Renal Carcinoma and von Hippel–Lindau Disease


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.

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

Figure 1.

Increased metabolic intermediates lead to HIF stabilisation. In normal cells, the transcription factor hypoxia‐inducible factor (HIF) is targeted for degradation in a manner dependent on prolyl hydroxylase (PHD) and von Hippel–Lindau protein (VHL). 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 hydrogenase (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 from Esteban and Maxwell , by permission of Nature Publishing Group.



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Further Reading

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Web Links

Carbonic anhydrase IX (CA9); Gene ID: 768. Entrez Gene:

Carbonic anhydrase IX (CA9); MIM number: 603179. OMIM:

Fragile histidine triad gene (FHIT); Gene ID: 2272. Entrez Gene:

Fragile histidine triad gene (FHIT); MIM number: 601153. OMIM:

Met proto‐oncogene (hepatocyte growth factor receptor) (MET); Gene ID: 4233. Entrez Gene:

Met proto‐oncogene (hepatocyte growth factor receptor) (MET); MIM number: 164860. OMIM:

Von Hippel–Lindau Syndrome (VHL); Gene ID: 7428. Entrez Gene:

Von Hippel–Lindau Syndrome (VHL); MIM number: 193300. OMIM:

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Connor, Thomas M, and Maxwell, Patrick H(Oct 2010) Renal Carcinoma and von Hippel–Lindau Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006062.pub2]