VHL and nonpapillary renal cell carcinoma: It is interesting to note that although the VHL mutation is observed in the majority of familial ccRCC cases, less than 4% of ccRCC cases are familial in nature, with the vast majority being accounted for by sporadic carcinogenesis (reviewed in [10,11]), yet between 60% and 70% of these sporadic cases also exhibit loss of VHL function either through point mutation, or promoter hypermethylation indicating the importance of VHL in ccRCC [12,13].