Renal Carcinoma and von Hippel–Lindau Disease

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.

Keywords: tumour suppressor gene; ubiquitin; hypoxia‐inducible factor; proteolysis; angiogenesis

Figure 1. Clinical manifestations of von‐Hippel–Lindau (VHL) disease. (a) Nephrectomy specimen demonstrating multiple solid tumours (arrow head) and cystic change (arrowed) in a patient with VHL disease. (b) Large cerebellar haemangioblastoma in a 35‐year‐old with VHL disease, arrowed (T1‐weighted contrast‐enhanced MRI (magnetic resonance imaging)). (c) Retinal photograph demonstrating a large retinal angioma in a patient with VHL disease (arrowed) (Image courtesy of Professor Sue Lightman, UCL). (d) Multiple areas of cystic change (arrowed) in the pancreas of a 33‐year‐old with VHL disease; note possible soft tissue enhancement (T1‐weighted contrast‐enhanced MRI).
Figure 2. Increased metabolic intermediates lead to HIF (hypoxia‐inducible factor) stabilisation. In normal cells, the transcription factor HIF is targeted for degradation in a manner dependent on prolyl hydroxylase (PHD) and VHL protein. When oxygen levels drop, PHD is inhibited and HIF is stabilised. Activation of HIF changes gene expression, causing increases in angiogenesis, glucose uptake and glycolysis. Fumarate hydratase (FH) and succinate dehydrogenase (SDH) are enzymes of the tricarboxylic acid (TCA) cycle. Loss‐of‐function mutations in FH and SDH lead to inherited cancer syndromes. Recent work shows that these mutations lead to increased levels of fumarate and succinate, which inhibit PHD and stabilise HIF. Reproduced with permission from Esteban and Maxwell 2005 © Nature Publishing Group.
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Connor, Thomas M, and Maxwell, Patrick H(Jan 2018) Renal Carcinoma and von Hippel–Lindau Disease. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0006062.pub3]