Molecular Genetic Study of the VHL Tumor Suppressor Gene in Human Renal Cell Carcinoma

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We have examined 232 primary sporadic renal cell carcinomas (RCCs) as well as 77 Japanese VHL families for VHL gene mutations. Mutation of the VHL gene was found in 56% of the clear-cell subtype RCCs and 73% of the VHL families. Truncating mutations were predominantly (more than 70%) in sporadic renal carcinomas, while missense mutations were more common in germ-lines. Mutations were detected even in low grade and/or low stage clear cell RCCs, suggesting that the inactivation of the gene is a very early event in the tumorigenesis. In VHL families, genotype-phenotype correlation study suggested non-missense mutations predicted to result in the loss of VHL function were associated with the occurrence of renal carcinoma like in sporadic RCCs. These data suggested, in spite of the different mutational mechanisms between somatic and germ-lines, gross disruption of the VHL protein is the critical molecular genetic change in the development of clear-cell RCCs both in sporadic and hereditary forms. We also found somatic VHL mutations in sporadic low grade gliomas, suggesting this gene is involved in tumorigenesis of some of glial tumors. We examined VHL gene expression by in situ hybridization, and found that the proximal tubular epithelium, the putative origin of the common type of clear cell renal carcinoma, showed intense signal.