MERIT Award Recipient: Kenneth W. Kinzler, Ph.D.
Genes from the FAP Locus
Colorectal cancer is a leading cause of cancer deaths in the United States with approximately 150,000 new cases and approximately 50,000 deaths each year. Colorectal cancer, like other cancers, can develop when a cell suffers defects in its genetic instruction set that allow it to grow in an uncontrolled manner. Such newly arising defects acquired by individual cells are commonly referred to as somatic mutations. In some cases, people can also inherit variations in their genetic instruction set that predispose them to cancer. Such inherited variants are commonly referred to as germline mutations. Work previously supported by this grant helped define several major somatic and germline mutations that can initiate colorectal cancer, including mutations of the APC intracellular signaling pathway.
The future goal of this project is to further define the mutations that lead to colorectal cancer in four key ways. The first is to identify inherited mutations that potentially predispose people to multiple polyp formation. We will study two such inherited polyposis syndromes, Serrated Polyposis Syndrome (SPS) and atypical adenomatous oligopolyposis (AAOP). The second area of study is intended to determine the order and timing of key mutations, and whether such factors affect a tumor's propensity to progress to deadly disease. In a third area, we will look at the level and nature of somatic mutations in normal tissue, to see if they are correlated with the distribution of intestinal cancers in the general population and are related to colorectal cancer risk. Finally, we will perform comprehensive genetic analyses of multiple adenomas removed from the same patients to look for recurring changes that may act as additional early genetic events in tumor development. These studies should provide a more complete understanding of the genetic defects that lead to colorectal cancer, and provide important information for the prevention and treatment of this deadly disease.