INHERITANCE OF DISCRETE COLORECTAL ADENOMATOUS POLYPS

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The objective of this proposal is to investigate the inheritance of discrete colonic adenomatous polyps and colorectal cancer. Present investigation provides evidence that the majority of commonly occurring adenomatous polyps are found in individuals with an inherited susceptibility to polyp formation. Because colon cancer develops from adenomatous polyps, this finding suggests that randomly occurring colorectal cancers likewise occur in those who are genetically susceptible. The specific aims of the proposal are therefore to test the hypothesis that inheritance plays an important role in the development of randomly occurring colorectal cancers; and to verify, characterize and refine the initial findings of adenomatous polyp inheritance. To examine the hypothesis of colon cancer inheritance, the occurrence and pedigree distribution of adenomatous polyps will be determined in family members of pedigrees systematically selected on the basis of a single individual with colorectal cancer. Adenomas are detected by 60 cm flexible proctosigmoidoscopy. Pedigree analysis which employs likelihood methods will be used to evaluate the presence of inherited susceptibility to colonic polyps and cancer. These results will be compared to the adenoma inheritance which has been observed in pedigrees selected on the basis of an individual with an adenomatous polyp, and in pedigrees selected on the basis of a sibling pair with colorectal cancer. Additional pedigrees in each of these selection categories will also be examined to substantiate observed polyp characteristic differences between the groups. Larger study sizes are likewise required to refine estimates of population gene frequencies, to improve confidence limits of estimates and to more rigorously test inheritance mode. A final aim of the investigation is to collect blood for anticipated DNA mapping studies. The delineation of inherited susceptibility to common colonic polyps and cancer is expected to impact clinical cancer screening efforts significantly. The population characterized by this study will also provide the basis for DNA marker linkage studies, subsequent studies of gene-environment interactions, and studies of molecular mechanisms of cancer.