Familial clear cell renal cell carcinoma (FCRC): clinical features and mutation analysis of the VHL, MET, and CUL2 candidate genes

Familial renal cell carcinoma (RCC) is genetically heterogeneous. Genetic p redisposition to clear cell RCC (CCRCC) is a major feature of von Hippel-Li ndau (VHL) disease (MIM 193300) and has rarely been associated with chromos ome 3 translocations. In addition, familial papillary (non-clear cell) RCC may result from germline mutations in the MET protooncogene (MIM 164860). H owever, rare kindreds with familial CCRCC (FCRC) not linked to the VHL tumo ur suppressor gene have been described suggesting that further familial RCC susceptibility genes exist. To investigate the genetic epidemiology of FCR C, we undertook a clinical and molecular study of FCRC in nine kindreds wit h two or more cases of CCRCC in first degree relatives. FCRC was characteri sed by an earlier age at onset (mean 47.1 years, 52% of cases <50 years of age) than sporadic cases. These findings differ from the only previous repo rt of two FCRC kindreds and have important implications for renal surveilla nce in FCRC. The molecular basis of CCRCC susceptibility was investigated i n nine FCRC kindreds and seven isolated cases with features of possible gen etic susceptibility to CCRCC (four bilateral CCRCC aged <50 years and three with unilateral CCRCC aged <30 years). No germline mutations were detected in the VHL or MET genes, suggesting that FCRC is not allelic with VHL dise ase or HPRC. As binding of the VHL gene product to the CUL2 protein is impo rtant for pVHL function, we then searched for germline CUL2 mutations. Alth ough CUL2 polymorphisms were identified, no pathogenic mutations were detec ted. These findings further define the clinical features of FCRC and exclud e a major role for mutations in VHL, MET, or CUL2 in this disorder.