performed in 851 women aged 45 to 64 years. Outcomes were levels of high-density lipoprotein cholesterol, insulin (2 hours after challenge), fibrinogen, systolic blood pressure. Race-stratified models were adjusted for age, smoking, alcohol, and previous noncontraceptive estrogen use. Models were also run with body mass index as an additional covariate.In white women, leisure physical activity was positively associated with levels of high-density lipoprotein cholesterol (P = .001) and inversely associated with levels of insulin (P = .04) and fibrinogen (P = .02). Compared with high-density lipoprotein cholesterol levels in the inactive and light leisure physical activity groups, moderate (P < .001) and heavy (P = .004) leisure activities were associated with higher high-density lipoprotein cholesterol levels. High-density lipoprotein cholesterol levels in the heavy leisure physical activity group were significantly higher than those in the moderate group (P = .01). Compared with lesser levels of leisure physical activity, significantly lower mean values of fibrinogen (P = .02) and insulin (P = .01) were associated with the highest-intensity leisure physical activity. Home physical activity was positively related to high-density lipoprotein cholesterol level (P = .01); relative to lower levels of home physical activity, the heavy home physical activity group demonstrated significantly higher mean high-density lipoprotein cholesterol levels. The effects of leisure and home physical activities were independent of each other. systolic blood pressure did not vary by leisure, occupational, or home physical activity.The unique relationships between type of physical activity and cardiac risk factors underscore the necessity of including multiple domains of activity in epidemiologic studies of epidemiologic studies of physical activity in women.

    View details for Web of Science ID A1996TW32800008

    View details for PubMedID 8607727

  • Gene expression in familial breast cancer: A genetic-epidemiologic study of premenopausal bilateral breast cancer HORMONAL CARCINOGENESIS II Haile, R. W., Ingles, S., Cortessis, V. K., Millikan, R. C., Diep, A., Sparkes, R. S. 1996: 107-112
  • A case-control study of reproductive variables, alcohol, and smoking in premenopausal bilateral breast cancer BREAST CANCER RESEARCH AND TREATMENT Haile, R. W., Witte, J. S., Ursin, G., Siemiatycki, J., Bertolli, J., Thompson, W. D., PAGANINIHILL, A. 1996; 37 (1): 49-56

    Abstract

    Premenopausal bilateral breast cancer is characterized by a strong family risk, and, consequently, a high probability that inherited susceptibility genes may be segregating in these families. Determining whether risk factors that affect other breast cancer cases have a similar effect in the etiology of bilateral breast cancer is of interest. Therefore, as part of an ongoing genetic-epidemiologic study of premenopausal bilateral breast cancer, we conducted a case-control analysis of reproductive variables, benign breast disease, alcohol, and smoking. Cases had premenopausal bilateral breast cancer, and their unaffected sisters served as controls. A set of reproductive variables--including earlier age at menarche, nulliparity, and late age at first full term pregnancy--appeared to increase the risk of breast cancer; the corresponding confidence limits, however, were wide and straddled the null. In addition, other variables associated with increased premenopausal bilateral breast cancer risk were: use of oral contraceptives, history of benign breast disease, and high alcohol consumption. We found no positive association for smoking. Nulliparity and late age at first full-term pregnancy appeared to have different effects in women with family histories of breast cancer than in women without such a history. We detected no substantial effect modification for the other risk factors. In general, risk factors previously identified for breast cancer (usually postmenopausal, unilateral cases) appear also to increase the risk for premenopausal, bilateral breast cancer.

    View details for Web of Science ID A1996TG75700006

    View details for PubMedID 8750527

  • MAMMOGRAPHIC FEATURES AND BREAST-CANCER RISK - EFFECTS WITH TIME, AGE, AND MENOPAUSE STATUS JOURNAL OF THE NATIONAL CANCER INSTITUTE Byrne, C., Schairer, C., Wolfe, J., Parekh, N., Salane, M., Brinton, L. A., Hoover, R., Haile, R. 1995; 87 (21): 1622-1629

    Abstract

    Mammographic images from women with a high proportion of epithelial and stromal breast tissues are described as showing high-density parenchymal patterns. Most past studies that noted an increase in breast cancer risk associated with mammographic parenchymal patterns showing high density either 1) lacked information on other breast cancer risk factors, 2) were too small, or 3) included insufficient follow-up time to adequately resolve persisting doubts whether mammographic features are "independent" measures of breast cancer risk and not a detection artifact.The purpose of this study was twofold: 1) to evaluate the associations between mammographic features and other breast cancer risk factors and 2) to assess effects of mammographic features on breast cancer risk by time, age, and menopause status.To address these questions, we analyzed detailed information from a large, nested case-control study with 16 years of follow-up. This study used information from both screening and follow-up phases of the Breast Cancer Detection Demonstration Project, a nationwide program that offered annual breast cancer screening for more than 280,000 women from 1973 to 1980. Mammographic features were assessed from the base-line screening mammographic examination for 1880 incident case subjects and 2152 control subjects. Control subjects were randomly selected from women of the same age and race as each case subject. Control subjects attended the same screening center as the case subject and were free of breast cancer at the case subject's date of diagnosis. Odds ratios (ORs) with 95% confidence intervals (CIs) provided estimates of the relative risk of breast cancer.Mammographic features were associated with known breast cancer risk factors. However, the high-density parenchymal pattern effects were independent of family history, age at first birth, alcohol consumption, and benign breast disease. The increase risk for women with Wolfe's two high-density parenchymal patterns, P2 (OR = 3.2; 95% CI = 2.5-4.0) and Dy (OR = 2.9; 95% CI = 2.2-3.9), was explained primarily by measured percent of the breast with dense mammographic appearance. Compared with women with no visible breast density, women who had a breast density of 75% or greater had an almost fivefold increased risk of breast cancer (95% CI = 3.6-7.1). These effects persisted for 10 or more years and were noted for both premenopausal and postmenopausal women of all ages.Of the breast cancer risk factors assessed in the participants, high-density mammographic parenchymal patterns, as measured by the proportion of breast area composed of epithelial and stromal tissue, had the greatest impact on breast cancer risk. Of the breast cancers in this study, 28% were attributable to having 50% or greater breast density.

    View details for Web of Science ID A1995TB16200012

    View details for PubMedID 7563205

  • RED-CELL AND PLASMA FOLATE, FOLATE CONSUMPTION, AND THE RISK OF COLORECTAL ADENOMATOUS POLYPS CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Bird, C. L., Swendseid, M. E., Witte, J. S., Shikany, J. M., HUNT, I. F., Frankl, H. D., Lee, E. R., Longnecker, M. P., Haile, R. W. 1995; 4 (7): 709-714

    Abstract

    Epidemiological and experimental evidence suggests that dietary folate may protect against colorectal carcinogenesis. The epidemiological relationship between a biochemical measure of folate status and colorectal neoplasia in a sizeable and generally healthy population does not yet appear to have been reported. We conducted a case-control study of the relationships among red cell folate, plasma folate, folate intake, and adenomatous polyps, intermediate markers for colorectal cancer. During 1991-1993, fasting blood samples were assayed and dietary and nondietary risk factor questionnaires were administered to men and women ages 50-75 years who had a free sigmoidoscopy at a health maintenance organization. We analyzed data from 682 subjects (332 cases and 350 controls), controlling for potential confounding by sex, age, sigmoidoscopy date, and clinic. For red cell folate levels 160 ng/ml (363 nmol/liter) or more, compared to lower levels, the odds ratio was 0.76 [95% confidence interval (CI) = 0.53-1.08]. For men, the corresponding odds ratio was 0.53 (CI = 0.32-0.87); for women, it was 1.16 (CI = 0.67-2.00). Results were essentially unchanged when adjusted for levels of blood nutrients and other potential confounding variables. Plasma folate and folate intake results were similar to red cell folate results, but the associations with polyps were weaker. Results are consistent with a protective effect of red cell folate concentration against the development of colorectal polyps, at least in men. A folate effect may depend on sex-specific interactions with other nutritional or physiological factors.

    View details for Web of Science ID A1995RZ11000003

    View details for PubMedID 8672986

  • CALCIUM SUPPLEMENTATION AND RECTAL MUCOSAL PROLIFERATION - A RANDOMIZED CONTROLLED TRIAL JOURNAL OF THE NATIONAL CANCER INSTITUTE Baron, J. A., Tosteson, T. D., Wargovich, M. J., SANDIER, R., Mandel, J., Bond, J., Haile, R., Summers, R., VANSTOLK, R., Rothstein, R., Weiss, J. 1995; 87 (17): 1303-1307

    Abstract

    Data from studies using rodents suggest that dietary calcium inhibits bile acid-induced mucosal damage and experimental carcinogenesis in the large bowel. However, in humans, the effect of dietary calcium and calcium supplementation on proliferation and carcinogenesis in the large bowel has been unclear.To assess the effect of calcium supplementation on rectal mucosal proliferation in humans, we conducted a multicenter, randomized, placebo-controlled, double-blinded trial.Participants were part of a larger multicenter chemoprevention trial; all were at high risk for large-bowel neoplasia, with at least one large-bowel adenoma removed endoscopically within the 3 months before study entry but with no known polyps remaining. Subjects were randomly assigned to receive daily either 3000 mg of calcium carbonate (providing 1200 mg elemental calcium) or an identical-appearing placebo tablet. During a scheduled endoscopy 6-9 months after random assignment (approximately 1 year after the qualifying endoscopy), rectal mucosal samples were obtained from 333 patients (173 assigned to calcium and 160 assigned to placebo). Proliferating cell nuclear antigen (PCNA) labeling indices (LIs) were computed as the measure of proliferation in specimens from 146 patients receiving calcium and 129 patients receiving placebo. Bromodeoxyuridine (BrdU) labeling was used to measure proliferation in a smaller number of specimens (27 calcium-receiving and 31 placebo-receiving participants). For each scorable crypt having at least one labeled cell (or surrounded by crypts with at least one labeled cell), a crypt LI was calculated as the number of labeled cells divided by the total number of crypt cells. Crypt LIs were averaged to produce a participant's average LI.The overall unadjusted mean PCNA LIs (+/- SE) were similar in the calcium and placebo groups (3.85% +/- 0.08% versus 3.92% +/- 0.08%, respectively, P = .30). The overall unadjusted mean BrdU LIs (+/- SE) were 3.88% +/- 0.30% in the calcium group and 3.54% +/- 0.21% in the placebo group (P = .54). PCNA labeling indices in the most luminal 40% of the crypt were small but, if anything, were higher in the calcium group. There was no patient subgroup within which calcium had an antiproliferative effect; the overall findings persisted among patients with high and low calcium intake, high and low fat intake, and high and low fiber intake.Calcium supplementation does not decrease rectal mucosal proliferation, as measured by PCNA (and BrdU) immunohistochemistry, in patients with previous large-bowel adenomas. This study, therefore, does not provide evidence for an anticarcinogenic effect of calcium.

    View details for Web of Science ID A1995RR58300012

    View details for PubMedID 7658482

  • LATE PHYSICAL AND FUNCTIONAL-EFFECTS OF OSTEOPOROTIC FRACTURE IN WOMEN - THE RANCHO-BERNARDO STUDY JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Greendale, G. A., BARRETTCONNOR, E., Ingles, S., Haile, R. 1995; 43 (9): 955-961

    Abstract

    To examine the associations between osteoporotic fractures and difficulty performing selected physical and functional activities.Cross sectional analysis of a cohort study.Geographically defined cohort located in Rancho Bernardo, California.Community-dwelling women aged 55 and older who participated in a study of osteoporosis between 1988-1991. Eighty percent of eligible women participated in the study.Self-reported difficulty performing seven physical activities and four functional tasks.The mean age of the 1010 women was 72.6 years. A total of 160 first minimal trauma fractures occurred between 1972 and 1991, including 62 wrist, 29 rib, 25 hip, and 23 spine fractures. The mean time since fracture was 6.7 years (range, 1 to 17 years). In multiply adjusted analyses, having experienced any osteoporotic fracture was significantly associated with a 1.7 to 3.0-fold increase in difficulty bending, lifting, reaching, walking, climbing stairs, and descending stairs. Any fracture was significantly associated with 1.9 to 6.7 times more difficulty in dressing, cooking, shopping, and performing heavy housework. Compared with the relative odds of physical limitation associated with any osteoporotic fracture, hip fractures were more strongly associated with difficulty walking (OR 3.6) and descending stairs (OR 4.1), whereas spine fractures demonstrated a stronger association with difficulty bending (OR 3.1), lifting (OR 3.4), and descending stairs (OR 4.2).Among older women, remote osteoporotic fracture at any site is associated with an approximate doubling of the risk of physical limitations and an even higher risk of functional limitations. Although this cross-sectional analysis cannot secure the direction of the association, the specificity of the effect of particular fractures on discrete activities supports causality.

    View details for Web of Science ID A1995RT90800001

    View details for PubMedID 7657934

  • LIFETIME LEISURE EXERCISE AND OSTEOPOROSIS - THE RANCHO-BERNARDO STUDY AMERICAN JOURNAL OF EPIDEMIOLOGY Greendale, G. A., BARRETTCONNOR, E., EDELSTEIN, S., Ingles, S., Haile, R. 1995; 141 (10): 951-959

    Abstract

    Between 1988 and 1991, the relation between leisure time physical activity, bone mineral density (BMD), and osteoporotic fracture was evaluated in a cohort of community-dwelling California adults (1,014 women and 689 men) with a mean age of 73 years. By means of a modified Paffenbarger questionnaire, participants were asked to report exercise from the past year and to recall their level of exercise during three other periods: the teenage years, age 30 years, and age 50 years. The survey asked the number of times strenuous (e.g., jogging), moderate (e.g., fast walking), or mild (e.g., golfing) exercise was undertaken in an average week. A summary score was constructed to represent lifetime exercise. Analysis of the exercise-fracture and exercise-BMD associations were performed using logistic and linear regression analyses, respectively. Linear regression models were controlled for age, body mass index, sex, diagnosis of arthritis, dietary calcium intake, and use of cigarettes, alcohol, thiazides, and estrogen (women only). No association between current or former exercise and BMD at the radius, wrist, or spine was found. A positive association between current exercise and BMD was found at the total hip (p = 0.001) and at each hip component--greater trochanter (p = 0.02), intertrochanter (p = 0.001), and femoral neck (p = 0.02). Mean hip bone densities of strenuous (p = 0.004) and moderate (p = 0.004) current exercisers were higher than those of mild or less than mild exercisers. Lifetime exercise was also positively associated with BMD of the total hip (p = 0.008) and hip components, and demonstrated a borderline-significant association (p = 0.06) with spine BMD. At the hip, each pairwise comparison between the highest and lowest tertiles of lifetime exercise showed a significant difference (p < or = 0.007). Exercise was unassociated with minimal trauma fracture occurring at any site between 1972 and 1991. These data suggest a protective effect of current and lifelong exercise on hip BMD, but not on osteoporotic fracture, in older men and women.

    View details for Web of Science ID A1995QX41200009

    View details for PubMedID 7741125

  • ACETYLATION POLYMORPHISM AND PREVALENCE OF COLORECTAL ADENOMAS CANCER RESEARCH PROBSTHENSCH, N. M., Haile, R. W., Ingles, S. A., Longnecker, M. P., Han, C. Y., Lin, B. K., Lee, D. B., Sakamoto, G. T., Frankl, H. D., Lee, E. R., Lin, H. J. 1995; 55 (10): 2017-2020

    Abstract

    Polymorphic N-acetyltransferase (NAT2), an enzyme present in the colon, may effect incidence of colon cancer. Individuals with NAT2 fast acetylator genotypes may have higher colon cancer risks due to faster conversion of certain carcinogens to mutagens. We determined NAT2 genotypes in 447 subjects with distal colon adenomas and in 487 controls. No significant increase in adenoma prevalence among fast acetylators was observed. However, there was a suggestion of ethnic differences in NAT2 effects. For example, white fast acetylators potentially had slightly increased risks for adenomas (odds ratio, 1.29; 95% confidence interval, 0.90-1.84), whereas fast acetylation was potentially protective among blacks (odds ratio, 0.64; 95% confidence interval, 0.32-1.28). The apparent difference between blacks and whites may simply reflect random variation around an overall null effect, or it could represent a real difference. There was preliminary evidence for a possible interaction between NAT2 and the glutathione transferase M1 null genotype. Smokers' adenoma prevalence was 10-fold higher for fast acetylators with the null genotype compared to slow acetylators without the null genotype. Large, multiethnic populations and analysis of combinations of genes for carcinogen metabolism may be needed to further assess the role of NAT2 in colorectal tumorigenesis.

    View details for Web of Science ID A1995QX36700004

    View details for PubMedID 7743494

  • QUESTIONNAIRE ASSESSMENT OF INTAKE OF SPECIFIC CAROTENOIDS CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Enger, S. M., Longnecker, M. P., Shikany, J. M., SWENSEID, M. E., Chen, M. J., Harper, J. M., Haile, R. W. 1995; 4 (3): 201-205

    Abstract

    We determined whether estimation of intake of specific carotenoids with a standard food-frequency questionnaire (FFQ) could be improved by collection of additional data on the intake of carotenoid-rich food items. The foods included on an addendum to the standard FFQ were potentially important dietary contributors of alpha- and beta-carotene, beta-cryptoxanthin, lutein, zeaxanthin, or lycopene. Participants (n = 215), ages 50-74 years, provided fasting blood samples and completed the FFQ and the addendum. The participants were enrolled in a prepaid health plan and had undergone screening sigmoidoscopy for detection of colorectal polyps. Addendum foods were identified that accounted for variation in blood levels of specific carotenoids, conditional on intake of foods on the standard FFQ. Estimated carotenoid intakes from the standard FFQ, and from the modified FFQ with the selected addendum foods, were examined in relation to plasma carotenoid levels. The correlation coefficient between estimated carotenoid intake and plasma levels (adjusted for age, sex, serum cholesterol, alcohol intake, smoking status, and energy intake) were essentially the same for the standard and modified FFQs. The adjusted correlations for the standard FFQ only were 0.26 for alpha-carotene, 0.22 for beta-carotene, 0.36 for beta-cryptoxanthin, 0.32 for lutein+zeaxanthin, and 0.34 for lycopene. Adding carotenoid-rich foods to the FFQ did not improve estimation of intake for the carotenoids examined in this population. We conclude that assessment of intake of specific carotenoids with the FFQs currently in use may not necessarily be improved by a modified list of carotenoid-rich foods.

    View details for Web of Science ID A1995QT14500003

    View details for PubMedID 7606194

  • GLUTATHIONE TRANSFERASE (GSTM1) NULL GENOTYPE, SMOKING, AND PREVALENCE OF COLORECTAL ADENOMAS CANCER RESEARCH Lin, H. J., PROBSTHENSCH, N. M., Ingles, S. A., Han, C. Y., Lin, B. K., Lee, D. B., Frankl, H. D., Lee, E. R., Longnecker, M. P., Haile, R. W. 1995; 55 (6): 1224-1226

    Abstract

    Colorectal cancer is caused by environmental exposures and genetic predisposition. However, little is known of hereditary factors that influence development of common, non-Mendelian forms of this cancer. Interactions among carcinogen exposure, hereditary variants of enzymes involved in carcinogen metabolism, and other host factors may play a role. Genetic polymorphisms of carcinogen metabolism, such as the glutathione transferase M1 (GSTM1) null genotype, are thus possibly related to cancer risk. The GSTM1 enzyme detoxifies mutagens formed from polycyclic aromatic hydrocarbons which are found in tobacco smoke. We analyzed GSTM1 genotypes and smoking among 488 controls and 446 individuals with a first time diagnosis of colorectal adenomas which are precursors to cancer. Subjects were from two Kaiser Permanente sigmoidoscopy clinics in southern California. We observed no overall effect of the GSTM1 null genotype on the risk for colorectal adenomas (odds ratio, 0.85; 95% confidence interval = 0.65-1.10). The odds ratio for smokers with the null genotype was 2.07 (95% confidence interval = 1.14-3.77) when compared to "never smokers" without the null genotype. Using this same reference group, the odds ratio for smokers without the null genotype was 1.73 (95% confidence interval = 1.03-2.90). These two odds ratios were not significantly different (P = 0.30).

    View details for Web of Science ID A1995QL40500006

    View details for PubMedID 7882312

  • A METAANALYSIS OF BODY-MASS INDEX AND RISK OF PREMENOPAUSAL BREAST-CANCER EPIDEMIOLOGY Ursin, G., Longnecker, M. P., Haile, R. W., Greenland, S. 1995; 6 (2): 137-141

    Abstract

    Increased body mass index (BMI) has been found to be associated with elevated risk of postmenopausal breast cancer. Whether BMI is related to premenopausal breast cancer has not yet been established. We performed a meta-analyses of data from 23 studies that provided information on BMI and incidence of premenopausal breast cancer. Overall, the data support a modest inverse association. For a BMI difference of 8 kg per m2, that is, the difference between a thin person and someone who is morbidly obese, the random effects estimate of the rate ratio from the four cohort studies was 0.70 [95% confidence interval (CI) = 0.54-0.91], and the random effects estimate of the odds ratio from the 19 case-control studies was 0.88 (95% CI = 0.76-1.02). Because of substantial heterogeneity among the study-specific estimates, however, we also examined the influence of certain aspects of study design. Case-control studies with community controls had a more inverse association, whereas case-control studies that interviewed cases shortly after diagnosis applied the same exclusion criteria to cases and controls, or with confounder adjustment beyond age had a more positive association between BMI and breast cancer. Possible reasons for the discrepancies among the case-control studies are discussed.

    View details for Web of Science ID A1995QJ25900009

    View details for PubMedID 7742399

  • A collaborative survey of 80 mutations in the BRCA1 breast and ovarian cancer susceptibility gene. Implications for presymptomatic testing and screening. JAMA Shattuck-Eidens, D., McClure, M., Simard, J., Labrie, F., Narod, S., Couch, F., Hoskins, K., Weber, B., Castilla, L., Erdos, M. 1995; 273 (7): 535-541

    Abstract

    To report the initial experience of an international group of investigators in identifying mutations in the BRCA1 breast and ovarian cancer susceptibility gene, to assess the spectrum of such mutations in samples from patients with different family histories of cancer, and to determine the frequency of recurrent mutations.Nine laboratories in North America and the United Kingdom tested for BRCA1 mutations in DNA samples obtained from a total of 372 unrelated patients with breast or ovarian cancer largely chosen from high-risk families. Three of these laboratories also analyzed a total of 714 additional samples from breast or ovarian cancer cases, including 557 unselected for family history, for two specific mutations that had been found to recur in familial samples.A total of 1086 women with either breast or ovarian cancer.The detection of sequence variation in patients' DNA samples that is not found in sets of control samples.BRCA1 mutations have now been identified in a total of 80 patient samples. Thirty-eight distinct mutations were found among 63 mutations identified through a complete screen of the BRCA1 gene. Three specific mutations appeared relatively common, occurring eight, seven, and five times, respectively. When specific tests for the two most common mutations were performed in larger sets of samples, they were found in 17 additional patients. Mutations predicted to result in a truncated protein accounted for 86% of the mutations detected by complete screening.The high frequency of protein-terminating mutations and the observation of many recurrent mutations found in a diverse set of samples could lead to a relatively simple diagnostic test for BRCA1 mutations. More data must be accumulated to address specifically the sensitivity and specificity of such a diagnostic testing procedure and to better estimate the age-specific risk for breast and ovarian cancer associated with such mutations.

    View details for PubMedID 7837387

  • EARLY ADULT BODY-WEIGHT, BODY-MASS INDEX, AND PREMENOPAUSAL BILATERAL BREAST-CANCER - DATA FROM A CASE-CONTROL STUDY BREAST CANCER RESEARCH AND TREATMENT Ursin, G., PAGANINIHILL, A., Siemiatycki, J., Thompson, W. D., Haile, R. W. 1995; 33 (1): 75-82

    Abstract

    Previous studies using current or recent adult body weight and body mass index are inconclusive as to a possible effect of increased body mass on premenopausal breast cancer incidence. Only five studies have presented data on early adult body mass, and no study has reported these data for premenopausal bilateral breast cancer. Because premenopausal bilateral breast cancer is assumed to be partly genetic and partly environmental in origin, it is crucial to identify possible modifiable risk factors for this cancer. We present data on early adult body weight and body mass (Quetelet Index, QI) from a case-control study of 142 premenopausal bilateral breast cancer cases from Los Angeles County, California, Connecticut, and Quebec, Canada, and 229 sister controls. The odds ratio (and 95% confidence interval) of premenopausal breast cancer adjusted for age, education, alcohol consumption, and oral contraceptive use was 0.7 (0.3-1.4) for women in the highest tertile of QI at age 18. The results do not suggest that elevated body mass index at a young age increases the risk of premenopausal bilateral breast cancer, but lend only weak support to the hypothesis of an inverse association between body mass index and premenopausal breast cancer.

    View details for Web of Science ID A1995PZ32400008

    View details for PubMedID 7749135

  • EPIDEMIOLOGIC USE OF RECTAL PROLIFERATION MEASURES CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Baron, J. A., Wargovich, M. J., Tosteson, T. D., Sandler, R., Haile, R., Summers, R., VANSTOLK, R., Rothstein, R., Weiss, J. 1995; 4 (1): 57-61

    Abstract

    Measures of rectal mucosal proliferation have been developed and used in research clinical settings, but their utility for larger-scale epidemiological studies remains uncertain. We assessed the suitability of bromodeoxyuridine (BrdUrd) and proliferating cell nuclear antigen (PCNA)-labeling indices (LIs) in the setting of a multicenter clinical trial of adenoma recurrence. Subjects at participating practices were asked to permit biopsy of normal rectal mucosa during a colonoscopy scheduled for other reasons. PCNA and BrdUrd labeling was performed, and corresponding LIs were computed. In general, subjects were willing to undergo biopsy during their scheduled procedures; less than 10% refused. Specimen preparation for PCNA was acceptable; the mean number of scorable crypts (+/- SE) was 12.99 +/- 0.37. Preparation for BrdUrd labeling was less successful, with a higher proportion of unscorable specimens and a lower mean number of scorable crypts. Among the 54 specimens with both LIs computed, the LI for PCNA was modestly higher than that for BrdUrd LI (4.1 +/- 0.2 and 3.7 +/- 0.2 respectively; P = 0.03). The rank order correlation between the two indices was 0.38). There was variation across centers in the PCNA LIs but few differences according to number of crypts scored. Measurement of rectal mucosal proliferation is feasible among endoscopy patients in large studies if PCNA is used; BrdUrd seems more difficult. The relationship between these two labels requires further study.

    View details for Web of Science ID A1995QA97100008

    View details for PubMedID 7894325

  • HIERARCHICAL REGRESSION-ANALYSIS APPLIED TO A STUDY OF MULTIPLE DIETARY EXPOSURES AND BREAST-CANCER EPIDEMIOLOGY Witte, J. S., Greenland, S., Haile, R. W., Bird, C. L. 1994; 5 (6): 612-621

    Abstract

    Hierarchical regression attempts to improve standard regression estimates by adding a second-stage "prior" regression to an ordinary model. Here, we use hierarchical regression to analyze case-control data on diet and breast cancer. This regression yields semi-Bayes relative risk estimates for dietary items by using a second-stage model to pull estimates toward each other when the corresponding variables have similar levels of nutrients. Unlike classical Bayesian analysis, however, no use is made of previous studies on nutrient effects. Compared with results obtained with one-stage conditional maximum-likelihood logistic regression, our hierarchical regression model gives more stable and plausible estimates. In particular, certain effects with implausible maximum-likelihood estimates have more reasonable semi-Bayes estimates.

    View details for Web of Science ID A1994PP46800009

    View details for PubMedID 7841243

  • DIETARY-SODIUM AND BONE-MINERAL DENSITY - RESULTS OF A 16-YEAR FOLLOW-UP-STUDY JOURNAL OF THE AMERICAN GERIATRICS SOCIETY Greendale, G. A., BARRETTCONNOR, E., EDELSTEIN, S., Ingles, S., Haile, R. 1994; 42 (10): 1050-1055

    Abstract

    It has been proposed that high dietary sodium intake, resulting in a sodium-mediated increase in renal calcium excretion, is a risk factor for osteoporosis. To evaluate the relationship between dietary sodium intake and bone mineral density (BMD), a prospective study of the Rancho Bernardo cohort was performed.A 24-hour diet recall was done for the period 1973 through 1975; follow-up bone mineral density of the ultradistal radius, midradius, total hip, and spine was measured between 1988 and 1991. Covariates were ascertained by self-report and examination at baseline. Multivariable analysis of the sodium-BMD association was performed using gender and menopause-specific linear regressions.All subjects were white. At the bone evaluation, there were 258 women (average age 73.3 years) and 169 men (average age 72.4 years). In both men and women, higher levels of sodium intake were strongly associated with higher levels of calcium intake and total calories. Body mass index increased with sodium quartile in women, while a modest negative association was seen in men. In women, after age adjustment, positive associations between dietary sodium and bone density were found at the ultradistal radius (beta = 0.01, P = 0.03) and the total hip (beta = 0.019, P = 0.02). BMD increased by 0.01 to 0.02 g/cm2 per gram increase in sodium ingested. After adjustment for estrogen use, body mass, dietary calcium, alcohol, and total calories, these effects were no longer significant. Similar patterns were seen in pre- and postmenopausal women. In men, age and multivariate-adjusted BMD increased with higher sodium intake at the ultradistal radius only (beta = 0.013, P = 0.05). Stratification by gender-specific median calcium level did not significantly effect the results.After control for confounders, a small, statistically significant protective effect of sodium was found at the ultradistal radius in men only. At other sites in women and men, no effect of sodium on BMD was apparent in the multivariable models. These results do not support a detrimental effect of dietary sodium on bone mineral density. Rather, the findings suggest that sodium intake, in the range measured, is not a major osteoporosis risk factor.

    View details for Web of Science ID A1994PK17900003

    View details for PubMedID 7930328

  • CLINICAL-TRIAL OF ANTIOXIDANT VITAMINS TO PREVENT COLORECTAL ADENOMA NEW ENGLAND JOURNAL OF MEDICINE Greenberg, E. R., Baron, J. A., Tosteson, T. D., Freeman, D. H., Beck, G. J., Bond, J. H., Colacchio, T. A., Coller, J. A., Frankl, H. D., Haile, R. W., Mandel, J. S., Nierenberg, D. W., Rothstein, R., Snover, D. C., Stevens, M. M., Summers, R. W., VANSTOLK, R. U. 1994; 331 (3): 141-147

    Abstract

    People who consume a diet high in vegetables and fruits have a lower risk of cancer of the large bowel. Antioxidant vitamins, which are present in vegetables and fruits, have been associated with a diminished risk of cancers at various anatomical sites. We conducted a randomized, controlled clinical trial to test the efficacy of beta carotene and vitamins C and E in preventing colorectal adenoma, a precursor of invasive cancer.We randomly assigned 864 patients, using a two-by-two factorial design, to four treatment groups, which received placebo; beta carotene (25 mg daily); vitamin C (1 g daily) and vitamin E (400 mg daily); or the beta carotene plus vitamins C and E. In order to identify new adenomas, we performed complete colonoscopic examinations in the patients one year and four years after they entered the study. The primary end points for analyses were new adenomas identified after the first of these two follow-up examinations.Patients adhered well to the prescribed regimen, and 751 completed the four-year clinical trial. There was no evidence that either beta carotene or vitamins C and E reduced the incidence of adenomas; the relative risk for beta carotene was 1.01 (95 percent confidence interval, 0.85 to 1.20); for vitamins C and E, it was 1.08 (95 percent confidence interval, 0.91 to 1.29). Neither treatment appeared to be effective in any subgroup of patients or in the prevention of any subtype of polyp defined by size or location.The lack of efficacy of these vitamins argues against the use of supplemental beta carotene and vitamins C and E to prevent colorectal cancer. Although our data do not prove definitively that these antioxidants have no anticancer effect, other dietary factors may make more important contributions to the reduction in the risk of cancer associated with a diet high in vegetables and fruits.

    View details for Web of Science ID A1994NW79700001

  • ERYTHROCYTE FOLATE LEVELS, ORAL-CONTRACEPTIVE USE AND ABNORMAL CERVICAL CYTOLOGY ACTA CYTOLOGICA Harper, J. M., Levine, A. J., ROSENTHAL, D. L., WIESMEIER, E., HUNT, I. F., Swendseid, M. E., Haile, R. W. 1994; 38 (3): 324-330

    Abstract

    The initial hypothesis of this study was that folate depletion is a risk factor for human papillomavirus infection and cervical epithelial cell abnormalities, including dysplasia. The prevalences of low erythrocyte folate levels (defined as < 140 ng/mL erythrocytes and determined by the growth of Lactobacillus) were measured in 250 University of California at Los Angeles students. Among oral contraceptive users, low erythrocyte folate was a risk factor for an abnormal cytologic smear in both benign atypia and squamous intraepithelial lesions. Odds ratios were statistically significant for biopsied women who did not have condyloma and for those who did not have squamous intraepithelial lesions but not for those with histologically confirmed intraepithelial lesions. Low erythrocyte folate was a risk factor for a positive Virapap result in oral contraceptive users. If the folate effects are causal, the findings suggest that erythrocyte folate levels should be higher in oral contraceptive users than in nonusers to protect against an abnormal cytologic smear.

    View details for Web of Science ID A1994NN31500006

    View details for PubMedID 8191820

  • LINKAGE ANALYSIS OF DRD2, A MARKER LINKED TO THE ATAXIA-TELANGIECTASIA GENE, IN 64 FAMILIES WITH PREMENOPAUSAL BILATERAL BREAST-CANCER CANCER RESEARCH Cortessis, V., Ingles, S., Millikan, R., Diep, A., GATTI, R. A., Richardson, L., Thompson, W. D., PAGANINIHILL, A., Sparkes, R. S., Haile, R. W. 1993; 53 (21): 5083-5086

    Abstract

    Recent reports suggest that subjects who are heterozygous for the ataxia-telangiectasia gene are at increased risk of breast cancer. We conducted linkage analyses of 64 families with premenopausal bilateral breast cancer using DRD2, a marker linked to the ataxia-telangiectasia locus at 11q22-23. We assumed a model with dominant transmission of breast cancer. Lod scores summed over all families provided strong evidence against tight linkage (e.g., a lod score of -6.08 at theta = 0.00001), although a single family provides suggestive evidence of tight linkage to DRD2. Evidence against linkage to 11q was strongest among families that may involve the BRCA1 breast cancer susceptibility gene on 17q21. However, we did not observe evidence of linkage to 11q among the remaining subgroup with neither a family history of ovarian cancer nor the appearance of linkage to 17q21.

    View details for Web of Science ID A1993MD95000005

    View details for PubMedID 8221639

  • HPV DNA AND THE RISK OF SQUAMOUS INTRAEPITHELIAL LESIONS OF THE UTERINE CERVIX IN YOUNG-WOMEN AMERICAN JOURNAL OF CLINICAL PATHOLOGY Levine, A. J., Harper, J., Hilborne, L., ROSENTHAL, D. L., WEISMEIER, E., Haile, R. W. 1993; 100 (1): 6-11

    Abstract

    A population-based case-control study of college students was undertaken to estimate the effect of a positive clinical test for human papillomavirus (HPV) DNA (the Virapap test) on the rate of squamous intraepithelial lesions (SIL) of the uterine cervix. When age, multiple lifetime sexual partners, and oral contraceptive use were controlled by logistic regression, the adjusted odds ratio (OR) for a positive Virapap test was 7.3 (3.3, 17) for a cytologic diagnosis of SILs and 3.4 (1.4, 8.5) for a cytologic diagnosis of squamous intraepithelial lesions of undetermined significance (equivocal atypia). When case status was defined as patients whose Pap smears were confirmed histologically as high-grade SIL, the adjusted OR was 10.3 (3.3, 32), reflecting the high proportion of individuals with SILs who were harboring high-grade squamous intraepithelial lesions. These results confirm the many previous findings of a strong association between HPV DNA, and demonstrate that strength of the association persists when important confounding variables are controlled. This suggests a causal role for HPV in cervical neogenesis. Believing that HPV infection is a major causal agent for cervical cancer precursors suggests that in this time of rapidly increasing HPV prevalence, especially among young persons, the incidence of cervical neoplasia will rise. This underscores the importance of increasing the availability, usage, and perhaps the frequency of Pap smear screening.

    View details for Web of Science ID A1993LM75000003

    View details for PubMedID 8394050

  • REDUCED RISK OF LARGE-BOWEL ADENOMAS AMONG ASPIRIN USERS JOURNAL OF THE NATIONAL CANCER INSTITUTE Greenberg, E. R., Baron, J. A., Freeman, D. H., Mandel, J. S., Haile, R. 1993; 85 (11): 912-916

    Abstract

    Epidemiological studies have indicated that aspirin consumption can lower the risk of large-bowel cancer. These studies are not entirely consistent, however, and their interpretation has been complicated by the possibility that cancer symptoms may have led patients to avoid aspirin or that aspirin may have influenced cancer diagnosis and treatment.Our purpose was to determine the effect of aspirin on risk of large-bowel neoplasms in a study in which aspirin use would not be expected to affect tumor detection and tumor-related symptoms would not likely influence aspirin use. A less complicated assessment of the relationship between aspirin and large-bowel tumors should thus be possible.We studied 793 patients enrolled in a clinical trial of nutrient supplements to prevent large-bowel adenomas. Unlike invasive cancers, adenomas usually do not cause symptoms or detectable gastrointestinal bleeding; thus, adenomas are unlikely to influence aspirin use. Each patient had at least one large-bowel adenoma diagnosed and removed shortly before study entry and had been judged to be free of further tumors by colonoscopy. Use of aspirin was assessed by responses on questionnaires administered 6 and 12 months after enrollment. We performed complete colonoscopies on all patients 1 year after they entered the study and removed all polyps.Patients who reported taking aspirin on both questionnaires (consistent users) had a lower risk of new adenomas at their 1-year follow-up colonoscopy (odds ratio = 0.52; 95% confidence interval = 0.31-0.89) compared with patients who did not report using aspirin on either of the questionnaires. The apparent protective effect of consistent aspirin use was present among both men and women and did not appear to be influenced by the number of prior adenomas.These data further support the hypothesis that aspirin has an antineoplastic effect in the large bowel. Nevertheless, the question of whether aspirin should be used to prevent large-bowel tumors would be best answered by a randomized controlled clinical trial specifically designed to address this issue.

    View details for Web of Science ID A1993LE27900018

    View details for PubMedID 8492320

  • DIETARY PATTERNS ASSOCIATED WITH A LOW-FAT DIET IN THE NATIONAL-HEALTH EXAMINATION FOLLOW-UP-STUDY - IDENTIFICATION OF POTENTIAL CONFOUNDERS FOR EPIDEMIOLOGIC ANALYSES AMERICAN JOURNAL OF EPIDEMIOLOGY Ursin, G., Ziegler, R. G., Subar, A. F., Graubard, B. I., Haile, R. W., Hoover, R. 1993; 137 (8): 916-927

    Abstract

    To identify systematically the nutrient and food group intakes associated with a low-fat diet, the authors used the detailed dietary information collected from 10,306 individuals aged 32-86 years in the 1982-1984 National Health Epidemiologic Follow-up Study. Intakes of vitamin C and percentages of calories from carbohydrates, dietary fiber, poultry, low-fat dairy products, fruits, vegetables, cereals, and whole grains were markedly higher, while intakes of protein, total fat, saturated fat, oleic and linoleic acids, cholesterol, sodium, all red meats, high-fat dairy products, eggs, nuts, white bread, fried potatoes, desserts, fats, and oils were much lower in the quartile with the lowest percentage of calories from fat. These dietary patterns associated with a low-fat diet were essentially constant across strata of age, sex, race, and socioeconomic status. This study suggests that individuals on a low-fat diet substitute certain carbohydrate-rich foods such as fruits and vegetables for fat. Given these associations between low-fat diets and other dietary factors independently associated with certain cancers, these dietary factors should be considered potential confounders in studies of dietary fat and these cancers.

    View details for Web of Science ID A1993LC83000011

    View details for PubMedID 8484383

  • A LINKAGE ANALYSIS OF D17S74 (CMM86) IN 35 FAMILIES WITH PREMENOPAUSAL BILATERAL BREAST-CANCER CANCER RESEARCH Haile, R. W., Cortessis, V. K., Millikan, R., Ingles, S., Aragaki, C. C., Richardson, L., Thompson, W. D., PAGANINIHILL, A., Sparkes, R. S. 1993; 53 (2): 212-214

    Abstract

    We report here results of a linkage analysis of a marker in 35 families in which the proband had premenopausal bilateral breast cancer. This group is of particular interest given their high family risk and the question of etiological heterogeneity. Probands were ascertained from cancer registries in Los Angeles County and Connecticut and major hospitals in Montréal and Québec. Assuming no residual heterogeneity and summing lod scores over all families, we obtained strong evidence against tight linkage (e.g., lod score at theta = 0.000001 is -3.39). To address the issue of heterogeneity, we performed admixture and predivided sample analyses. Using an admixture model we were able to reject the hypothesis of no linkage versus that of linkage with homogeneity (P = 0.045). However, we were unable to reject the hypothesis of no linkage versus linkage with heterogeneity (P = 0.119) or to distinguish between linkage with homogeneity and linkage with heterogeneity (P = 0.500). Predivided sample analyses based upon age of onset, pathological characteristics, time between diagnoses of the breast cancers in each bilateral proband, and the span of ages at diagnoses within a family did not discriminate between apparently linked and unlinked families.

    View details for Web of Science ID A1993KF73100002

    View details for PubMedID 8417809

  • ORAL-CONTRACEPTIVES AND PREMENOPAUSAL BILATERAL BREAST-CANCER - A CASE-CONTROL STUDY EPIDEMIOLOGY Ursin, G., Aragaki, C. C., PAGANINIHILL, A., Siemiatycki, J., Thompson, W. D., Haile, R. W. 1992; 3 (5): 414-419

    Abstract

    We estimated the effect of oral contraceptive (OC) use on premenopausal bilateral breast cancer in a matched case-control study. One hundred forty-four cases were identified from population-based registries of Los Angeles County, California, and of Connecticut and from the major hospitals in Montreal and Quebec City. Matched controls were the unaffected sisters of the cases. When age was included in the model, ever-use of OCs for 1 year or more was associated with an odds ratio 1.7 (95% confidence interval = 1.0-2.9). The odds ratios associated with 1-2, 3-6, and 7 years of use were 1.2 (0.61-2.4), 2.5 (1.2-5.3), and 2.0 (0.93-4.2), respectively. Too few women had used OCs before their first full-term pregnancy or before age 25 for these estimates to be informative. Restricting the analyses to women who had ever given birth yielded an odds ratio for ever-use of OCs of 2.1 (1.0-4.4). The results indicate an increased risk of premenopausal bilateral breast cancer associated with OC use.

    View details for Web of Science ID A1992JM78900006

    View details for PubMedID 1391133

  • Heterogeneity of the effect of family history on breast cancer risk. Epidemiology Byrne, C., Brinton, L. A., Haile, R. W., Schairer, C. 1991; 2 (4): 276-284

    Abstract

    We studied the effects of family history on breast cancer risk among 2,908 cases and 3,180 controls, selected from participants in a nationwide screening project. First-degree family history was associated with a twofold risk increase. Second-degree family history effects were minimal, after adjusting for effects of first-degree relatives. Family history effects were not confounded by age at menarche, age at first full-term birth, age at natural menopause, or previous benign breast disease. Risks from mother's and sister's history were independent. The odds ratio (OR) from a maternal history, 1.9 (95% confidence interval [CI]: 1.6-2.3), varied little by the subject's age at diagnosis, menopause status, or disease laterality. Interactions of maternal history effects with multiple breast biopsies and age at menopause were greater than additive, indicating common mechanistic pathways. The OR from a sister's history was 2.3 (95% CI: 1.9-2.8) and was increased among women who were less than 45 (OR = 6.9), had bilateral disease (OR = 4.7), or were premenopausal (OR = 4.4). The effects from a mother's history and a sister's history are modified in different directions by different factors, providing further indication of the separate roles of a mother's and sister's history in breast cancer etiology.

    View details for PubMedID 1912043

  • GENETIC EPIDEMIOLOGY OF BILATERAL BREAST-CANCER - A LINKAGE ANALYSIS USING THE AFFECTED-PEDIGREE-MEMBER METHOD GENETIC EPIDEMIOLOGY Haile, R. W., Goldstein, A. M., Weeks, D. E., Sparkes, R. S., PAGANINIHILL, A. 1990; 7 (1): 47-55

    Abstract

    We used the affected-pedigree-member (APM) method to conduct linkage analyses on 19 pedigrees in which the probands had premenopausal bilateral breast cancer. This method analyzes all affected pairs of relatives, as opposed to siblings only, and incorporates into the analyses information on the frequency of marker alleles. Fourteen codominant marker systems were evaluated in two separate analyses. In the first, only premenopausal cases of breast cancer were coded as affected because we assumed that postmenopausal cases were due to a different etiology. In the second analysis, all cases of breast cancer were coded as affected, irrespective of menopausal status. In the premenopausal-cases-only analysis, we observed evidence suggestive of nonindependent segregation for C3 and ESD. In the all-cases analysis, we observed much weaker evidence for C3 and ESD and noted a suggestion of nonindependent segregation for AMY2 and PGM1.

    View details for Web of Science ID A1990CV91600011

    View details for PubMedID 2328913

  • SELECTION BIAS IN CASE-CONTROL STUDIES USING RELATIVES AS THE CONTROLS INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Goldstein, A. M., Hodge, S. E., HAILE, R. W. 1989; 18 (4): 985-989

    Abstract

    Investigators have suggested using relatives of cases as the control group when studying complex diseases thought to have a major genetic component. However, there is a concern about possible bias and we developed a model to examine the possibility of bias in the selection of relatives as the control group. Assuming the exposure-specific risks of disease remain constant over time, the results indicate that even when there is a correlation in the exposure status among relatives, selection of controls from relatives of cases does not, of itself, introduce bias in the estimate of effect.

    View details for Web of Science ID A1989CL70800037

    View details for PubMedID 2621037

  • A GENETIC EPIDEMIOLOGIC INVESTIGATION OF BREAST-CANCER IN FAMILIES WITH BILATERAL BREAST-CANCER .2. LINKAGE ANALYSIS CLINICAL GENETICS Goldstein, A. M., Haile, R. W., SPENCE, M. A., Sparkes, R. S., PAGANINIHILL, A. 1989; 36 (2): 100-106

    Abstract

    We conducted genetic linkage analyses of breast cancer in 20 pedigrees, each having at least one case of bilateral breast cancer diagnosed before 50 years of age. We tested for linkage using inheritance models from previous segregation analyses, incorporating differences in risk based on menopausal status into the analyses. We tested for heterogeneity by predividing the data set based on the interval between diagnoses of the proband's two primaries (less than 1 year (synchronous) versus at least 2 years (asynchronous], and on the histological types of breast cancer in the pedigrees. Very tight linkage could be excluded between breast cancer and ABO, GC, GPT, MNS, and PGM1 for some of the different linkage analyses. A maximum lod score of +1.01 (at theta = 0.001) between ACP1 and a breast cancer susceptibility locus was seen in the asynchronous all-cases subsample.

    View details for Web of Science ID A1989AH55300003

    View details for PubMedID 2766568

  • COMPARISON OF THE AFFECTED-PEDIGREE-MEMBER AND LOD-SCORE METHODS MULTIPOINT MAPPING AND LINKAGE BASED UPON AFFECTED PEDIGREE MEMBERS Goldstein, A. M., Weeks, D. E., Cortessis, V., Haile, R. W. 1989; 329: 135-140

    View details for Web of Science ID A1989BP95B00022

    View details for PubMedID 2622942

  • HORMONAL FACTORS AND RISK OF OVARIAN GERM-CELL CANCER IN YOUNG-WOMEN BRITISH JOURNAL OF CANCER Walker, A. H., Ross, R. K., HAILE, R. W., Henderson, B. E. 1988; 57 (4): 418-422

    Abstract

    No previous controlled studies of ovarian germ cell tumours have been reported; however the tumour is similar to germ cell testicular cancer in terms of histology, age-specific incidence rates (i.e. highest rates in young adulthood), and secular trends of increasing incidence. The investigation was designed to determine if maternal hormonal factors which have been found to increase the risk of testis cancer in male offspring are also risk factors for the ovarian tumour. The analysis is based on 73 cases diagnosed before age 35 and 138 age-race matched controls. The cases were identified by tumour registries in Los Angeles (1972-84) and Seattle (1974-84) and controls were selected from friends and/or neighbourhood residents. Interviews were conducted on the telephone with mothers of cases and controls. The primary finding was that mother's use of exogenous hormones (including the hormonal pregnancy test, DES or other supportive hormones, and inadvertant use of oral contraceptives after conception) increased risk (Odds ratio, OR = 3.60, 95% CL = 1.2-13.1). Other maternal factors associated with elevated risk were high pre-pregnancy body mass (OR = 2.7, 95% CL = 1.0-7.6), more rapid achievement of regular menstruation after menarche (OR = 1.8, 95% CL = 0.9-3.8), and age at index pregnancy under 20 (OR = 2.8, 95% CL = 1.0-10.7). In conclusion, these results support findings from testis cancer studies regarding a hormonal aetiology for germ cell tumours, and a mechanism by which oestrogen may affect the germ cells is proposed.

    View details for Web of Science ID A1988N590700018

    View details for PubMedID 3390378

  • POSSIBLE HETEROGENEITY IN THE SEGREGATION PATTERN OF BREAST-CANCER IN FAMILIES WITH BILATERAL BREAST-CANCER GENETIC EPIDEMIOLOGY Goldstein, A. M., HAILE, R. W., Hodge, S. E., PAGANINIHILL, A., SPENCE, M. A. 1988; 5 (2): 121-133

    Abstract

    We investigated the segregation pattern of breast cancer in families with bilateral breast cancer, classifying families with respect to menopausal status (premenopausal versus postmenopausal) and the interval between diagnosis of the two primary tumors in the probands. Probands were "synchronous" if both primaries were diagnosed within 1 year; "asynchronous" if the interval was at least 2 years. Results for four complex segregation analyses are here presented; the findings support heterogeneity in the transmission of breast cancer. In the asynchronous premenopausal-cases-only analysis, a dominant Mendelian gene can explain the breast cancer pattern. A recessive gene is sufficient to describe the breast cancer distribution in the synchronous premenopausal-cases-only analysis. The synchronous all-cases and the asynchronous all-cases analyses add postmenopausal cases of breast cancer to the premenopausal ones, considering any case to be affected. In the asynchronous all-cases analysis, neither the single-locus model nor the mixed model (that is, a major locus plus other factors, genetic and/or cultural) without generation differences in heritability can be rejected by the unrestricted mixed model with generation differences in heritability. For the synchronous all-cases analysis, a mixed model with generation differences in heritability is necessary to explain the breast cancer transmission. Potential sources of error and possible interpretations are discussed.

    View details for Web of Science ID A1988P147900006

    View details for PubMedID 3402724

  • A GENETIC EPIDEMIOLOGIC INVESTIGATION OF BREAST-CANCER IN FAMILIES WITH BILATERAL BREAST-CANCER .1. SEGREGATION ANALYSIS JOURNAL OF THE NATIONAL CANCER INSTITUTE Goldstein, A. M., HAILE, R. W., Marazita, M. L., PAGANINIHILL, A. 1987; 78 (5): 911-918

    Abstract

    A complex segregation analysis was conducted of breast cancer in 200 families with bilateral breast cancer. Results for two analyses are presented. The first analysis considered only premenopausal cases of breast cancer as affected. The results indicate that mendelian transmission of a single locus is not sufficient to explain the distribution of premenopausal breast cancer seen. A mixed model, i.e., a major locus plus other transmission (genetic and/or cultural), is necessary to explain the distribution. The second analysis added postmenopausal cases of breast cancer to the premenopausal ones, thus considering all breast cancer cases to be affected with the same disorder. The all-cases analysis is unable to reject a mixed model with no generation differences in heritability when tested against the general model, which allows for generation differences (i.e., the likelihoods for the two models were not significantly different). Approaches to studying etiologic heterogeneity in segregation analysis and results of other segregation analyses of breast cancer are presented.

    View details for Web of Science ID A1987H387800015

    View details for PubMedID 3472000

  • IDENTIFYING A LIMITED NUMBER OF FOODS IMPORTANT IN SUPPLYING SELECTED DIETARY NUTRIENTS JOURNAL OF THE AMERICAN DIETETIC ASSOCIATION HAILE, R. W., HUNT, I. F., Buckley, J., Browdy, B. L., Murphy, N. J., Alpers, D. 1986; 86 (5): 611-616

    Abstract

    Three methods were developed to identify a limited number of foods that are important dietary contributors of fat, dietary fiber, and vitamins A, C, and E. In the first method, foods were ranked by the amount of each nutrient supplied per person per day and the effect each food had on the relative ranking of individuals with respect to the intake of those nutrients. Foods scoring high on both scales for a given nutrient were selected as important dietary contributors of that nutrient. In the second method, foods were selected according to the mean nutrient contribution per consumer (nonconsumers of a food were eliminated from this estimation procedure). In the third method, foods were selected that contributed a relatively large percentage of the total dietary intake of a given nutrient. The three methods were applied to data from an extensive dietary questionnaire. The authors then compared the limited lists of foods identified by each method. Generally, the methods yielded similar food lists. Regression analysis was then employed to test the ability of the selected foods to predict the nutrient totals calculated from the original, more extensive dietary questionnaire. The results suggest that a limited number of foods may have strong predictive ability, but that has not been tested in any other population.

    View details for Web of Science ID A1986C268100003

    View details for PubMedID 3700922

  • COMBINED SEGREGATION AND LINKAGE ANALYSIS OF MULTIPLE-SCLEROSIS GENETIC EPIDEMIOLOGY Sherman, S. L., HAILE, R. W., MacLean, C. J., Yee, S. 1986: 393-398

    View details for Web of Science ID A1986H534300058

    View details for PubMedID 3471671

  • CORRECTING FOR VARIABLE AGE OF ONSET IN THE ESTIMATION OF FAMILIAL RELATIVE RISK WHEN THERE IS A SECULAR TREND IN INCIDENCE OF DISEASE HUMAN HEREDITY HAILE, R. W., Cortessis, V. K., Perdue, S. T. 1986; 36 (4): 227-232

    Abstract

    We discuss the effects that a secular trend in incidence would have on estimation of familial relative risk (ratio of observed to expected cumulative incidence among relatives of index cases). For example, when age-specific incidence rates of a condition have increased during the lifetimes of relatives among whom relative risk is to be estimated, familial relative risk will be biased downward if cross-sectional, age-specific incidence data are used to estimate expected cumulative incidence among relatives. The stronger the trend and the older the ages of unaffected relatives, the greater the bias will be. Incorporating different age-specific incidence curves for different birth cohorts into the analysis is an approach we suggest for correcting the bias.

    View details for Web of Science ID A1986D816700005

    View details for PubMedID 3759099

  • A linkage analysis of the Gm locus and multiple sclerosis. Genetic epidemiology Haile, R. W., Goldstein, A., Field, L., Marazita, M. L. 1985; 2 (1): 29-34

    Abstract

    We conducted linkage analyses of immunoglobulin G heavy chain marker (Gm) phenotypes and multiple sclerosis (MS) in 30 families, each having at least two first-degree relatives with definite/probable MS. These families yielded positive evidence for linkage to human leukocyte antigen (HLA) loci in previous analyses. In the present analysis, however, the results for Gm were negative. Most lod scores were negative, particularly at the smaller recombination values (theta). We explored the possibility of heterogeneity by subgrouping our data on the basis of specific HLA types (A3, B7) and Gm types (Gm1, Gm1,2) within the pedigrees. The results were again negative with no substantial differences in estimates of theta between subgroups.

    View details for PubMedID 3876966

  • SEGREGATION AND LINKAGE ANALYSES OF 72 LEPROSY PEDIGREES HUMAN HEREDITY HAILE, R. W., Iselius, L., Fine, P. E., Morton, N. E. 1985; 35 (1): 43-52

    Abstract

    Data on 72 families with multiple cases of leprosy were analyzed for a susceptibility gene linked to the HLA loci. We conducted segregation analysis with the program POINTER and identity of HLA types by descent analysis to determine the most likely mode of inheritance. We then conducted linkage analysis with the program LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. Segregation results suggest a recessive mode of inheritance, especially for the tuberculoid forms of leprosy. The linkage results, limited to tuberculoid forms and assuming a recessive model, suggest a hypothesis of loose linkage with no unlinked locus. When an additive model is assumed, the best fit is obtained with a hypothesis of complete linkage (theta = 0.0) with heterogeneity. We currently favor the additive model as the more plausible one.

    View details for Web of Science ID A1985AAE0200010

    View details for PubMedID 3972424

  • PROSPECTIVE-STUDY OF CANCER IN PATIENTS WITH HYPOGAMMAGLOBULINEMIA LANCET Kinlen, L. J., Webster, A. D., Bird, A. G., Haile, R., Peto, J., Soothill, J. F., Thompson, R. A. 1985; 1 (8423): 263-266

    Abstract

    Among 377 patients with primary hypogammaglobulinaemia, mainly common variable immunodeficiency (CVID), 316 patients survived the first 2 years after diagnosis and were the subject of a study of cancer incidence. Among the 220 patients with CVID, there was a 5-fold increase of cancer due mainly to large excesses of stomach cancer (47-fold) and lymphomas (30-fold). The excess of stomach cancer is probably related to the high frequency of achlorhydria in CVID. 3 of the 7 patients with stomach cancer and CVID survived for 5 years or longer.

    View details for Web of Science ID A1985AAV2800012

    View details for PubMedID 2857327

  • GENETIC SUSCEPTIBILITY TO MULTIPLE-SCLEROSIS - A REVIEW INTERNATIONAL JOURNAL OF EPIDEMIOLOGY Haile, R. W., Hodge, S. E., Iselius, L. 1983; 12 (1): 8-16

    Abstract

    We review evidence on genetic susceptibility to multiple sclerosis provided by studies of family resemblance, migrants, twins, HLA-associations, and segregation and linkage analyses. The higher concordance rate in MZ than DZ twins and the increasing prevalence with increasing degree of kinship to propositi suggest that genetic factors are involved in the aetiology of MS. Nonetheless, the low overall twin concordance rates, the increased prevalence of MS in DZ twins over siblings, and the weight of evidence from migrant studies strongly suggest the involvement of environmental factors as well. These results can be reconciled by hypothesizing an MS susceptibility gene with reduced penetrance, where full phenotypic expression depends on critical environmental exposures. The location of this gene in or near the HLA region is suggested by the reports of HLA-MS associations and is supported by results of formal linkage analyses. Two general hypotheses have emerged. One involves loose linkage with no heterogeneity while the other involves very tight linkage and substantial heterogeneity, ie no linkage in 25% of the pedigrees. Since the MS gene is probably not a recent mutation, the hypothesis of loose linkage requires one to postulate intense selection to maintain linkage disequilibrium. It is primarily because of this intense selection that we currently favour the hypothesis of tight linkage with heterogeneity over any single-gene hypothesis involving loose linkage, given our present biological knowledge. Areas for future research are suggested.

    View details for Web of Science ID A1983QE57100003

    View details for PubMedID 6341273

  • Urethral narrowing and its treatment: a possible solution for the problems of recurrent urinary infection and the "irritable bladder". International urology and nephrology McCannel, D. A., Haile, W. 1982; 14 (4): 407-414

    Abstract

    A surgical treatment for longstanding urinary and pelvic complaints of women is described and evaluated. The procedure includes urethral dilatation to 40 F and "snowplowing" (dull curettage) of urethral, bladder neck, and trigonal mucosa with the heel of the cystoscope, removing granulated tissue, polyps, and villous fronds, and unroofing infected periurethral glands. Vigorous urethral massage is performed, and the patient is hospitalized overnight with large-catheter drainage to continue dilatation. Follow-up dilatations in the office are essential. The procedure was evaluated by comparing presenting and post-treatment symptoms for each patient and by asking each patient to rate the effectiveness of the treatment. Results suggest that treatment is very effective, with 80 per cent of respondents rating it either excellent or good.

    View details for PubMedID 7182377

  • A STUDY OF MEASLES-VIRUS AND CANINE-DISTEMPER VIRUS-ANTIBODIES, AND OF CHILDHOOD INFECTIONS IN MULTIPLE-SCLEROSIS PATIENTS AND CONTROLS JOURNAL OF THE NEUROLOGICAL SCIENCES Haile, R., Smith, P., Read, D., NASSIM, D., Warlow, C., Russell, W. C. 1982; 56 (1): 1-10

    Abstract

    We investigated the levels of neutralizing antibodies to measles virus and canine distemper virus (CDV) in 72 multiple sclerosis patients (MS) and matched controls and also examined the frequency and age of onset of a number of childhood illnesses, including measles. The frequency of each childhood illness was not significantly different between cases and controls, but cases did report a later age at measles infection. Our data suggest that the risk of MS is increased by a factor of 1.9 if measles infection occurs between 5 and 9 years of age. A validity survey, based on a questionnaire to general practitioners, suggested substantial inaccuracy in the patients' reports of when they had measles, but the direction and degree of inaccuracy did not appear to be different between cases and controls. We also found higher titres of neutralizing antibodies in cases than controls to both measles virus and CDV, although the CDV difference was not statistically significant. In the light of a significant correlation between measles and CDV titres in both cases and controls, we used paired logistic regression to determine if the case-control difference in titres for each virus could be explained by a confounding effect on one by the other. The numbers were too small, however, to enable us to separate out any independent association of either virus with MS.

    View details for Web of Science ID A1982PK83700001

    View details for PubMedID 7143023

  • HLA-LINKED AND UNLINKED DETERMINANTS OF MULTIPLE-SCLEROSIS IMMUNOGENETICS HO, H. Z., TIWARI, J. L., Haile, R. W., Terasaki, P. I., Morton, N. E. 1982; 15 (5): 509-517

    View details for Web of Science ID A1982NQ81400008

    View details for PubMedID 6179862

  • RELATIONSHIP BETWEEN MEASLES HI TITERS AND AN MS SUSCEPTIBILITY GENE JOURNAL OF NEUROLOGY Haile, R. W., Visscher, B. R., Detels, R., VALDIVIEZO, N. L., Sever, J. L., Madden, D. L. 1981; 224 (4): 235-242

    Abstract

    Recently published studies of formal linkage analyses strongly suggest that a multiple sclerosis susceptibility (MSS) gene is linked to the HLA region of the sixth chromosome. The objective of this analysis was to investigate whether or not the gene has any demonstrable relationship to the immune status with regard to measles within members of multiple-case MS families. Family members were HLA-typed, and levels of antibodies to measles were determined using the hemagglutination inhibition assay. Since a specific, HLA-defined haplotype within each family is presumably a marker for the MSS gene, family members were characterized as either carrying [(+) controls] or not carrying [(-) controls] the MSS gene by the presence of this specific haplotype. Twenty families were entered into the analyses. Results revealed that the mean titer to measles was not different between (+) and (-) controls, and that MS cases had significantly higher titers than both control groups combined.

    View details for Web of Science ID A1981LE84000001

    View details for PubMedID 6162924

  • SEGREGATION AND LINKAGE ANALYSIS OF 40 MULTIPLEX MULTIPLE-SCLEROSIS FAMILIES HUMAN HEREDITY Haile, R. W., Iselius, L., Hodge, S. E., Morton, N. E., Detels, R. 1981; 31 (4): 252-258

    Abstract

    40 multiplex multiple sclerosis (MS) families were analyzed for evidence of an MS susceptibility gene linked to the HLA region of the sixth chromosome. We assumed that population associations between specific HLA alleles and MS are due to linkage disequilibrium, so preference was given to hypotheses compatible with tight linkage, and explanations were sought for conflicting evidence. The analyses proceeded in two steps: (1) segregation analysis using the computer program POINTER, and (2) linkage analysis using LINKAS, first assuming linkage equilibrium and then allowing for linkage disequilibrium and etiological heterogeneity. The results of the segregation analyses were indeterminate. The results of the linkage analyses suggest that analyses that do not allow for disequilibrium lose substantial evidence on linkage. Of the models that were investigated under linkage disequilibrium, the best fit is with a model of complete linkage (theta= 0.0) in 75% of the pedigrees and no linkage in the remaining pedigrees. We were unable, however, to statistically reject another model involving loose linkage and no heterogeneity.

    View details for Web of Science ID A1981ME04000011

    View details for PubMedID 7287016

  • SIMILAR LEVELS OF IMMUNE-COMPLEXES IN CASES OF MULTIPLE-SCLEROSIS AND THEIR UNAFFECTED RELATIVES JOURNAL OF NEUROIMMUNOLOGY Haile, R. W., Karavodin, L. M., Visscher, B. R., Detels, R., VALDIVIEZO, N. L. 1981; 1 (2): 183-190

    Abstract

    To investigate the possible effect of the hypothetical multiple sclerosis susceptibility (MSS) gene on circulating immune complexes, we employed a sensitive assay to test for the presence of immune complexes in sera of MS patients and unaffected relatives classified by the presence/absence of HLA-defined markers for the MSS gene. We found no significant differences between cases and relatives. The results suggest that elevated immune complex levels in MS patients' sera reported by others may not be unique to MS cases, but may represent instead a familial phenomenon. We also report a possible association between the A3 + B7 haplotype and increased immune complexes.

    View details for Web of Science ID A1981MF44000003

    View details for PubMedID 7338554

  • GENETIC SUSCEPTIBILITY TO MULTIPLE-SCLEROSIS - A LINKAGE ANALYSIS WITH AGE-OF-ONSET CORRECTIONS CLINICAL GENETICS Haile, R. W., Hodge, S. E., Visscher, B. R., SPENCE, M. A., Detels, R., McAuliffe, T. L., Park, M. S., Dudley, J. P. 1980; 18 (3): 160-167

    Abstract

    To test the hypothesis that a multiple sclerosis susceptibility (MSS) gene is linked to the HLA loci, formal linkage analysis was conducted on 40 multiplex families, 20 each from the Seattle and Los Angeles areas. The computer program LIPED was utilized. A dominant model of inheritance was assumed. Penetrance values of 0.05, 0.35, and 0.67 were entered into the analyses, and an age-of-onset correction was incorporated. The resulting lod scores were supportive of linkage at the lower penetrance levels. The maximum lod score, 2.411, at an estimated recombination fraction of 0.10 in both males and females, was generated at a penetrance value of 0.05. With a penetrance value of 0.67, the lod scores did not support linkage. Under an autosomal dominant model of inheritance, the results were supportive of linkage when the presumed penetrance of the MSS gene is low. The results also confirmed the importance of incorporating an age-of-onset correction into linkage analyses.

    View details for Web of Science ID A1980KL88000002

    View details for PubMedID 7438496

  • GENETIC SUSCEPTIBILITY TO MULTIPLE-SCLEROSIS NEUROLOGY Visscher, B. R., Detels, R., Dudley, J., Haile, R. W., MALMGREN, R. M., Terasaki, P. I., Park, M. S. 1979; 29 (10): 1354-1360

    Abstract

    Previous studies of histocompatibility (HLA) types in multiple sclerosis (MS) families did not provide convincing proof of an HLA-linked susceptibility factor. In 12 families we studied, all MS cases in each family shared at least one chromosome. The probability of this occurring in the absence of genetic linkage is approximately 0.001. The estimated penetrance is 5 percent, implying that the genetic susceptibility factor may be a necessary but not a sufficient cause of MS. Additional studies are needed to identify other differences between affected and unaffected susceptible individuals.

    View details for Web of Science ID A1979HP74500005

    View details for PubMedID 573379

  • MULTIPLE-SCLEROSIS AND AGE AT MIGRATION AMERICAN JOURNAL OF EPIDEMIOLOGY Detels, R., Visscher, B. R., Haile, R. W., MALMGREN, R. M., Dudley, J. P., Coulson, A. H. 1978; 108 (5): 386-393

    View details for Web of Science ID A1978FX05300008

    View details for PubMedID 727208

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