Do human renal cell carcinomas arise by a double-loss mechanism?

Combined consideration of a constitutional t(3;8) that was regularly associated with renal cell carcinoma (RCC) within a large family and cytogenetic and restriction fragment length polymorphism studies on sporadic RCC has led to the tentative conclusion that RCC may arise by a similar double-loss mechanism as retinoblastoma and Wilms' tumor. This hypothesis predicts single-hit kinetics for the age distribution of hereditary RCC and two-hit kinetics for sporadic tumors, in analogy with Knudson's original prediction for retinoblastoma and Wilms' tumor. We have compared the age distribution of 51 hereditary and 56 sporadic cases of RCC sampled from the literature. The age-incidence curve of the hereditary RCC is compatible with a single event, whereas the sporadic tumors arise as predicted from a two-hit curve. We therefore suggest that RCC arises by the loss of a recessive cancer gene, probably localized to the short arm of chromosome 3 (in band 3p14.2).