Molecular Genetics of Renal Cancer


Renal cancer affects 300 000 people worldwide, with about 75% of those cases being of the clear cell phenotype, which is characterised by somatic mutations acquired in the Von Hippel–Lindau (VHL) tumour suppressor gene (TSG). Most approved therapies for renal cancers have stemmed from understanding the molecular genetics of clear cell renal cancer, the study of which has entirely focused on VHL biology until recently. The remaining 25% of renal cell carcinoma (RCC) has distinct, yet related, molecular mechanisms, which are just beginning to be understood. For example, Type 1 papillary RCC is associated with mutations in the MET protooncogene and therapies targeting this pathway in these patients appear to be effective. Personalised medicine aims to tailor treatments to suit patients based on individual molecular signatures. With the increased availability of next generation sequencing in the clinical setting, the molecular genetics of primary and metastasised RCC will help determine treatment options available.

Key Concepts

  • There are several subtypes of renal cell carcinoma (RCC), each associated with distinct molecular genetics.
  • The most common type of RCC is the clear cell subtype, which is typically associated with inactivating mutations of the von Hippel–Lindau tumour suppressor on chromosome 3p.
  • 3p deletion can also affect other tumour suppressors commonly mutated in RCC: PBRM1, SETD2 and BAP1, all chromatin remodelling factors.
  • Type 1 and 2 papillary renal cell carcinoma are also associated with their own mutations in the genes MET and FH, respectively
  • Understanding the molecular genetics of RCC is essential for the development of targeted therapies.

Keywords: renal cell carcinoma; kidney cancer; VHL; molecular genetics; tumour suppressors; cilia; epigenetics

Figure 1. Hematoxylin/eosin histochemistry staining of paraffin sections of RCC tumours as indicated. All photographs were taken at 200x. For clear cell RCC, note the pale ‘clear’ cytoplasm of the cells. For papillary RCc, there are ‘finger‐like’ projections of fibrovascular stroma lined by malignant tumour cells that lack the abundant clear cytoplasm seen in a clear cell RCC. Chromophobe RCC is composed of cells with clear, reticular cytoplasm and some with eosinophilic cytoplasm. The cell borders are often more distinct in this carcinoma than others and the nuclei are often smaller and darker. Oncocytoma is characterised by large eosinophilic cells having small, round, benign‐appearing nuclei with large nucleoli with excessive amounts of mitochondria. Angiomyolipoma has evident lipid‐filled (white) vesicles. Courtesy of Dr. T.Q. Nguyen (University Medical Center Utrecht).
Figure 2. Schematic overview of the molecular action of pVHL in normal physiology and under (pseudo‐) hypoxic conditions. Prolyl hydroxylases (PHDs) use oxygen to hydroxylate the alpha subunits of hypoxia‐indicable factor (HIFα), which is then recognised by pVHL and associated proteins, and is subsequently polyubiquitinylated (Ub) and targeted for destruction by the proteasome. Under hypoxic conditions, or where VHL is mutated and cannot function, HIFα escapes poly‐Ub modification and accumulates in the nucleus where it functions as a heterodimeric transcription factor with HIF1β driving the expression of genes with a hypoxia response element (HRE) in the promotor.
Figure 3. Schematic of clear cell renal cell carcinoma progression. A single healthy ciliated renal tubule cell undergoes biallelic inactivation of the VHL gene, which stabilises HIFα and contributes to cilia loss and E2F1 stabilisation (although these may require additional mutations). In the case of VHL patients simple cysts may arise which may or may not degenerate to ccRCC. Additional mutations are required to drive full transformation, as indicated. HIF1α is no longer required at later stages.
Figure 4. The pathways driving most subtypes of RCC converge on nutrient‐ and/or oxygen‐sensing pathways in the renal cell. Pink circles indicate proteins whose genes are mutated in various subtypes of RCC.
Figure 5. Tumour suppressor genes mutated in renal tumour syndromes (red, associated syndromes and renal tumour type listed together) converge on the oxygen‐sensing pathway and TCA/Krebs cycle.


Albers J, Rajski M, Schonenberger D, et al. (2013) Combined mutation of Vhl and Trp53 causes renal cysts and tumours in mice. EMBO Molecular Medicine 5 (6): 949–964.

Albiges L, Guegan J, Le Formal A, et al. (2014) MET is a potential target across all papillary renal cell carcinomas: result from a large molecular study of pRCC with CGH array and matching gene expression array. Clinical Cancer Research 20 (13): 3411–3421.

Azzouzi HE, Leptidis S, Doevendans PA and De Windt LJ (2015) HypoxamiRs: regulators of cardiac hypoxia and energy metabolism. Trends in Endocrinology and Metabolism 26 (9): 502–508.

Bartels M, van der Zalm MM, van Oirschot BA, et al. (2015) Novel homozygous mutation of the internal translation initiation start site of VHL is exclusively associated with erythrocytosis: indications for distinct functional roles of von Hippel‐Lindau Tumor suppressor isoforms. Human Mutation 36 (11): 1039–1042.

Basten SG, Willekers S, Vermaat JS, et al. (2013) Reduced cilia frequencies in human renal cell carcinomas versus neighboring parenchymal tissue. Cilia 2 (1): 2.

Blankenship C, Naglich JG, Whaley JM, Seizinger B and Kley N (1999) Alternate choice of initiation codon produces a biologically active product of the von Hippel Lindau gene with tumor suppressor activity. Oncogene 18 (8): 1529–1535.

Buchwalter RA, Chen JV, Zheng Y and Megraw TL (2001) Centrosome in Cell Division, Development and Disease. Chichester, UK: John Wiley & Sons Ltd.

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

Cheng CN, Verdun VA and Wingert RA (2015) Recent advances in elucidating the genetic mechanisms of nephrogenesis using zebrafish. Cells 4 (2): 218–233.

Choueiri TK, Vaishampayan U, Rosenberg JE, et al. (2013) Phase II and biomarker study of the dual MET/VEGFR2 inhibitor foretinib in patients with papillary renal cell carcinoma. Journal of Clinical Oncology 31 (2): 181–186.

Durinck S, Stawiski EW, Pavia‐Jimenez A, et al. (2015) Spectrum of diverse genomic alterations define non‐clear cell renal carcinoma subtypes. Nature Genetics 47 (1): 13–21.

Essers PB, Klasson TD, Pereboom TC, et al. (2015) The von Hippel‐Lindau tumor suppressor regulates programmed cell death 5‐mediated degradation of Mdm2. Oncogene 34 (6): 771–779.

Esteban MA, Harten SK, Tran MG and Maxwell PH (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.

Frantzen C, Klasson T, Links T and Giles R (2015) Von Hippel‐Lindau Syndrome. GeneReviews. Seattle, WA: University of Washington.

Frew IJ, Smole Z, Thoma CR and Krek W (2013) Genetic deletion of the long isoform of the von Hippel‐Lindau tumour suppressor gene product alters microtubule dynamics. European Journal of Cancer 49 (10): 2433–2440.

Gerlinger M, Horswell S, Larkin J, et al. (2014) Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. Nature Genetics 46 (3): 225–233.

Gnarra JR, Tory K, Weng Y, et al. (1994) Mutations of the VHL tumour suppressor gene in renal carcinoma. Nature Genetics 7 (1): 85–90.

Gnarra JR, Ward JM, Porter FD, et al. (1997) Defective placental vasculogenesis causes embryonic lethality in VHL‐deficient mice. Proceedings of the National Academy of Sciences of the United States of America 94 (17): 9102–9107.

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

Guinot A, Lehmann H, Wild PJ and Frew IJ (2016) Combined deletion of Vhl, Trp53 and Kif3a causes cystic and neoplastic renal lesions. Journal of Pathology 239 (3): 365–373.

Ha M and Kim VN (2014) Regulation of microRNA biogenesis. Nature Reviews. Molecular Cell Biology 15 (8): 509–524.

Hildebrandt F, Benzing T and Katsanis N (2011) Ciliopathies. New England Journal of Medicine 364 (16): 1533–1543.

Kapitsinou PP and Haase VH (2008) The VHL tumor suppressor and HIF: insights from genetic studies in mice. Cell Death and Differentiation 15 (4): 650–659.

Klasson TD and Giles RH (2014) The role of the cilium in hereditary tumor predisposition syndromes. Journal of Pediatric Genetics 3 (2): 129–140.

Kleymenova E, Everitt JI, Pluta L, et al. (2004) Susceptibility to vascular neoplasms but no increased susceptibility to renal carcinogenesis in Vhl knockout mice. Carcinogenesis 25 (3): 309–315.

Lehmann H, Vicari D, Wild PJ and Frew IJ (2015) Combined Deletion of Vhl and Kif3a Accelerates Renal Cyst Formation. Journal of the American Society of Nephrology 26 (11): 2778–2788.

Li P, Znaor A, Holcatova I, et al. (2015) Regional geographic variations in kidney cancer incidence rates in European countries. European Urology 67 (6): 1134–1141.

Liao L, Testa JR and Yang H (2015) The roles of chromatin‐remodelers and epigenetic modifiers in kidney cancer. Cancer Genetics 208 (5): 206–214.

Linehan WM (2012) Genetic basis of kidney cancer: role of genomics for the development of disease‐based therapeutics. Genome Research 22 (11): 2089–2100.

Ljungberg B, Bensalah K, Canfield S, et al. (2015) EAU guidelines on renal cell carcinoma: 2014 update. European Urology 67 (5): 913–924.

Lubensky IA, Schmidt L, Zhuang Z, et al. (1999) Hereditary and sporadic papillary renal carcinomas with c‐met mutations share a distinct morphological phenotype. American Journal of Pathology 155 (2): 517–526.

Maher ER (2013) Genomics and epigenomics of renal cell carcinoma. Seminars in Cancer Biology 23 (1): 10–17.

Mans DA, Lolkema MP, van Beest M, et al. (2008) Mobility of the von Hippel‐Lindau tumour suppressor protein is regulated by kinesin‐2. Experimental Cell Research 314 (6): 1229–1236.

Massari F, Ciccarese C, Santoni M, et al. (2015) Metabolic alterations in renal cell carcinoma. Cancer Treatment Reviews 41 (9): 767–776.

Metelo AM, Noonan HR, Li X, et al. (2015) Pharmacological HIF2alpha inhibition improves VHL disease‐associated phenotypes in zebrafish model. Journal of Clinical Investigation 125 (5): 1987–1997.

Montani M, Heinimann K, von Teichman A, et al. (2010) VHL‐gene deletion in single renal tubular epithelial cells and renal tubular cysts: further evidence for a cyst‐dependent progression pathway of clear cell renal carcinoma in von Hippel‐Lindau disease. American Journal of Surgical Pathology 34 (6): 806–815.

Monzon FA, Alvarez K, Peterson L, et al. (2011) Chromosome 14q loss defines a molecular subtype of clear‐cell renal cell carcinoma associated with poor prognosis. Modern Pathology 24 (11): 1470–1479.

Moore LE, Jaeger E, Nickerson ML, et al. (2012) Genomic copy number alterations in clear cell renal carcinoma: associations with case characteristics and mechanisms of VHL gene inactivation. Oncogenesis 1: e14.

Mullen AR, Wheaton WW, Jin ES, et al. (2012) Reductive carboxylation supports growth in tumour cells with defective mitochondria. Nature 481 (7381): 385–388.

Pena‐Llopis S, Vega‐Rubin‐de‐Celis S, Liao A, et al. (2012) BAP1 loss defines a new class of renal cell carcinoma. Nature Genetics 44 (7): 751–759.

Popova T, Hebert L, Jacquemin V, et al. (2013) Germline BAP1 mutations predispose to renal cell carcinomas. American Journal of Human Genetics 92 (6): 974–980.

Rondinelli B, Rosano D, Antonini E, et al. (2015) Histone demethylase JARID1C inactivation triggers genomic instability in sporadic renal cancer. Journal of Clinical Investigation 125 (12): 4625–4637.

van Rooijen E, Santhakumar K, Logister I, et al. (2011) A zebrafish model for VHL and hypoxia signaling. Methods in Cell Biology 105: 163–190.

Rydzanicz M, Wrzesinski T, Bluyssen HA and Wesoly J (2013) Genomics and epigenomics of clear cell renal cell carcinoma: recent developments and potential applications. Cancer Letters 341 (2): 111–126.

Santhakumar K, Judson EC, Elks PM, et al. (2012) A zebrafish model to study and therapeutically manipulate hypoxia signaling in tumorigenesis. Cancer Research 72 (16): 4017–4027.

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

Schmidt L, Duh FM, Chen F, et al. (1997) Germline and somatic mutations in the tyrosine kinase domain of the MET proto‐oncogene in papillary renal carcinomas. Nature Genetics 16 (1): 68–73.

Schmidt LS and Linehan WM (2014) Hereditary leiomyomatosis and renal cell carcinoma. International Journal of Nephrology and Renovascular Disease 7: 253–260.

Schonenberger D, Harlander S, Rajski M, et al. (2016) Formation of renal cysts and tumors in Vhl/Trp53‐deficient mice requires HIF1alpha and HIF2alpha. Cancer Research 76 (7): 2025–2036.

Shen C and Kaelin WG Jr (2013) The VHL/HIF axis in clear cell renal carcinoma. Seminars in Cancer Biology 23 (1): 18–25.

Siegel RL, Miller KD and Jemal A (2016) Cancer statistics, 2016. CA: A Cancer Journal for Clinicians 66 (1): 7–30.

Simon JM, Hacker KE, Singh D, et al. (2014) Variation in chromatin accessibility in human kidney cancer links H3K36 methyltransferase loss with widespread RNA processing defects. Genome Research 24 (2): 241–250.

Slaats GG and Giles RH (2015) Are renal ciliopathies (replication) stressed out? Trends in Cell Biology 25 (6): 317–319.

Tomlinson IP, 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 (4): 406–410.

Varela I, Tarpey P, Raine K, et al. (2011) Exome sequencing identifies frequent mutation of the SWI/SNF complex gene PBRM1 in renal carcinoma. Nature 469 (7331): 539–542.

Wang SS, Gu YF, Wolff N, et al. (2014) Bap1 is essential for kidney function and cooperates with Vhl in renal tumorigenesis. Proceedings of the National Academy of Sciences of the United States of America 111 (46): 16538–16543.

Zaidan M, Stucker F, Stengel B, et al. (2014) Increased risk of solid renal tumors in lithium‐treated patients. Kidney International 86 (1): 184–190.

Zhuang Z, Park WS, Pack S, et al. (1998) Trisomy 7‐harbouring non‐random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nature Genetics 20 (1): 66–69.

Further Reading

de Bono E, Gillesen S and Mehra N (eds) (2015) ESMO Essentials for Clinicians: Genitourinary Tract Tumors, European Society for Medical Oncology.‐for‐Clinicians/Genitourinary‐Tract‐Tumours/Editors‐and‐Contributors.

Jonasch E, Matin S, Pagliaro LC, Wood CG and Tannir NM (2011) Renal Cell Carcinoma. In: Kantarjian HM, Wolff RA and Koller CA (eds) MD Anderson Manual of Medical Oncology, 2nd edn, pp. 905–924. New York: McGraw‐Hill.

Maher ER (2013) Genomics and epigenomics of renal cell carcinoma. Seminars in Cancer Biology 23 (1): 10–17.

Medscape (2016) Renal Cell Carcinoma.‐overview

Su D, Singer EA and Srinivasan R (2015) Molecular pathways in renal cell carcinoma: recent advances in genetics and molecular biology. Current Opinion in Oncology 27 (3): 217–223.

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

* Required Field

How to Cite close
Klasson, Timothy D, and Giles, Rachel H(Sep 2016) Molecular Genetics of Renal Cancer. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024468]