HIGH RISK FAMILIAL COLON CANCER

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The objective of this study is to determine the genetic etiology and clinical characteristics of high-risk familial colon cancer. It is estimated that 20-30% of all colon cancers have some hereditary basis but the identified genes account for only 5% of these. Our hypothesis is that mutations in additional, yet to be defined, genes cause an increased risk of developing colon cancer, and by genetic linkage studies of large families and sibling pairs, these genes can be identified. There are four components to our research project: 1) Determine the genetic susceptibility locus (or loci) of high-risk colon cancer families that do not have one of the known inheritied syndromes of colon cancer and determine genetic modifier loci in a large family with attenuated familial adenomatous polyposis; 2) Clincally characterize the high-risk families with physical and endoscopic examination in order to precisely define the phenotype for linkage analysis and to allow clarification of the penetrance and phenotype of each disease gene and mutation once these are identified; 3) establish molecular characteristics of the high-risk and known colon cancer syndrome families with gene expression profiling (by microarray analysis) of normal and neoplastic colon tissue, both to assist in identification of disease genes, and once genetic diagnosis is possible, to precisely clarify the molecular phenotypes associated with each type of genetic predisposition; 4) Determine common genetic susceptibility loci by genetic linkage and nonparametric analysis of 500 sibling pairs with colorectal cancer.