Familial and sporadic human renal cell carcinoma: Evidence against a double-loss mechanism of carcinogenesis

It has been speculated that renal cell carcinoma (RCC) is an example of a double-loss mutation. We analyzed the age distribution of 71 cases of familial RCC and of 11 population-based cancer registries [German Democratic Republic, Denmark, Finland, Norway, Sweden, U.S.A. Whites, U.S.A. Blacks, Miyagi and Osaka Prefectures (Japan), Hong Kong, and Israeli Jews] according to the multi-hit and clonal growth models of carcinogenesis. The analysis rules out a double-loss mechanism for RCC. On both of the two models analyzed, carcinogenesis in the familial cases of RCC arises as a result of a three- to ten-fold increase in the average rate of mutation at the susceptible loci, as compared with the sporadic cases. In general, the clonal growth model provides a somewhat better fit to the age-distribution of RCC incidence than does the multi-hit model.