Renal Carcinoma and von H ippel– L indau Disease

Abstract

Abstract von Hippel–Lindau (VHL) disease is a rare autosomal dominant condition with a high risk of renal carcinoma. The underlying tumour suppressor gene is also mutated in most sporadic clear cell renal carcinomas. The VHL gene product functions as an E3 ubiquitin ligase that mediates the degradation of the hypoxia‐inducible factor (HIF). Loss of VHL leads to constitutive activation of HIF target genes that normally mediate responses to hypoxia, including those that regulate diverse processes such as angiogenesis and cellular metabolism. Novel therapies for renal cancer target angiogenesis mediated by the vascular endothelial growth factor (VEGF). Renal cancers also exhibit common driver mutations subsequent to VHL loss, which influence pathways involved in chromatin remodelling and mammalian target of rapamycin (mTOR) signalling. A number of other kidney cancer genes have been found from studying other familial cancer syndromes. These genes are involved in metabolism and responses to cellular stress and nutrient deprivation. Key Concepts von Hippel–Lindau (VHL) disease is a dominantly inherited familial cancer syndrome caused by mutations in the VHL tumour suppressor gene. VHL disease exhibits a striking genotype–phenotype correlation. The great majority of sporadic clear cell renal cancers also show loss of VHL function. The VHL gene product functions as an E3 ubiquitin ligase that mediates the degradation of hypoxia‐inducible factor (HIF) alpha. Loss of VHL leads to constitutive activation of HIF target genes that play key roles in angiogenesis and metabolism. Novel therapies for renal cancer target specific effects of VHL loss, including inhibitors of angiogenesis. Renal cancers exhibit common driver mutations affecting chromatin remodelling and nutrient signalling. A number of other kidney cancer genes have been found to be involved in cellular pathways involved in cellular stress and nutrient deprivation.