Molecular Genetics of Renal Cancer

Abstract

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.
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Further Reading

de Bono E, Gillesen S and Mehra N (eds) (2015) ESMO Essentials for Clinicians: Genitourinary Tract Tumors, European Society for Medical Oncology. http://oncologypro.esmo.org/Publications/Essentials‐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. http://emedicine.medscape.com/article/281340‐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.

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