Hereditary predisposition to cancer.

Both hereditary and environmental factors influence the risk of cancer. Four risk categories, or oncodemes, can exist for a particular kind of cancer, depending upon the presence of neither, one, or both factors: (1) spontaneous, or background; (2) hereditary; (3) environmental; (4) interactive. In the second, mutation imparts a high relative risk, but a generally low attributable risk; in the fourth, the opposite obtains. The second oncodeme contains genes that are also important for the non-hereditary forms of the same cancer. Probably all forms of cancer exist in a dominantly heritable form. Most of the genes are tumor suppressors, although a few are oncogenes or DNA repair genes. The mutations are in most, if not all cases, maintained in a population by an equilibrium between mutation and selection. Most of the cloned genes are expressed widely among tissues, yet there is typically some tumor specificity. Somatic mutations in second alleles at the relevant loci are necessary, but generally not sufficient for carcinogenesis, although they, in some instances, lead to the formation of benign precursor lesions. Further events are necessary for carcinogenesis. This is particularly true for carcinomas. The benign lesions appear to involve an increase in number of long-lived cells that can accumulate other mutations. For some tumors, physiologic events, such as tissue growth at puberty or proliferation of embryonic stem cells, may produce this effect. Mutations of DNA mismatch repair genes underscore the effect that changes in somatic mutation rates can have, especially in the risk for multi-event carcinomas. Conversely, these are the tumors that offer the greatest opportunity for prevention.