Von Hippel-Lindau disease: clinical and molecular perspectives.

Von Hippel-Lindau (VHL) disease (MIM 193300) is the most common cause of familial clear cell renal cell carcinoma (RCC). VHL disease results from germline mutations in the VHL tumor suppressor gene and is characterized by variable expression and the development of benign and malignant neoplasms in multiple organs. The clinical management of VHL disease is challenging and requires a coordinated multidisciplinary approach. However, early detection of VHL tumors by annual surveillance has improved the prognosis for VHL gene carriers. Complex genotype-phenotype correlations for the major manifestations of VHL disease result from allelic heterogeneity and suggest that the VHL gene product has multiple and tissue-specific functions. Recent studies suggest that the VHL protein represents the adaptor unit of an Skp1-Cdc53/Cul1-F-box (SCF)-like protein complex which targets specific proteins for ubiquitinylation and proteolysis. Tumors from VHL patients and sporadic tumors with VHL gene inactivation (e.g., most clear cell RCC) are hypervascular and overexpress hypoxia-inducible mRNAs such as vascular epithelial growth factor (VEGF). Recently, pVHL has been shown to regulate proteolysis of the transcription factors HIF-1 and HIF-2 (EPAS). Thus absence or inactivation of pVHL leads to constitutive HIF-1 and HIF-2 expression, which activates transcription of VEGF and other hypoxia-inducible mRNAs. Evidence for further pVHL functions including roles in fibronectin metabolism and cell cycle regulation has also been reported, but it is unclear whether these functions are mediated via pVHL-targeted proteolysis or other mechanisms. Clinical and laboratory studies of VHL disease have provided a paradigm for demonstrating the importance of familial cancer syndromes in elucidating mechanisms of tumorigenesis in familial and sporadic cancer.