Statistical analysis of the two stage mutation model in von Hippel-Lindau disease, and in sporadic cerebellar haemangioblastoma and renal cell carcinoma.

Analysis of the age incidence curves for unilateral and bilateral retinoblastoma led Knudson to propose that hereditary tumours may arise by a single event and sporadic tumours by a two stage mutation process. It has been suggested recently that sporadic renal cell carcinoma may arise from a two stage mutation process. We analysed the age incidence curves for symptomatic renal cell carcinoma (n = 26) and cerebellar haemangioblastoma (n = 68) in 109 patients with von Hippel-Lindau (VHL) disease, and compared them to 104 patients with sporadic renal cell carcinoma and 43 patients with sporadic cerebellar haemangioblastoma. The age incidence curves for renal cell carcinoma and cerebellar haemangioblastoma in VHL disease were compatible with a single mutation model, whereas the age incidence curves for sporadic renal cell carcinoma and cerebellar haemangioblastoma suggested a two stage mutation process. These data are compatible with the VHL gene functioning as a recessive tumour suppressor gene. Sporadic cerebellar haemangioblastoma and some renal cell carcinoma may arise from somatic mutations inactivating both alleles at the VHL locus.