Somatic Cell Genetic Disease: Cancer

Abstract The molecular pathophysiology of carcinogenesis is based to a great ex tent on somatic mutation. Through a process of clonal selection, tumor cells accumulate mutations that increase their ability to proliferate. These mutations are of two general types: (1) activating mutations in growth promoting genes known as oncogenes and (2) inactivating mutations in growth-restricting genes known as tumor suppressor genes. The vast majority of these mutations occur within the tumor cells only, either spontaneously or in response to an environmental mutagen. In the case of the tumor suppressor genes, however, rare germline loss-of-function mutations can result in a hereditary predisposition to cancer, as de scribed for the WTl gene in the WAGR syndrome (see Chapter 6). In these cases, the affected individual is heterozygous for an inactivating mutation in all cells of the body. When a somatic mutation occurs on the second allele within a target cell, both alleles have been inactivated and the process of oncogenesis is initiated, in accordance with the “two hit” model originally proposed by Knudson (1971; Knudson et al., 1975). For these affected individuals, the risk of developing a cancer (such as Wilms tumor in patients heterozygous for deletion of WTl) is greatly increased, approaching 100% in some cases. In addition to an extremely high incidence of tumorigenesis, the tumors appear at an earlier age, are bilateral in paired organs, and multifocal.