Human carcinogenesis is a multistep process that results from a clonal expansion of cells that gain selective growth advantages through the accumulation of genetic alterations. Studies of age-dependent cancer incidence in humans indicate that as many as four to six independent steps are required for malignancy to occur [1, 2]. It has long been appreciated that the predisposition to develop specific tumors can be found clustered in families. At least 50 different malignancies can be found in familial and corresponding sporadic forms. Analysis of these rare cancerprone families shows that the trait is often inherited in a Mendelian autosomal dominant manner. Features of hereditary cancer include the observations that such patients tend to develop multiple tumors in the same organ (and bilateral tumors when sites such as the kidney, adrenal, or eye are affected), they may develop multiple primary tumors of different histologic types and sites, and they tend to develop tumors at a younger age than patients without a family history of cancer.

Knudson's epidemiological studies of the rare childhood tumor, retinoblastoma, led to a model for tumorigenesis [3, 4]. In this model Knudson proposed that as few as two inactivating mutations provide the rate-limiting step for entry of a cell into a neoplastic pathway. In familial cases an inherited germinal mutation is present in each precursor cell and is unmasked by a second genetic event, and in sporadic tumors the same two mutations occur except that they must occur in the same somatic cell. Therefore, familial and sporadic tumors result from the same two-step process, and the difference lies in the inheritance or somatic occurrence of the first mutation.