[Hippel-Lindau syndrome and sporadic renal cell carcinomas. Pathogenesis, morphologic spectrum and molecular...

von Hippel-Lindau (VHL) disease is an autosomal dominant heritable disease that often occurs in association with various benign and malignant tumours. Clinically the disease is classified as VHL 1 (without phaeochromocytoma) and VHL 2 (with phaeochromocytoma). Genetically, VHL is caused by germline mutations in the VHL tumour suppressor gene. More than 100 germline mutations and rearrangements have been identified, but the biological function of a hypothetical VHL protein is not yet known. Genotype-phenotype correlations should aid in the understanding of this biological role. All VHL manifestations subsequently develop to VHL mutations, but some mutations may act in a tissue-specific manner. Whereas missense mutations cause tumour suppression to fail in adrenal cells, more severe structural mutations are usually necessary for tumour development in renal cells. As predicted by the tumour suppressor theory, the VHL gene also plays a critical part in the pathogenesis of sporadic non-VHL-associated tumours. In a large number of sporadic renal clear cell carcinomas, mutations and hypermethylation cause inactivation of the VHL gene. Together with allelic 3p loss, these constitute rate-limiting events in renal tumourigenesis. Insights into the molecular basis of phenotypic variability in VHL disease and the confirmation of the tumour-suppressor criteria in VHL and non-VHL sporadic tumours indicate an important role of the VHL gene in the development of these tumours.