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  • Obesity and survival among women with ovarian cancer: results from the Ovarian Cancer Association Consortium BRITISH JOURNAL OF CANCER Nagle, C. M., Dixon, S. C., Jensen, A., Kjaer, S. K., Modugno, F., Defazio, A., Fereday, S., Hung, J., Johnatty, S. E., Fasching, P. A., Beckmann, M. W., Lambrechts, D., Vergote, I., Van Nieuwenhuysen, E., Lambrechts, S., Risch, H. A., Rossing, M. A., Doherty, J. A., Wicklund, K. G., Chang-Claude, J., Goodman, M. T., Ness, R. B., Moysich, K., Heitz, F., du Bois, A., Harter, P., Schwaab, I., Matsuo, K., Hosono, S., Goode, E. L., Vierkant, R. A., Larson, M. C., Fridley, B. L., Hogdall, C., Schildkraut, J. M., WEBER, R. P., Cramer, D. W., Terry, K. L., Bandera, E. V., Paddock, L., Rodriguez-Rodriguez, L., Wentzensen, N., Yang, H. P., Brinton, L. A., Lissowska, J., Hogdall, E., Lundvall, L., Whittemore, A., McGuire, V., Sieh, W., Rothstein, J., Sutphen, R., Anton-Culver, H., Ziogas, A., Pearce, C. L., Wu, A. H., Webb, P. M. 2015; 113 (5): 817-826

    Abstract

    Observational studies have reported a modest association between obesity and risk of ovarian cancer; however, whether it is also associated with survival and whether this association varies for the different histologic subtypes are not clear. We undertook an international collaborative analysis to assess the association between body mass index (BMI), assessed shortly before diagnosis, progression-free survival (PFS), ovarian cancer-specific survival and overall survival (OS) among women with invasive ovarian cancer.We used original data from 21 studies, which included 12 390 women with ovarian carcinoma. We combined study-specific adjusted hazard ratios (HRs) using random-effects models to estimate pooled HRs (pHR). We further explored associations by histologic subtype.Overall, 6715 (54%) deaths occurred during follow-up. A significant OS disadvantage was observed for women who were obese (BMI: 30-34.9, pHR: 1.10 (95% confidence intervals (CIs): 0.99-1.23); BMI: ⩾35, pHR: 1.12 (95% CI: 1.01-1.25)). Results were similar for PFS and ovarian cancer-specific survival. In analyses stratified by histologic subtype, associations were strongest for women with low-grade serous (pHR: 1.12 per 5 kg m(-2)) and endometrioid subtypes (pHR: 1.08 per 5 kg m(-2)), and more modest for the high-grade serous (pHR: 1.04 per 5 kg m(-2)) subtype, but only the association with high-grade serous cancers was significant.Higher BMI is associated with adverse survival among the majority of women with ovarian cancer.British Journal of Cancer advance online publication, 7 July 2015; doi:10.1038/bjc.2015.245 www.bjcancer.com.

    View details for DOI 10.1038/bjc.2015.245

    View details for Web of Science ID 000360727200016

  • Genome-wide significant risk associations for mucinous ovarian carcinoma NATURE GENETICS Kelemen, L. E., Lawrenson, K., Tyrer, J., Li, Q., Lee, J. M., Seo, J., Phelan, C. M., Beesley, J., Chen, X., Spindler, T. J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Baker, H., Bandera, E. V., Bean, Y., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bruinsma, F., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Chen, Y. A., Chen, Z., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., Dennis, J., Dicks, E., Doherty, J. A., Dicks, E., Doherty, J. A., Doerk, T., du Bois, A., Duerst, M., Eccles, D., Easton, D. T., Edwards, R. P., Eilber, U., Ekici, A. B., Engelholm, S. A., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goode, E. L., Goodman, M. T., Grownwald, J., Harrington, P., Harter, P., Hasmad, H. N., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, E., Hogdall, C., Hosono, S., Iversen, E. S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kellar, M., Kelley, J. L., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Modugno, F., Moes-Sosnowska, J., Moysich, K. B., Narod, S. A., Nedergaard, L., Ness, R. B., Nevanlinna, H., Adenan, N. A., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Permuth-Wey, J., Pike, M. C., Poole, E. M., Ramus, S. J., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schildkraut, J. M., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Sucheston, L., Tangen, I. L., Teo, S., Terry, K. L., Thompson, P. J., Tworoger, S. S., van Altena, A. M., van Nieuwenhuysen, E., Vergote, I., Vierkant, R. A., Wang-Gohrke, S., Walsh, C., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Sawicki, W., Woo, Y., Wu, X., Wu, A. H., Yang, H., Zheng, W., Ziogas, A., Sellers, T. A., Freedman, M. L., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A., Berchuck, A. 2015; 47 (8): 888-?

    View details for DOI 10.1038/ng.3336

    View details for Web of Science ID 000358674100012

  • Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk PLOS ONE Chornokur, G., Lin, H., Tyrer, J. P., Lawrenson, K., Dennis, J., Amankwah, E. K., Qu, X., Tsai, Y., Jim, H. S., Chen, Z., Chen, A. Y., Permuth-Wey, J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., du Bois, A., Despierre, E., Dicks, E., Doherty, J. A., Dork, T., Durst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kelemen, L. E., Kellar, M., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lim, B. K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Moysich, K. B., Ness, R. B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schernhammer, E., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston, L., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L., Tangen, I. L., Tworoger, S. S., van Altena, A. M., Vierkant, R. A., Vergote, I., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Hasmad, H. N., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Ramus, S. J., Goode, E. L., Monteiro, A. N., Gayther, S. A., Narod, S. A., Pharoah, P. P., Sellers, T. A., Phelan, C. M. 2015; 10 (6)
  • Evaluating the ovarian cancer gonadotropin hypothesis: A candidate gene study GYNECOLOGIC ONCOLOGY Lee, A. W., Tyrer, J. P., Doherty, J. A., Stram, D. A., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Spiewankiewicz, B., Myers, E. J., Chenevix-Trench, G., Fasching, P. A., Beckmann, M. W., Ekici, A. B., Hein, A., Vergote, I., van Nieuwenhuysen, E., Lambrechts, D., Wicklund, K. G., Eilber, U., Wang-Gohrke, S., Chang-Claude, J., Rudolph, A., Sucheston-Campbell, L., Odunsi, K., Moysich, K. B., Shvetsov, Y. B., Thompson, P. J., Goodman, M. T., Wilkens, L. R., Doerk, T., Hillemanns, P., Duerst, M., Runnebaum, I. B., Bogdanova, N., Pelttari, L. M., Nevanlinna, H., Leminen, A., Edwards, R. P., Kelley, J. L., Harter, P., Schwaab, I., Heitz, F., du Bois, A., Orsulic, S., Lester, J., Walsh, C., Karlan, B. Y., Hogdall, E., Kjaer, S. K., Jensen, A., Vierkant, R. A., Cunningham, J. M., Goode, E. L., Fridley, B. L., Southey, M. C., Giles, G. G., Bruinsma, F., Wu, X., Hildebrandt, M. A., Lu, K., Liang, D., Bisogna, M., Levine, D. A., Weber, R. P., Schildkraut, J. M., Iversen, E. S., Berchuck, A., Terry, K. L., Cramer, D. W., Tworoger, S. S., Poole, E. M., Olson, S. H., Orlow, I., Bandera, E. V., Bjorge, L., Tangen, I. L., Salvesen, H. B., Krakstad, C., Massuger, L. F., Kiemeney, L. A., Aben, K. K., van Altena, A. M., Bean, Y., Pejovic, T., Kellar, M., Le, N. D., Cook, L. S., Kelemen, L. E., Brooks-Wilson, A., Lubinski, J., Gronwald, J., Cybulski, C., Jakubowska, A., Wentzensen, N., Brinton, L. A., Lissowska, J., Yang, H., Nedergaard, L., Lundvall, L., Hogdall, C., Song, H., Campbell, I. G., Eccles, D., Glasspool, R., Siddiqui, N., Carty, K., Paul, J., McNeish, L. A., Sieh, W., McGuire, V., Rothstein, J. H., Whittemore, A. S., McLaughlin, J. R., Risch, H. A., Phelan, C. M., Anton-Culver, H., Ziogas, A., Menon, U., Ramus, S. J., Gentry-Maharaj, A., Harrington, P., Pike, M. C., Modugno, F., Rossing, M. A., Ness, R. B., Pharoah, P. D., Stram, D. O., Wu, A. H., Pearce, C. L. 2015; 136 (3): 542-548

    Abstract

    Ovarian cancer is a hormone-related disease with a strong genetic basis. However, none of its high-penetrance susceptibility genes and GWAS-identified variants to date are known to be involved in hormonal pathways. Given the hypothesized etiologic role of gonadotropins, an assessment of how variability in genes involved in the gonadotropin signaling pathway impacts disease risk is warranted.Genetic data from 41 ovarian cancer study sites were pooled and unconditional logistic regression was used to evaluate whether any of the 2185 SNPs from 11 gonadotropin signaling pathway genes was associated with ovarian cancer risk. A burden test using the admixture likelihood (AML) method was also used to evaluate gene-level associations.We did not find any genome-wide significant associations between individual SNPs and ovarian cancer risk. However, there was some suggestion of gene-level associations for four gonadotropin signaling pathway genes: INHBB (p=0.045, mucinous), LHCGR (p=0.046, high-grade serous), GNRH (p=0.041, high-grade serous), and FSHB (p=0.036, overall invasive). There was also suggestive evidence for INHA (p=0.060, overall invasive).Ovarian cancer studies have limited sample numbers, thus fewer genome-wide susceptibility alleles, with only modest associations, have been identified relative to breast and prostate cancers. We have evaluated the majority of ovarian cancer studies with biological samples, to our knowledge, leaving no opportunity for replication. Using both our understanding of biology and powerful gene-level tests, we have identified four putative ovarian cancer loci near INHBB, LHCGR, GNRH, and FSHB that warrant a second look if larger sample sizes and denser genotype chips become available.

    View details for DOI 10.1016/j.ygyno.2014.12.017

    View details for Web of Science ID 000351187300020

    View details for PubMedID 25528498

  • Identification of six new susceptibility loci for invasive epithelial ovarian cancer. Nature genetics Kuchenbaecker, K. B., Ramus, S. J., Tyrer, J., Lee, A., Shen, H. C., Beesley, J., Lawrenson, K., McGuffog, L., Healey, S., Lee, J. M., Spindler, T. J., Lin, Y. G., Pejovic, T., Bean, Y., Li, Q., Coetzee, S., Hazelett, D., Miron, A., Southey, M., Terry, M. B., Goldgar, D. E., Buys, S. S., Janavicius, R., Dorfling, C. M., Van Rensburg, E. J., Neuhausen, S. L., Ding, Y. C., Hansen, T. v., Jønson, L., Gerdes, A., Ejlertsen, B., Barrowdale, D., Dennis, J., Benitez, J., Osorio, A., Garcia, M. J., Komenaka, I., Weitzel, J. N., Ganschow, P., Peterlongo, P., Bernard, L., Viel, A., Bonanni, B., Peissel, B., Manoukian, S., Radice, P., Papi, L., Ottini, L., Fostira, F., Konstantopoulou, I., Garber, J., Frost, D., Perkins, J., Platte, R., Ellis, S., Godwin, A. K., Schmutzler, R. K., Meindl, A., Engel, C., Sutter, C., Sinilnikova, O. M., Damiola, F., Mazoyer, S., Stoppa-Lyonnet, D., Claes, K., De Leeneer, K., Kirk, J., Rodriguez, G. C., Piedmonte, M., O'Malley, D. M., de la Hoya, M., Caldes, T., Aittomäki, K., Nevanlinna, H., Collée, J. M., Rookus, M. A., Oosterwijk, J. C., Tihomirova, L., Tung, N., Hamann, U., Isaccs, C., Tischkowitz, M., Imyanitov, E. N., Caligo, M. A., Campbell, I. G., Hogervorst, F. B., Olah, E., Diez, O., Blanco, I., Brunet, J., Lazaro, C., Pujana, M. A., Jakubowska, A., Gronwald, J., Lubinski, J., Sukiennicki, G., Barkardottir, R. B., Plante, M., Simard, J., Soucy, P., Montagna, M., Tognazzo, S., Teixeira, M. R., Pankratz, V. S., Wang, X., Lindor, N., Szabo, C. I., Kauff, N., Vijai, J., Aghajanian, C. A., Pfeiler, G., Berger, A., Singer, C. F., Tea, M., Phelan, C. M., Greene, M. H., Mai, P. L., Rennert, G., Mulligan, A. M., Tchatchou, S., Andrulis, I. L., Glendon, G., Toland, A. E., Jensen, U. B., Kruse, T. A., Thomassen, M., Bojesen, A., Zidan, J., friedman, e., Laitman, Y., Soller, M., Liljegren, A., Arver, B., Einbeigi, Z., Stenmark-Askmalm, M., Olopade, O. I., Nussbaum, R. L., Rebbeck, T. R., Nathanson, K. L., Domchek, S. M., Lu, K. H., Karlan, B. Y., Walsh, C., Lester, J., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., van Nieuwenhuysen, E., Vergote, I., Lambrechts, S., Dicks, E., Doherty, J. A., Wicklund, K. G., Rossing, M. A., Rudolph, A., Chang-Claude, J., Wang-Gohrke, S., Eilber, U., Moysich, K. B., Odunsi, K., Sucheston, L., Lele, S., Wilkens, L. R., Goodman, M. T., Thompson, P. J., Shvetsov, Y. B., Runnebaum, I. B., Dürst, M., Hillemanns, P., Dörk, T., Antonenkova, N., Bogdanova, N., Leminen, A., Pelttari, L. M., Butzow, R., Modugno, F., Kelley, J. L., Edwards, R. P., Ness, R. B., du Bois, A., Heitz, F., Schwaab, I., Harter, P., Matsuo, K., Hosono, S., Orsulic, S., Jensen, A., Kjaer, S. K., Hogdall, E., Hasmad, H. N., Azmi, M. A., Teo, S., Woo, Y., Fridley, B. L., Goode, E. L., Cunningham, J. M., Vierkant, R. A., Bruinsma, F., Giles, G. G., Liang, D., Hildebrandt, M. A., Wu, X., Levine, D. A., Bisogna, M., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Concannon, P., Weber, R. P., Cramer, D. W., Terry, K. L., Poole, E. M., Tworoger, S. S., Bandera, E. V., Orlow, I., Olson, S. H., Krakstad, C., Salvesen, H. B., Tangen, I. L., Bjorge, L., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Kellar, M., Brooks-Wilson, A., Kelemen, L. E., Cook, L. S., Le, N. D., Cybulski, C., Yang, H., Lissowska, J., Brinton, L. A., Wentzensen, N., Hogdall, C., Lundvall, L., Nedergaard, L., Baker, H., Song, H., Eccles, D., McNeish, I., Paul, J., Carty, K., Siddiqui, N., Glasspool, R., Whittemore, A. S., Rothstein, J. H., McGuire, V., Sieh, W., Ji, B., Zheng, W., Shu, X., Gao, Y., Rosen, B., Risch, H. A., McLaughlin, J. R., Narod, S. A., Monteiro, A. N., Chen, A., Lin, H., Permuth-Wey, J., Sellers, T. A., Tsai, Y., Chen, Z., Ziogas, A., Anton-Culver, H., Gentry-Maharaj, A., Menon, U., Harrington, P., Lee, A. W., Wu, A. H., Pearce, C. L., Coetzee, G., Pike, M. C., Dansonka-Mieszkowska, A., Timorek, A., Rzepecka, I. K., Kupryjanczyk, J., Freedman, M., Noushmehr, H., Easton, D. F., Offit, K., Couch, F. J., Gayther, S., Pharoah, P. P., Antoniou, A. C., Chenevix-Trench, G. 2015; 47 (2): 164-171

    Abstract

    Genome-wide association studies (GWAS) have identified 12 epithelial ovarian cancer (EOC) susceptibility alleles. The pattern of association at these loci is consistent in BRCA1 and BRCA2 mutation carriers who are at high risk of EOC. After imputation to 1000 Genomes Project data, we assessed associations of 11 million genetic variants with EOC risk from 15,437 cases unselected for family history and 30,845 controls and from 15,252 BRCA1 mutation carriers and 8,211 BRCA2 mutation carriers (3,096 with ovarian cancer), and we combined the results in a meta-analysis. This new study design yielded increased statistical power, leading to the discovery of six new EOC susceptibility loci. Variants at 1p36 (nearest gene, WNT4), 4q26 (SYNPO2), 9q34.2 (ABO) and 17q11.2 (ATAD5) were associated with EOC risk, and at 1p34.3 (RSPO1) and 6p22.1 (GPX6) variants were specifically associated with the serous EOC subtype, all with P < 5 × 10(-8). Incorporating these variants into risk assessment tools will improve clinical risk predictions for BRCA1 and BRCA2 mutation carriers.

    View details for DOI 10.1038/ng.3185

    View details for PubMedID 25581431

  • Common Genetic Variation In Cellular Transport Genes and Epithelial Ovarian Cancer (EOC) Risk. PloS one Chornokur, G., Lin, H., Tyrer, J. P., Lawrenson, K., Dennis, J., Amankwah, E. K., Qu, X., Tsai, Y., Jim, H. S., Chen, Z., Chen, A. Y., Permuth-Wey, J., Aben, K. K., Anton-Culver, H., Antonenkova, N., Bruinsma, F., Bandera, E. V., Bean, Y. T., Beckmann, M. W., Bisogna, M., Bjorge, L., Bogdanova, N., Brinton, L. A., Brooks-Wilson, A., Bunker, C. H., Butzow, R., Campbell, I. G., Carty, K., Chang-Claude, J., Cook, L. S., Cramer, D. W., Cunningham, J. M., Cybulski, C., Dansonka-Mieszkowska, A., du Bois, A., Despierre, E., Dicks, E., Doherty, J. A., Dörk, T., Dürst, M., Easton, D. F., Eccles, D. M., Edwards, R. P., Ekici, A. B., Fasching, P. A., Fridley, B. L., Gao, Y., Gentry-Maharaj, A., Giles, G. G., Glasspool, R., Goodman, M. T., Gronwald, J., Harrington, P., Harter, P., Hein, A., Heitz, F., Hildebrandt, M. A., Hillemanns, P., Hogdall, C. K., Hogdall, E., Hosono, S., Jakubowska, A., Jensen, A., Ji, B., Karlan, B. Y., Kelemen, L. E., Kellar, M., Kiemeney, L. A., Krakstad, C., Kjaer, S. K., Kupryjanczyk, J., Lambrechts, D., Lambrechts, S., Le, N. D., Lee, A. W., Lele, S., Leminen, A., Lester, J., Levine, D. A., Liang, D., Lim, B. K., Lissowska, J., Lu, K., Lubinski, J., Lundvall, L., Massuger, L. F., Matsuo, K., McGuire, V., McLaughlin, J. R., McNeish, I., Menon, U., Milne, R. L., Modugno, F., Moysich, K. B., Ness, R. B., Nevanlinna, H., Eilber, U., Odunsi, K., Olson, S. H., Orlow, I., Orsulic, S., Weber, R. P., Paul, J., Pearce, C. L., Pejovic, T., Pelttari, L. M., Pike, M. C., Poole, E. M., Risch, H. A., Rosen, B., Rossing, M. A., Rothstein, J. H., Rudolph, A., Runnebaum, I. B., Rzepecka, I. K., Salvesen, H. B., Schernhammer, E., Schwaab, I., Shu, X., Shvetsov, Y. B., Siddiqui, N., Sieh, W., Song, H., Southey, M. C., Spiewankiewicz, B., Sucheston, L., Teo, S., Terry, K. L., Thompson, P. J., Thomsen, L., Tangen, I. L., Tworoger, S. S., van Altena, A. M., Vierkant, R. A., Vergote, I., Walsh, C. S., Wang-Gohrke, S., Wentzensen, N., Whittemore, A. S., Wicklund, K. G., Wilkens, L. R., Wu, A. H., Wu, X., Woo, Y., Yang, H., Zheng, W., Ziogas, A., Hasmad, H. N., Berchuck, A., Iversen, E. S., Schildkraut, J. M., Ramus, S. J., Goode, E. L., Monteiro, A. N., Gayther, S. A., Narod, S. A., Pharoah, P. D., Sellers, T. A., Phelan, C. M. 2015; 10 (6)

    Abstract

    Defective cellular transport processes can lead to aberrant accumulation of trace elements, iron, small molecules and hormones in the cell, which in turn may promote the formation of reactive oxygen species, promoting DNA damage and aberrant expression of key regulatory cancer genes. As DNA damage and uncontrolled proliferation are hallmarks of cancer, including epithelial ovarian cancer (EOC), we hypothesized that inherited variation in the cellular transport genes contributes to EOC risk.In total, DNA samples were obtained from 14,525 case subjects with invasive EOC and from 23,447 controls from 43 sites in the Ovarian Cancer Association Consortium (OCAC). Two hundred seventy nine SNPs, representing 131 genes, were genotyped using an Illumina Infinium iSelect BeadChip as part of the Collaborative Oncological Gene-environment Study (COGS). SNP analyses were conducted using unconditional logistic regression under a log-additive model, and the FDR q<0.2 was applied to adjust for multiple comparisons.The most significant evidence of an association for all invasive cancers combined and for the serous subtype was observed for SNP rs17216603 in the iron transporter gene HEPH (invasive: OR = 0.85, P = 0.00026; serous: OR = 0.81, P = 0.00020); this SNP was also associated with the borderline/low malignant potential (LMP) tumors (P = 0.021). Other genes significantly associated with EOC histological subtypes (p<0.05) included the UGT1A (endometrioid), SLC25A45 (mucinous), SLC39A11 (low malignant potential), and SERPINA7 (clear cell carcinoma). In addition, 1785 SNPs in six genes (HEPH, MGST1, SERPINA, SLC25A45, SLC39A11 and UGT1A) were imputed from the 1000 Genomes Project and examined for association with INV EOC in white-European subjects. The most significant imputed SNP was rs117729793 in SLC39A11 (per allele, OR = 2.55, 95% CI = 1.5-4.35, p = 5.66x10-4).These results, generated on a large cohort of women, revealed associations between inherited cellular transport gene variants and risk of EOC histologic subtypes.

    View details for DOI 10.1371/journal.pone.0128106

    View details for PubMedID 26091520

  • The Role of Genome Sequencing in Personalized Breast Cancer Prevention CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Sieh, W., Rothstein, J. H., McGuire, V., Whittemore, A. S. 2014; 23 (11): 2322-2327
  • Consortium analysis of gene and gene-folate interactions in purine and pyrimidine metabolism pathways with ovarian carcinoma risk MOLECULAR NUTRITION & FOOD RESEARCH Kelemen, L. E., Terry, K. L., Goodman, M. T., Webb, P. M., Bandera, E. V., McGuire, V., Rossing, M. A., Wang, Q., Dicks, E., Tyrer, J. P., Song, H., Kupryjanczyk, J., Dansonka-Mieszkowska, A., Plisiecka-Halasa, J., Timorek, A., Menon, U., Gentry-Maharaj, A., Gayther, S. A., Ramus, S. J., Narod, S. A., Risch, H. A., McLaughlin, J. R., Siddiqui, N., Glasspool, R., Paul, J., Carty, K., Gronwald, J., Lubinski, J., Jakubowska, A., Cybulski, C., Kiemeney, L. A., Massuger, L. F., van Altena, A. M., Aben, K. K., Olson, S. H., Orlow, I., Cramer, D. W., Levine, D. A., Bisogna, M., Giles, G. G., Southey, M. C., Bruinsma, F., Kjaer, S. K., Hogdall, E., Jensen, A., Hogdall, C. K., Lundvall, L., Engelholm, S., Heitz, F., du Bois, A., Harter, P., Schwaab, I., Butzow, R., Nevanlinna, H., Pelttari, L. M., Leminen, A., Thompson, P. J., Lurie, G., Wilkens, L. R., Lambrechts, D., van Nieuwenhuysen, E., Lambrechts, S., Vergote, I., Beesley, J., Investigators, A. S., Fasching, P. A., Beckmann, M. W., Hein, A., Ekici, A. B., Doherty, J. A., Wu, A. H., Pearce, C. L., Pike, M. C., Stram, D., Chang-Claude, J., Rudolph, A., Doerk, T., Duerst, M., Hillemanns, P., Runnebaum, I. B., Bogdanova, N., Antonenkova, N., Odunsi, K., Edwards, R. P., Kelley, J. L., Modugno, F., Ness, R. B., Karlan, B. Y., Walsh, C., Lester, J., Orsulic, S., Fridley, B. L., Vierkant, R. A., Cunningham, J. M., Wu, X., Lu, K., Liang, D., Hildebrandt, M. A., Weber, R. P., Iversen, E. S., Tworoger, S. S., Poole, E. M., Salvesen, H. B., Krakstad, C., Bjorge, L., Tangen, I. L., Pejovic, T., Bean, Y., Kellar, M., Wentzensen, N., Brinton, L. A., Lissowska, J., Garcia-Closas, M., Campbell, I. G., Eccles, D., Whittemore, A. S., Sieh, W., Rothstein, J. H., Anton-Culver, H., Ziogas, A., Phelan, C. M., Moysich, K. B., Goode, E. L., Schildkraut, J. M., Berchuck, A., Pharoah, P. D., Sellers, T. A., Brooks-Wilson, A., Cook, L. S., Le, N. D. 2014; 58 (10): 2023-2035
  • Variation in NF-kappa B Signaling Pathways and Survival in Invasive Epithelial Ovarian Cancer CANCER EPIDEMIOLOGY BIOMARKERS & PREVENTION Block, M. S., Charbonneau, B., Vierkant, R. A., Fogarty, Z., Bamlet, W. R., Pharoah, P. D., Chenevix-Trench, G., Rossing, M. A., Cramer, D., Pearce, C. L., Schildkraut, J., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y. T., Hays, L. E., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L. A., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C. S., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Den Berg, D., Terry, K. L., Vitonis, A. F., Ramirez, S. M., Rider, D. N., Knutson, K. L., Sellers, T. A., Phelan, C. M., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Kalli, K. R., Fridley, B. L., Cunningham, J. M., Goode, E. L. 2014; 23 (7): 1421-1427

    Abstract

    Survival in epithelial ovarian cancer (EOC) is influenced by the host immune response, yet the key genetic determinants of inflammation and immunity that impact prognosis are not known. The nuclear factor-kappa B (NF-κB) transcription factor family plays an important role in many immune and inflammatory responses, including the response to cancer. We studied common inherited variation in 210 genes in the NF-κB family in 10,084 patients with invasive EOC (5,248 high grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous) from the Ovarian Cancer Association Consortium. Associations between genotype and overall survival were assessed using Cox regression for all patients and by major histology, adjusting for known prognostic factors and correcting for multiple testing (threshold for statistical significance-p < 2.5x10-5). Results were statistically significant when assessed for patients of a single histology. Key associations were with CARD11 (caspase recruitment domain family, member 11) rs41324349 in patients with mucinous EOC (HR 1.82, 95% CI 1.41-2.35, p=4.13x10-6) and TNFRSF13B (tumor necrosis factor receptor superfamily, member 13B) rs7501462 in patients with endometrioid EOC (HR 0.68, 95% CI 0.56-0.82, p=2.33x10-5). Other associations of note included TRAF2 (TNF receptor-associated factor 2) rs17250239 in patients with high-grade serous EOC (HR 0.84, 95% CI 0.77-0.92, p=6.49x10-5) and PLCG1 (phospholipase C, gamma 1) rs11696662 in patients with clear cell EOC (HR 0.43, 95% CI 0.26-0.73, p=4.56x10-4). These associations highlight the potential importance of genes associated with host inflammation and immunity in modulating clinical outcomes in distinct EOC histologies.

    View details for DOI 10.1158/1055-9965.EPI-13-0962

    View details for Web of Science ID 000345273700033

  • Genome-wide association study of subtype-specific epithelial ovarian cancer risk alleles using pooled DNA HUMAN GENETICS Earp, M. A., Kelemen, L. E., Magliocco, A. M., Swenerton, K. D., Chenevix-Trench, G., Lu, Y., Hein, A., Ekici, A. B., Beckmann, M. W., Fasching, P. A., Lambrechts, D., Despierre, E., Vergote, I., Lambrechts, S., Doherty, J. A., Rossing, M. A., Chang-Claude, J., Rudolph, A., Friel, G., Moysich, K. B., Odunsi, K., Sucheston-Campbell, L., Lurie, G., Goodman, M. T., Carney, M. E., Thompson, P. J., Runnebaum, I. B., Duerst, M., Hillemanns, P., Doerk, T., Antonenkova, N., Bogdanova, N., Leminen, A., Nevanlinna, H., Pelttari, L. M., Butzow, R., Bunker, C. H., Modugno, F., Edwards, R. P., Ness, R. B., du Bois, A., Heitz, F., Schwaab, I., Harter, P., Karlan, B. Y., Walsh, C., Lester, J., Jensen, A., Kjaer, S. K., Hogdall, C. K., Hogdall, E., Lundvall, L., Sellers, T. A., Fridley, B. L., Goode, E. L., Cunningham, J. M., Vierkant, R. A., Giles, G. G., Baglietto, L., Severi, G., Southey, M. C., Liang, D., Wu, X., Lu, K., Hildebrandt, M. A., Levine, D. A., Bisogna, M., Schildkraut, J. M., Iversen, E. S., Weber, R. P., Berchuck, A., Cramer, D. W., Terry, K. L., Poole, E. M., Tworoger, S. S., Bandera, E. V., Chandran, U., Orlow, I., Olson, S. H., Wik, E., Salvesen, H. B., Bjorge, L., Halle, M. K., van Altena, A. M., Aben, K. K., Kiemeney, L. A., Massuger, L. F., Pejovic, T., Bean, Y. T., Cybulski, C., Gronwald, J., Lubinski, J., Wentzensen, N., Brinton, L. A., Lissowska, J., Garcia-Closas, M., Dicks, E., Dennis, J., Easton, D. F., Song, H., Tyrer, J. P., Pharoah, P. D., Eccles, D., Campbell, I. G., Whittemore, A. S., McGuire, V., Sieh, W., Rothstein, J. H., Flanagan, J. M., Paul, J., Brown, R., Phelan, C. M., Risch, H. A., McLaughlin, J. R., Narod, S. A., Ziogas, A., Anton-Culver, H., Gentry-Maharaj, A., Menon, U., Gayther, S. A., Ramus, S. J., Wu, A. H., Pearce, C. L., Pike, M. C., Dansonka-Mieszkowska, A., Rzepecka, I. K., Szafron, L. M., Kupryjanczyk, J., Cook, L. S., Le, N. D., Brooks-Wilson, A. 2014; 133 (5): 481-497

    Abstract

    Epithelial ovarian cancer (EOC) is a heterogeneous cancer with both genetic and environmental risk factors. Variants influencing the risk of developing the less-common EOC subtypes have not been fully investigated. We performed a genome-wide association study (GWAS) of EOC according to subtype by pooling genomic DNA from 545 cases and 398 controls of European descent, and testing for allelic associations. We evaluated for replication 188 variants from the GWAS [56 variants for mucinous, 55 for endometrioid and clear cell, 53 for low-malignant potential (LMP) serous, and 24 for invasive serous EOC], selected using pre-defined criteria. Genotypes from 13,188 cases and 23,164 controls of European descent were used to perform unconditional logistic regression under the log-additive genetic model; odds ratios (OR) and 95 % confidence intervals are reported. Nine variants tagging six loci were associated with subtype-specific EOC risk at P < 0.05, and had an OR that agreed in direction of effect with the GWAS results. Several of these variants are in or near genes with a biological rationale for conferring EOC risk, including ZFP36L1 and RAD51B for mucinous EOC (rs17106154, OR = 1.17, P = 0.029, n = 1,483 cases), GRB10 for endometrioid and clear cell EOC (rs2190503, P = 0.014, n = 2,903 cases), and C22orf26/BPIL2 for LMP serous EOC (rs9609538, OR = 0.86, P = 0.0043, n = 892 cases). In analyses that included the 75 GWAS samples, the association between rs9609538 (OR = 0.84, P = 0.0007) and LMP serous EOC risk remained statistically significant at P < 0.0012 adjusted for multiple testing. Replication in additional samples will be important to verify these results for the less-common EOC subtypes.

    View details for DOI 10.1007/s00439-013-1383-3

    View details for Web of Science ID 000334519900002

  • Large-Scale Evaluation of Common Variation in Regulatory T Cell-Related Genes and Ovarian Cancer Outcome CANCER IMMUNOLOGY RESEARCH Charbonneau, B., Moysich, K. B., Kalli, K. R., Oberg, A. L., Vierkant, R. A., Fogarty, Z. C., Block, M. S., Maurer, M. J., Goergen, K. M., Fridley, B. L., Cunningham, J. M., Rider, D. N., Preston, C., Hartmann, L. C., Lawrenson, K., Wang, C., Tyrer, J., Song, H., deFazio, A., Johnatty, S. E., Doherty, J. A., Phelan, C. M., Sellers, T. A., Ramirez, S. M., Vitonis, A. F., Terry, K. L., Van Den Berg, D., Pike, M. C., Wu, A. H., Berchuck, A., Gentry-Maharaj, A., Ramus, S. J., Diergaarde, B., Shen, H., Jensen, A., Menkiszak, J., Cybulski, C., Lubinski, J., Ziogas, A., Rothstein, J. H., McGuire, V., Sieh, W., Lester, J., Walsh, C., Vergote, I., Lambrechts, S., Despierre, E., Garcia-Closas, M., Yang, H., Brinton, L. A., Spiewankiewicz, B., Rzepecka, I. K., Dansonka-Mieszkowska, A., Seibold, P., Rudolph, A., Paddock, L. E., Orlow, I., Lundvall, L., Olson, S. H., Hogdall, C. K., Schwaab, I., du Bois, A., Harter, P., Flanagan, J. M., Brown, R., Paul, J., Ekici, A. B., Beckmann, M., Hein, A., Eccles, D., Lurie, G., Hays, L. E., Bean, Y. T., Pejovic, T., Goodman, M. T., Campbell, I., Fasching, P. A., Konecny, G., Kaye, S. B., Heitz, F., Hogdall, E., Bandera, E. V., Chang-Claude, J., Kupryjanczyk, J., Wentzensen, N., Lambrechts, D., Karlan, B. Y., Whittemore, A. S., Culver, H. A., Gronwald, J., Levine, D. A., Kjaer, S. K., Menon, U., Schildkraut, J. M., Pearce, C. L., Cramer, D. W., Rossing, M. A., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A., Ness, R. B., Odunsi, K., Sucheston, L. E., Knutson, K. L., Goode, E. L. 2014; 2 (4): 332-340
  • Large-scale evaluation of common variation in regulatory T cell-related genes and ovarian cancer outcome. Cancer immunology research Charbonneau, B., Moysich, K. B., Kalli, K. R., Oberg, A. L., Vierkant, R. A., Fogarty, Z. C., Block, M. S., Maurer, M. J., Goergen, K. M., Fridley, B. L., Cunningham, J. M., Rider, D. N., Preston, C., Hartmann, L. C., Lawrenson, K., Wang, C., Tyrer, J., Song, H., deFazio, A., Johnatty, S. E., Doherty, J. A., Phelan, C. M., Sellers, T. A., Ramirez, S. M., Vitonis, A. F., Terry, K. L., Van Den Berg, D., Pike, M. C., Wu, A. H., Berchuck, A., Gentry-Maharaj, A., Ramus, S. J., Diergaarde, B., Shen, H., Jensen, A., Menkiszak, J., Cybulski, C., Lubilski, J., Ziogas, A., Rothstein, J. H., McGuire, V., Sieh, W., Lester, J., Walsh, C., Vergote, I., Lambrechts, S., Despierre, E., Garcia-Closas, M., Yang, H., Brinton, L. A., Spiewankiewicz, B., Rzepecka, I. K., Dansonka-Mieszkowska, A., Seibold, P., Rudolph, A., Paddock, L. E., Orlow, I., Lundvall, L., Olson, S. H., Hogdall, C. K., Schwaab, I., du Bois, A., Harter, P., Flanagan, J. M., Brown, R., Paul, J., Ekici, A. B., Beckmann, M. W., Hein, A., Eccles, D., Lurie, G., Hays, L. E., Bean, Y. T., Pejovic, T., Goodman, M. T., Campbell, I., Fasching, P. A., Konecny, G., Kaye, S. B., Heitz, F., Hogdall, E., Bandera, E. V., Chang-Claude, J., Kupryjanczyk, J., Wentzensen, N., Lambrechts, D., Karlan, B. Y., Whittemore, A. S., Culver, H. A., Gronwald, J., Levine, D. A., Kjaer, S. K., Menon, U., Schildkraut, J. M., Pearce, C. L., Cramer, D. W., Rossing, M. A., Chenevix-Trench, G., Pharoah, P. D., Gayther, S. A., Ness, R. B., Odunsi, K., Sucheston, L. E., Knutson, K. L., Goode, E. L. 2014; 2 (4): 332-340

    Abstract

    The presence of regulatory T cells (Treg) in solid tumors is known to play a role in patient survival in ovarian cancer and other malignancies. We assessed inherited genetic variations via 749 tag single-nucleotide polymorphisms (SNP) in 25 Treg-associated genes (CD28, CTLA4, FOXP3, IDO1, IL10, IL10RA, IL15, 1L17RA, IL23A, IL23R, IL2RA, IL6, IL6R, IL8, LGALS1, LGALS9, MAP3K8, STAT5A, STAT5B, TGFB1, TGFB2, TGFB3, TGFBR1, TGRBR2, and TGFBR3) in relation to ovarian cancer survival. We analyzed genotype and overall survival in 10,084 women with invasive epithelial ovarian cancer, including 5,248 high-grade serous, 1,452 endometrioid, 795 clear cell, and 661 mucinous carcinoma cases of European descent across 28 studies from the Ovarian Cancer Association Consortium (OCAC). The strongest associations were found for endometrioid carcinoma and IL2RA SNPs rs11256497 [HR, 1.42; 95% confidence interval (CI), 1.22-1.64; P = 5.7 × 10(-6)], rs791587 (HR, 1.36; 95% CI, 1.17-1.57; P = 6.2 × 10(-5)), rs2476491 (HR, = 1.40; 95% CI, 1.19-1.64; P = 5.6 × 10(-5)), and rs10795763 (HR, 1.35; 95% CI, 1.17-1.57; P = 7.9 × 10(-5)), and for clear cell carcinoma and CTLA4 SNP rs231775 (HR, 0.67; 95% CI, 0.54-0.82; P = 9.3 × 10(-5)) after adjustment for age, study site, population stratification, stage, grade, and oral contraceptive use. The rs231775 allele associated with improved survival in our study also results in an amino acid change in CTLA4 and previously has been reported to be associated with autoimmune conditions. Thus, we found evidence that SNPs in genes related to Tregs seem to play a role in ovarian cancer survival, particularly in patients with clear cell and endometrioid epithelial ovarian cancer. Cancer Immunol Res; 2(4); 332-40. ©2014 AACR.

    View details for DOI 10.1158/2326-6066.CIR-13-0136

    View details for PubMedID 24764580

  • Risk of Ovarian Cancer and the NF-kappa B Pathway: Genetic Association with IL1A and TNFSF10 CANCER RESEARCH Charbonneau, B., Block, M. S., Bamlet, W. R., Vierkant, R. A., Kalli, K. R., Fogarty, Z., Rider, D. N., Sellers, T. A., Tworoger, S. S., Poole, E., Risch, H. A., Salvesen, H. B., Kiemeney, L. A., Baglietto, L., Giles, G. G., Severi, G., Trabert, B., Wentzensen, N., Chenevix-Trench, G., Whittemore, A. S., Sieh, W., Chang-Claude, J., Bandera, E. V., Orlow, I., Terry, K., Goodman, M. T., Thompson, P. J., Cook, L. S., Rossing, M. A., Ness, R. B., Narod, S. A., Kupryjanczyk, J., Lu, K., Butzow, R., Doerk, T., Pejovic, T., Campbell, I., Le, N. D., Bunker, C. H., Bogdanova, N., Runnebaum, I. B., Eccles, D., Paul, J., Wu, A. H., Gayther, S. A., Hogdall, E., Heitz, F., Kaye, S. B., Karlan, B. Y., Anton-Culver, H., Gronwald, J., Hogdall, C. K., Lambrechts, D., Fasching, P. A., Menon, U., Schildkraut, J., Pearce, C. L., Levine, D. A., Kjaer, S. K., Cramer, D., Flanagan, J. M., Phelan, C. M., Brown, R., Massuger, L. F., Song, H., Doherty, J. A., Krakstad, C., Liang, D., Odunsi, K., Berchuck, A., Jensen, A., Lubinski, J., Nevanlinna, H., Bean, Y. T., Lurie, G., Ziogas, A., Walsh, C., Despierre, E., Brinton, L., Hein, A., Rudolph, A., Dansonka-Mieszkowska, A., Olson, S. H., Harter, P., Tyrer, J., Vitonis, A. F., Brooks-Wilson, A., Aben, K. K., Pike, M. C., Ramus, S. J., Wik, E., Cybulski, C., Lin, J., Sucheston, L., Edwards, R., McGuire, V., Lester, J., du Bois, A., Lundvall, L., Wang-Gohrke, S., Szafron, L. M., Lambrechts, S., Yang, H., Beckmann, M. W., Pelttari, L. M., van Altena, A. M., Van Den Berg, D., Halle, M. K., Gentry-Maharaj, A., Schwaab, I., Chandran, U., Menkiszak, J., Ekici, A. B., Wilkens, L. R., Leminen, A., Modugno, F., Friel, G., Rothstein, J. H., Vergote, I., Garcia-Closas, M., Hildebrandt, M. A., Sobiczewski, P., Kelemen, L. E., Pharoah, P. D., Moysich, K., Knutson, K. L., Cunningham, J. M., Fridley, B. L., Goode, E. L. 2014; 74 (3): 852-861

    Abstract

    A missense single-nucleotide polymorphism (SNP) in the immune modulatory gene IL1A has been associated with ovarian cancer risk (rs17561). Although the exact mechanism through which this SNP alters risk of ovarian cancer is not clearly understood, rs17561 has also been associated with risk of endometriosis, an epidemiologic risk factor for ovarian cancer. Interleukin-1α (IL1A) is both regulated by and able to activate NF-κB, a transcription factor family that induces transcription of many proinflammatory genes and may be an important mediator in carcinogenesis. We therefore tagged SNPs in more than 200 genes in the NF-κB pathway for a total of 2,282 SNPs (including rs17561) for genotype analysis of 15,604 cases of ovarian cancer in patients of European descent, including 6,179 of high-grade serous (HGS), 2,100 endometrioid, 1,591 mucinous, 1,034 clear cell, and 1,016 low-grade serous, including 23,235 control cases spanning 40 studies in the Ovarian Cancer Association Consortium. In this large population, we confirmed the association between rs17561 and clear cell ovarian cancer [OR, 0.84; 95% confidence interval (CI), 0.76-0.93; P = 0.00075], which remained intact even after excluding participants in the prior study (OR, 0.85; 95% CI, 0.75-0.95; P = 0.006). Considering a multiple-testing-corrected significance threshold of P < 2.5 × 10(-5), only one other variant, the TNFSF10 SNP rs6785617, was associated significantly with a risk of ovarian cancer (low malignant potential tumors OR, 0.85; 95% CI, 0.79-0.91; P = 0.00002). Our results extend the evidence that borderline tumors may have a distinct genetic etiology. Further investigation of how these SNPs might modify ovarian cancer associations with other inflammation-related risk factors is warranted. Cancer Res; 74(3); 852-61. ©2013 AACR.

    View details for DOI 10.1158/0008-5472.CAN-13-1051

    View details for Web of Science ID 000331073900022

  • Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

    Abstract

    Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

    View details for DOI 10.1016/S1470-2045(13)70253-5

    View details for PubMedID 23845225

  • Hormone-receptor expression and ovarian cancer survival: an Ovarian Tumor Tissue Analysis consortium study. lancet oncology Sieh, W., Köbel, M., Longacre, T. A., Bowtell, D. D., deFazio, A., Goodman, M. T., Høgdall, E., Deen, S., Wentzensen, N., Moysich, K. B., Brenton, J. D., Clarke, B. A., Menon, U., Gilks, C. B., Kim, A., Madore, J., Fereday, S., George, J., Galletta, L., Lurie, G., Wilkens, L. R., Carney, M. E., Thompson, P. J., Matsuno, R. K., Kjær, S. K., Jensen, A., Høgdall, C., Kalli, K. R., Fridley, B. L., Keeney, G. L., Vierkant, R. A., Cunningham, J. M., Brinton, L. A., Yang, H. P., Sherman, M. E., García-Closas, M., Lissowska, J., Odunsi, K., Morrison, C., Lele, S., Bshara, W., Sucheston, L., Jimenez-Linan, M., Driver, K., Alsop, J., Mack, M., McGuire, V., Rothstein, J. H., Rosen, B. P., Bernardini, M. Q., Mackay, H., Oza, A., Wozniak, E. L., Benjamin, E., Gentry-Maharaj, A., Gayther, S. A., Tinker, A. V., Prentice, L. M., Chow, C., Anglesio, M. S., Johnatty, S. E., Chenevix-Trench, G., Whittemore, A. S., Pharoah, P. D., Goode, E. L., Huntsman, D. G., Ramus, S. J. 2013; 14 (9): 853-862

    Abstract

    Few biomarkers of ovarian cancer prognosis have been established, partly because subtype-specific associations might be obscured in studies combining all histopathological subtypes. We examined whether tumour expression of the progesterone receptor (PR) and oestrogen receptor (ER) was associated with subtype-specific survival.12 studies participating in the Ovarian Tumor Tissue Analysis consortium contributed tissue microarray sections and clinical data to our study. Participants included in our analysis had been diagnosed with invasive serous, mucinous, endometrioid, or clear-cell carcinomas of the ovary. For a patient to be eligible, tissue microarrays, clinical follow-up data, age at diagnosis, and tumour grade and stage had to be available. Clinical data were obtained from medical records, cancer registries, death certificates, pathology reports, and review of histological slides. PR and ER statuses were assessed by central immunohistochemistry analysis done by masked pathologists. PR and ER staining was defined as negative (<1% tumour cell nuclei), weak (1 to <50%), or strong (≥50%). Associations with disease-specific survival were assessed.2933 women with invasive epithelial ovarian cancer were included: 1742 with high-grade serous carcinoma, 110 with low-grade serous carcinoma, 207 with mucinous carcinoma, 484 with endometrioid carcinoma, and 390 with clear-cell carcinoma. PR expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001) and high-grade serous carcinoma (log-rank p=0·0006), and ER expression was associated with improved disease-specific survival in endometrioid carcinoma (log-rank p<0·0001). We recorded no significant associations for mucinous, clear-cell, or low-grade serous carcinoma. Positive hormone-receptor expression (weak or strong staining for PR or ER, or both) was associated with significantly improved disease-specific survival in endometrioid carcinoma compared with negative hormone-receptor expression, independent of study site, age, stage, and grade (hazard ratio 0·33, 95% CI 0·21-0·51; p<0·0001). Strong PR expression was independently associated with improved disease-specific survival in high-grade serous carcinoma (0·71, 0·55-0·91; p=0·0080), but weak PR expression was not (1·02, 0·89-1·18; p=0·74).PR and ER are prognostic biomarkers for endometrioid and high-grade serous ovarian cancers. Clinical trials, stratified by subtype and biomarker status, are needed to establish whether hormone-receptor status predicts response to endocrine treatment, and whether it could guide personalised treatment for ovarian cancer.Carraresi Foundation and others.

    View details for DOI 10.1016/S1470-2045(13)70253-5

    View details for PubMedID 23845225

  • Analysis of Over 10,000 Cases Finds No Association between Previously Reported Candidate Polymorphisms and Ovarian Cancer Outcome. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology White, K. L., Vierkant, R. A., Fogarty, Z. C., Charbonneau, B., Block, M. S., Pharoah, P. D., Chenevix-Trench, G., Rossing, M. A., Cramer, D. W., Pearce, C. L., Schildkraut, J. M., Menon, U., Kjaer, S. K., Levine, D. A., Gronwald, J., Culver, H. A., Whittemore, A. S., Karlan, B. Y., Lambrechts, D., Wentzensen, N., Kupryjanczyk, J., Chang-Claude, J., Bandera, E. V., Hogdall, E., Heitz, F., Kaye, S. B., Fasching, P. A., Campbell, I., Goodman, M. T., Pejovic, T., Bean, Y., Lurie, G., Eccles, D., Hein, A., Beckmann, M. W., Ekici, A. B., Paul, J., Brown, R., Flanagan, J. M., Harter, P., du Bois, A., Schwaab, I., Hogdall, C. K., Lundvall, L., Olson, S. H., Orlow, I., Paddock, L. E., Rudolph, A., Eilber, U., Dansonka-Mieszkowska, A., Rzepecka, I. K., Ziolkowska-Seta, I., Brinton, L., Yang, H., Garcia-Closas, M., Despierre, E., Lambrechts, S., Vergote, I., Walsh, C., Lester, J., Sieh, W., McGuire, V., Rothstein, J. H., Ziogas, A., Lubinski, J., Cybulski, C., Menkiszak, J., Jensen, A., Gayther, S. A., Ramus, S. J., Gentry-Maharaj, A., Berchuck, A., Wu, A. H., Pike, M. C., Van Denberg, D., Terry, K. L., Vitonis, A. F., Doherty, J. A., Johnatty, S. E., deFazio, A., Song, H., Tyrer, J., Sellers, T. A., Phelan, C. M., Kalli, K. R., Cunningham, J. M., Fridley, B. L., Goode, E. L. 2013; 22 (5): 987-992

    Abstract

    Ovarian cancer is a leading cause of cancer-related death among women. In an effort to understand contributors to disease outcome, we evaluated single-nucleotide polymorphisms (SNP) previously associated with ovarian cancer recurrence or survival, specifically in angiogenesis, inflammation, mitosis, and drug disposition genes.Twenty-seven SNPs in VHL, HGF, IL18, PRKACB, ABCB1, CYP2C8, ERCC2, and ERCC1 previously associated with ovarian cancer outcome were genotyped in 10,084 invasive cases from 28 studies from the Ovarian Cancer Association Consortium with over 37,000-observed person-years and 4,478 deaths. Cox proportional hazards models were used to examine the association between candidate SNPs and ovarian cancer recurrence or survival with and without adjustment for key covariates.We observed no association between genotype and ovarian cancer recurrence or survival for any of the SNPs examined.These results refute prior associations between these SNPs and ovarian cancer outcome and underscore the importance of maximally powered genetic association studies. Impact: These variants should not be used in prognostic models. Alternate approaches to uncovering inherited prognostic factors, if they exist, are needed. Cancer Epidemiol Biomarkers Prev; 22(5); 987-. ©2013 AACR.

    View details for DOI 10.1158/1055-9965.EPI-13-0028

    View details for PubMedID 23513043

  • Identification of novel susceptibility loci for Guam neurodegenerative disease: challenges of genome scans in genetic isolates HUMAN MOLECULAR GENETICS Sieh, W., Choi, Y., Chapman, N. H., Craig, U., Steinbart, E. J., Rothstein, J. H., Oyanagi, K., Garruto, R. M., Bird, T. D., Galasko, D. R., Schellenberg, G. D., Wijsman, E. M. 2009; 18 (19): 3725-3738

    Abstract

    Amyotrophic lateral sclerosis/parkinsonism-dementia complex (ALS/PDC) is a fatal neurodegenerative disease found in the Chamorro people of Guam and other Pacific Island populations. The etiology is unknown, although both genetic and environmental factors appear important. To identify loci for ALS/PDC, we conducted both genome-wide linkage and association analyses, using approximately 400 microsatellite markers, in the largest sample assembled to date, comprising a nearly complete sample of all living and previously sampled deceased cases. A single, large, complex pedigree was ascertained from a village on Guam, with smaller families and a case-control sample ascertained from the rest of Guam by population-based neurological screening and archival review. We found significant evidence for two regions with novel ALS/PDC loci on chromosome 12 and supportive evidence for the involvement of the MAPT region on chromosome 17. D12S1617 on 12p gave the strongest evidence of linkage (maximum LOD score, Z(max) = 4.03) in our initial scan, with additional support in the complete case-control sample in the form of evidence of allelic association at this marker and another nearby marker. D12S79 on 12q also provided significant evidence of linkage (Z(max) = 3.14) with support from flanking markers. Our results suggest that ALS/PDC may be influenced by as many as three loci, while illustrating challenges that are intrinsic in genetic analyses of isolated populations, as well as analytical strategies that are useful in this context. Elucidation of the genetic basis of ALS/PDC should improve our understanding of related neurodegenerative disorders including Alzheimer disease, Parkinson disease, frontotemporal dementia and ALS.

    View details for DOI 10.1093/hmg/ddp300

    View details for Web of Science ID 000270707900017

    View details for PubMedID 19567404