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 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 © Nature Publishing Group.


Ang SO, Chen H, Hirota K, et al. (2002) Disruption of oxygen homeostasis underlies congenital Chuvash polycythemia. Nature Genetics 32 (4): 614–621.

Binderup ML, Jensen AM, Budtz‐Jørgensen E, et al (2017) Survival and causes of death in patients with von Hippel‐Lindau disease. Journal of Medical Genetics 54 (1): 11–18.

Bishop T, Lau KW, Epstein AC, et al. (2004) Genetic analysis of pathways regulated by the von Hippel–Lindau tumour suppressor in Caenorhabditis elegans. PLoS Biology 2 (10): e289.

Bruick RK and McKnight SL (2001) A conserved family of prolyl‐4‐hydroxylases that modify HIF. Science 294: 1337–1340.

Cohen HT, Zhou M, Welsh AM, et al. (1999) An important von Hippel‐Lindau tumor suppressor domain mediates Sp1‐binding and self‐association. Biochemical and Biophysical Research Communications 266 (1): 43–50.

Creighton CJ et al. (Cancer Genome Atlas Research Network) (2013) Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature 499 (7456): 43–49.

Dalgliesh GL, Furge K, Greenman C, et al. (2010) Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes. Nature 463: 360–363.

Datta K, Mondal S, Sinha S, et al. (2005) Role of elongin‐binding domain of von Hippel Lindau gene product on HuR‐mediated VPF/VEGF mRNA stability in renal cell carcinoma. Oncogene 24 (53): 7850–7858.

Epstein ACR, Gleadle JM, McNeill LA, et al. (2001) C. elegans EGL‐9 and mammalian homologues define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43–54.

Esteban MA and Maxwell PH (2005) HIF, a missing link between metabolism and cancer. Nature Medicine 11 (10): 1047–1048.

Esteban MA, Harten SK, Tran MG, Maxwell PH, et al. (2006) Formation of primary cilia in the renal epithelium is regulated by the von Hippel–Lindau tumor suppressor protein. Journal of the American Society of Nephrology 17 (7): 1801–1806.

Forman JR, Worth CL, Bickerton RJ, et al. (2009) Structural bioinformatics mutation analysis reveals genotype‐phenotype correlations in von Hippel–Lindau disease and suggests molecular mechanisms of tumourigensis. Proteins 77: 84–96.

Gerlinger M, Rowan AJ, Horswell S, et al. (2012) Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. New England Journal of Medicine 366 (10): 883–892.

Guo G, Gui Y, Gao S, Tang A, et al. (2011) Frequent mutations of genes encoding ubiquitin‐mediated proteolysis pathway components in clear cell renal cell carcinoma. Nature Genetics 44 (1): 17–19.

Gossage L, Eisen T and Maher ER (2015) VHL, the story of a tumour suppressor gene. Nature Reviews. Cancer 15 (1): 55–64.

Herring JC, Enquist EG, Chernoff A, et al. (2001) Parenchymal sparing surgery in patients with hereditary renal cell carcinoma: 10‐year experience. Journal of Urology 165: 777–781.

Hsieh JJ, Purdue MP, Signoretti S, et al. (2017) Renal cell carcinoma. Nature Reviews Disease Primers 3: 17009.

Iliopoulos O, Kibel A, Gray S and Kaelin WG Jr (1995) Tumour suppression by the human von Hippel–Lindau gene product. Nature Medicine 1: 822–826.

Ivanov SV, Kuzmin I, Wei M‐H, et al. (1998) Down‐regulation of transmembrane carbonic anhydrases in renal cell carcinoma cell lines by wild‐type von Hippel–Lindau transgenes. Proceedings of the National Academy of Sciences of the United States of America 95: 12596–12601.

Kamura T, Koepp DM, Conrad MN, et al. (1999) Rbx1, a component of the VHL tumour suppressor complex and SCF ubiquitin ligase. Science 284: 657–661.

Kurban H, Hudon V, Duplan E, et al. (2006) Characterisation of a von Hippel–Lindau pathway involved in extracellular matrix remodelling, cell invasion, and angiogenesis. Cancer Research 66: 1313–1319.

Kuznetsova AV, Meller J, Schnell PO, et al. (2003) von Hippel–Lindau protein binds hyperphosphorylated subunit of RNA polymerase II through a proline hydroxylation motif and targets it for ubiquitination. Proceedings of the National Academy of Sciences of the United States of America 100 (5): 2706–2711.

Latif F, Tory K, Gnarra J, et al. (1993) Identification of the von Hippel–Lindau disease tumour suppressor gene. Science 260: 1317–1320.

Lee S, Nakamura E, Yang H, et al. (2005) Neuronal apoptosis linked to EglN3 prolyl hydroxylase and familial pheochromocytoma genes: developmental culling and cancer. Cancer Cell 8 (2): 155–167.

Lutz MS and Burk RD (2006) Primary cilium formation requires von Hippel–Lindau gene function in renal‐derived cells. Cancer Research 66: 6903–6907.

Maxwell PH, Wiesener MS, Chang G‐W, et al. (1999) The tumour suppressor protein VHL targets hypoxia‐inducible factors for oxygen‐dependent proteolysis. Nature 399: 271–275.

Metwalli AR and Linehan WM (2014) Nephron‐sparing surgery for multifocal and hereditary renal tumors. Curr Opin Urol. 24 (5): 466–473.

Mikhaylova O, Ignacak ML, Barankiewicz TJ, et al. (2008) The von Hippel–Lindau tumour suppressor protein and Egl‐9‐Type proline hydroxylases regulate the large subunit of RNA polymerase II in response to oxidative stress. Molecular and Cellular Biology 28 (8): 2701–2717.

Mukhopadhyay D, Knebelmann B, Cohen H, et al. (1997) The von Hippel–Lindau tumour suppressor protein interacts with Sp1 to repress vascular endothelial growth factor promoter activity. Molecular and Cellular Biology 17: 5629–5639.

Nickerson ML, Warren MB, Toro JR, et al. (2002) Mutations in a novel gene lead to kidney tumours, lung wall defects, and benign tumours of the hair follicle in patients with the Birt‐Hogg‐Dubé syndrome. Cancer Cell 2: 157–164.

Nickerson ML, Jaeger E, Shi Y, et al. (2008) Improved identification of von Hippel‐Lindau gene alterations in clear cell renal tumors. Clinical Cancer Research 14 (15): 4726–4734.

Ohh M, Yauch RL, Lonergan KM, et al. (1998) The von Hippel–Lindau tumor suppressor protein is required for proper assembly of an extracellular fibronectin matrix. Molecular Cell 1 (7): 959–968.

Ong KR, Woodward ER, Killick P, et al. (2006) Genotype‐phenotype correlations in von Hippel–Lindau disease. Human Mutation 28 (2): 143–149.

Ricketts C, Woodward ER, Killick P, et al. (2008) Germline SDHB mutations and familial renal cell carcinoma. Journal of the National Cancer Institute 100: 1260–1262.

Roe JS, Kim H, Lee SM, et al. (2006) p53 stabilisation and transcriptional activation by von Hippel–Lindau protein. Molecular Cell 22: 395–405.

Sato Y, Yoshizato T, Shiraishi Y, et al. (2013) Integrated molecular analysis of clear‐cell renal cell carcinoma. Nature Genetics 45 (8): 860–867.

Schermer B, Ghenoiu C, Bartram M, et al. (2006) The von Hippel–Lindau tumor suppressor protein controls ciliogenesis by orienting microtubule growth. Journal of Cell Biology 175 (4): 547–554.

Stebbins CE, Kaelin WG Jr and Pavletich NP (1999) Structure of the VHL–elonginC–elonginB complex: implications for VHL tumour suppressor function. Science 284: 455–461.

Tang N, Mack F, Hasse VH, et al. (2006) pVHL function is essential of endothelial extracellular matrix deposition. Molecular Cell. Biology 26: 2519–2530.

Thoma CR, Frew IJ, Hoerner CR, et al. (2007) pVHL and GSK3beta are components of a primary cilium‐maintenance signalling network. Nature Cell Biology 9 (5): 588–595.

Tomlinson AP, Alam NA, Rowan AJ, et al. (2002) Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nature Genetics 30: 406–410.

Vanharanta S, Buchta M, McWhinney SR, et al. (2004) Early onset renal cell carcinoma as a novel extraparaganglial component of SDHB‐associated heritable paraganglionoma. American Journal of Human Genetics 74: 153–159.

Further Reading

Bertout JA, Patel SA and Simon MS (2008) The impact of O2 availability on human cancer. Nature Reviews. Cancer 8: 967–975.

Bishop T and Ratcliffe PJ (2015) HIF hydroxylase pathways in cardiovascular physiology and medicine. Circulation Research 117 (1): 65–79.

Frew IJ and Moch H (2015) A clearer view of the molecular complexity of clear cell renal cell carcinoma. Annual Review of Pathology 10: 263–289.

Kaelin WG (2011) Cancer and altered metabolism: potential importance of hypoxia‐inducible factor and 2‐oxoglutarate‐dependent dioxygenases. Cold Spring Harbor Symposia on Quantitative Biology 76: 335–345.

Linehan WM, Bratslavsky G, Pinto PA, et al. (2010a) Molecular diagnosis and therapy of kidney cancer. Annual Review of Medicine 61: 329–343.

Linehan WM, Srinivasan R and Schmidt LS (2010b) The genetic basis of kidney cancer: a metabolic disease. Nature Reviews. Urology 7: 277–285.

Maxwell PH (2005) The HIF pathway in cancer. Seminars in Cell & Developmental Biology 16: 523–530.

Rankin EB and Giaccia AJ (2016) Hypoxic control of metastasis. Science 352 (6282): 175–180.

Semenza GL (2009) Involvement of oxygen sensing pathways in physiologic and pathologic erythropoesis. Blood 114 (10): 2015–2019.

Vander Heiden MG, Cantley LC and Thompson CB (2009) Understanding the Warburg effect: the metabolic requirements of cell proliferation. Science 324 (5930): 1029–1033.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Connor, Thomas M, and Maxwell, Patrick H(Jan 2018) Renal Carcinoma and von Hippel–Lindau Disease. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0006062.pub3]