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a Department of
Pathology, University of Cambridge, Cambridge, UK, b Section of Medical and
Molecular Genetics, Department of Paediatrics and Child Health,
University of Birmingham, Edgbaston, Birmingham B15 2TT, UK
Correspondence to: Professor Maher, ermaher{at}hgmp.mrc.ac.uk
Revised version received 13 December 1999;
Accepted for publication 15
December 1999
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 MET
proto-oncogene (MIM 164860). However, rare kindreds with familial CCRCC
(FCRC) not linked to the VHL
tumour 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 <50 years of age) than sporadic cases. These
findings differ from the only previous report of two FCRC kindreds and
have important implications for renal surveillance in FCRC. The
molecular basis of CCRCC susceptibility was investigated in nine FCRC
kindreds and seven isolated cases with features of possible genetic
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 disease or HPRC. As binding of the
VHL gene product to the CUL2
protein is important for pVHL function, we then searched for germline
CUL2 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 in
VHL,
MET, or CUL2 in this disorder.
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