Renal Carcinoma and von Hippel–Lindau 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 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 vascular endothelial growth factor (VEGF). A number of other kidney cancer genes have been found from studying other familial cancer syndromes. These genes mediate 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 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. A number of other kidney cancer genes have been found to be involved in cellular pathways involved in cellular stress and nutrient deprivation.