Current Research and Scholarly Interests
Our goal is to apply genomic and transcriptomic analysis technologies to elucidate the molecular cascade involved in the hereditary colon cancer syndrome, familial adenomatous polyposis (FAP). FAP affects children as young as 7 years of age and contributes to overall colon cancer incidence, which is the third most common cause of cancer related mortality in men and women nationwide. FAP is caused by heterozygous mutations in the adenomatous polyposis coli (APC) gene, both inherited and de novo. The condition is characterized by the development of hundreds of colonic polyps in affected individuals and confers a 100% lifetime risk of colorectal adenocarcinoma. Alterations in the APC gene lead to perturbations in the Wnt signaling cascade, and colon carcinoma from FAP patients show an accumulation of alterations in other genes associated with sporadic colorectal adenocarcinoma (i.e. Kras, p53, etc.), which appear to be initiated from the first APC mutation.
We hypothesize that there is a recurring minimum of accumulated mutations in FAP, starting with a mutation in APC, necessary for development first of benign polyps and later colorectal adenocarcinoma. We will test this using genomic and transcriptomic analyses which, when applied to FAP, present a unique opportunity to simultaneously collect genome wide data at numerous distinct points (represented by each polyp) along the cascade of molecular changes leading to cancer, allowing characterization of the order in which the critical molecular changes occur, enabling identification of novel drivers to malignancy, with the potential to increase understanding of FAP related genetic networks and how they respond to genetic changes and therapeutic perturbations. We seek to better understand the signal pathways responsible for the pathogenesis of FAP and develop improvements in methods of diagnosis and treatment of FAP related colorectal adenocarcinoma with potential application to non-FAP colon adenocarcinoma.