Von Hippel-Lindau disease and sporadic renal cell carcinoma.

The VHL gene, isolated by positional cloning, encodes a protein of 284 aminoacids that has no homology with other proteins in the databases. The nucleotide sequence lacks domains that would suggest (a) a DNA binding protein, (b) nuclear localization, (c) enzymatic activity or (d) membrane localization. Studies are in progress on the size and cellular localization of the VHL protein and how it may function in growth regulation. How mutations in this small protein lead to a specific tumour spectrum presents an enormous research challenge. Germline mutations in the VHL gene are heterogeneous, and the resulting heterogeneity of mutations in the VHL protein that lead to disease suggests a protein whose function can be compromised by mutations over a large area. Study of the germline mutations and correlation with disease patterns provide the basis for a new clinical classification of von Hippel-Lindau disease. Somatic VHL mutations and hypermethylation of the VHL gene are found in some 75-80% of sporadic clear cell renal carcinomas. About 20% of clear cell renal carcinomas show neither VHL gene mutation or hypermethylation. Whether other chromosome 3 tumour suppressor genes have a pathogenetic role in clear cell renal carcinoma remains to be determined. Sorting out the contributions of different tumour suppressor genes to the pathogenesis of clear cell renal carcinomas will require assays demonstrating somatic mutation of candidate genes and functional assays to determine whether replacement of the mutant gene is associated with suppressed tumour growth.