Familial clustering of colorectal cancer is common. The known syndromes of colon cancer account for a small fraction of cases, probably less than 5%, yet the fraction of cases that have inherited susceptibility as part of their etiology appears to be much higher. In this project we will search for yet unidentified, but possibly very common, colon cancer susceptibility loci. Finding such loci and eventually the relevant genes is important both to cancer screening and control, and to understanding the biology of this common malignancy. We will use two methodologies to find new susceptibility genes: 1) large kindreds with multiple cases of colon cancer and adenomatous polyps, but no known colon cancer syndrome, will be systematically developed for linkage analysis from unique Utah resources; 2) non-parametric analysis will be used to explore for susceptibility loci in a large group of sibling pairs with colon cancer. In all kindreds selected for study, kindred members will be examined by colonoscopy to characterize the polyp phenotype in addition to the known cancer phenotype. Both cancer and polyps will then be considered as a part of the phenotype for linkage studies to identify cancer susceptibility loci. For non-parametric analysis, archival tissues of cancer and normal mucosa from sibling pairs identified in the Utah Population Data Base will be used to obtain genetic markers. By using both approaches, the power for finding new, and possibly common susceptibility loci, is substantially increased. The kindred approach is vital if there are multiple important loci, the sibling pair approach increases power for finding susceptibility loci if only one or several susceptibility loci play a role in colon cancer. This project will also supply DNA and appropriate tissue samples to the tumor band and to investigators of other projects in this program project. Samples will come from members from known syndrome families as well as from kindreds undergoing linkage studies.
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