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FAMILIAL COLON CANCER

It has become increasingly clear that genetic predisposition plays a role in a substantial number of familial colon cancer. Although it is convenient to categorize colorectal cancers into hereditary (or familial) and nonhereditary (or sporadic) types, it is more appropriate to assume that all cancers have genetic components, which may be inherited or acquired.

Accordingly, persons with familial colon cancer are born with an altered genome, and the environment may contribute additional genotoxic events, leading to the malignant phenotype. In the case of "sporadic" cancers, multiple somatic mutations are contributed.

Hereditary Nonpolyposis Colorectal Cancer (HNPCC) is a disease of autosomal-dominant inheritance in which colon cancers arise in discrete adenomas, but polyposis (i.e., hundreds of polyps) does not occur. The definition of HNPCC has recently been standardized by the International Collaborative Group on Hereditary Nonpolyposis Colorectal Cancer. Families must have at least three relatives with colorectal cancer, one of whom is a first-degree relative of the other two. Colorectal cancer must involve at least two generations, and at least one case must occur before age 50 years. This includes families whose heritable cancer is limited to the colon and rectum (site-specific HNPCC, HNPCC type a, Lynch syndrome I) and families.

Both patients with HNPCC and some as yet unaffected family members have biologic markers that resemble those in patients with the familial polyposis syndromes. These include abnormal proliferative activity of colonic crypt cells, increased tetraploidy in vitro (twice the normal DNA content) in cultured skin fibroblasts, decreased degradation of fecal cholesterol, and cell-mediated Although colorectal cancer syndromes with readily apparent.

Genetic susceptibility to colorectal cancer in the general population is suggested by the two- to three-fold increase in colorectal cancer in first-degree relatives of patients with "sporadic" adenomas and colorectal cancers. The relative risk is even stronger when cancer occurs in family members younger than age 50. The precise role of genetic factors in this group, and their interaction with the environment in the evolution of colorectal cancer, remain to be defined.