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

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Abstract
Familial renal cell carcinoma (RCC) is genetically heterogeneous. Genetic predisposition to clear cell RCC (CCRCC) is a major feature of von Hippel-Lindau (VHL) disease (MIM 193300) and has rarely been associated with chromosome 3 translocations. In addition, familial papillary (non-clear cell) RCC may result from germline mutations in the METproto-oncogene (MIM 164860). However, rare kindreds with familial CCRCC (FCRC) not linked to the VHLtumour suppressor gene have been described suggesting that further familial RCC susceptibility genes exist. To investigate the genetic epidemiology of FCRC, we undertook a clinical and molecular study of FCRC in nine kindreds with two or more cases of CCRCC in first degree relatives. FCRC was characterised by an earlier age at onset (mean 47.1 years, 52% of cases VHL orMET genes, suggesting that FCRC is not allelic with VHL disease or HPRC. As binding of theVHL gene product to the CUL2 protein is important for pVHL function, we then searched for germlineCUL2 mutations. Although CUL2 polymorphisms were identified, no pathogenic mutations were detected. These findings further define the clinical features of FCRC and exclude a major role for mutations inVHL,MET, orCUL2 in this disorder.