The role of gene mutations in the genesis of familial cancers.

The simplest molecular mechanism of hereditary tumorigenesis is represented by retinoblastoma (RB). Knudson's model specifies that, in hereditary RB, the first mutation in an allele of the RB gene exists in the germline. A subsequent somatic mutation in the second normal RB allele releases RB formation in the eye. This mechanism of loss of function of both normal tumor suppressor gene copies applies to other hereditary cancer syndromes as well, including multiple endocrine neoplasia type 1, neurofibromatosis type 2, Li-Fraumeni syndrome, and probably familial breast/ovarian syndrome. In some syndromes, e.g. familial adenomatous polyposis and multiple endocrine neoplasia type 2, the mechanism may be slightly different. Loss of function of only one allele of the susceptibility locus appears to be sufficient to promote a proliferative advantage in target tissues. In many of these inherited cancer syndromes, variable expression and variable penetrance of phenotypes exist. Allelism, existence of a multigene complex, or modulation of expression by modifier genes may explain the phenomena.