Endocrine Abstracts

Von Hippel-Lindau (VHL) disease is a dominantly inherited familial cancer syndrome characterised by a predisposition to retinal and cerebellar haemangioblastomas, renal cell carcinoma (RCC) and renal cysts, phaeochromocytoma and, less frequently, pancreatic islet cell tumours. Although rare, VHL disease provides a paradigm for illustrating the clinical features and significance of familial cancer syndromes and how the molecular genetic analysis of rare inherited cancers can provide critical insights into the mechanism of tumourigenesis of common sporadic cancers.

VHL disease is caused by germline mutations in the VHL tumour suppressor gene (TSG). Phenotypic expression of VHL disease is influenced by allelic heterogeneity such that the risk of phaeochromocytoma depends on the type of VHL gene mutation. In some cases, specific mutations may cause a familial phaeochromocytoma only phenotype. The VHL TSG has a critical 'gatekeeper' role in regulating growth and differentiation of human kidney cells and inactivation of the VHL TSG is the most frequent somatic genetic event in the commonest form of kidney cancer (clear cell). However somatic VHL mutations are rare in sporadic phaeochromocytoma tumours. The VHL gene product, pVHL, is implicated in targeting proteins for proteosomal degradation. Hypoxia inducible factors (HIF-1 and HIF-2) are important targets for pVHL and inactivation of the VHL gene in tumours causes a HIF-mediated increase in VEGF expression and tumour angiogenesis. Trials of anti-angiogenesis therapies are being initiated for the treatment of haemangioblastomas in VHL disease, but the relevance of HIF-1 and Hif-2 dysregulation in the pathogenesis of phaeochromocytoma is unclear. Genetic modifiers may influence clinical phenotype and functional polymorphic variants in pVHL target genes (e.g., CCND1) provide candidates for genetic modifiers.