Cancer Research UK : Kidney cancer molecular biology and genetics

Kidney cancer molecular biology and genetics

This page presents information on the molecular biology and genetics of kidney cancer.

Most cases of kidney cancer are sporadic, although it is a major feature of a number of inherited disorders (Table 5.1).

inherited disorders in which renal cell carcinoma is a major feature

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Von Hippel-Lindau (VHL) disease displays autosomal dominant inheritance and can be divided into three types depending on the tumours that develop in affected families. These include tumours of the kidney, brain, spinal cord, pancreas, adrenal gland and eye. The risk of an affected family member developing clear-cell renal cell carcinoma increases with age, reaching 70% by age 60.1

The VHL gene was identified in 1993 on chromosome 3p25.5 and codes for a tumour suppressor gene.2 To date, around 500 different mutations in VHL have been described.3 Correlations between type of mutation and the phenotype of disease have been observed.4

The protein product of VHL is involved in the ubiquitination of the hypoxia inducible factor alpha family proteins (eg HIF-1? and HIF-2?) through binding to elongin B, C and Cul2 subunits.5-8 Loss of VHL function causes accumulation of HIF proteins and the transcriptional upregulation of genes normally expressed under hypoxic conditions. These encourage cell growth and survival, and include angiogenic (eg VEGF) and mitogenic (eg TGF-?, PDGF-B) factors.9

Hereditary papillary renal cell carcinoma (HPRCC) is characterised by occurrence of type 1 papillary RCC as well as tumours in other organs. HPRCC is inherited in an autosomal dominant manner with incomplete penetrance. It is caused by mutations in the c-MET proto-oncogene, which maps to chromosome 7q34.10

HPRCC renal tumours often show trisomy of chromosome 7 and two of these chromosomes have been shown to harbour c-MET mutations.11 c-MET codes for a receptor for the hepatocyte growth/scatter factor involved in various cancer-related processes including angiogenesis.12

Hereditary leiomyomatosis renal cell cancer (HLRCC) is an inherited syndrome,13 caused by mutation in the fumarate hydratase (FH) gene.14 Affected individuals develop benign skin and uterine leiomyomas and, in some cases, highly aggressive type-2 papillary renal cell cancer. The exact mechanism by which mutations in FH cause disease is not known, however, it is thought that lack of fumarate hydratase may activate hypoxia signalling pathways under normal oxygen conditions.15

Birt-Hogg-Dubé (BHD) syndrome is characterised by an increased risk of a number of different types of renal cancer. The BHD gene has been mapped to chromosome 17p11.2. It encodes a protein called folliculin, that has been linked to mTOR and AMPK signalling pathways.16

A wide number of genes that appear to play a role in the development of sporadic cases of renal cancer have been identified.9 These include genes involved in familial cancer, such as VHL, MET and BHD. However, FH does not appear to play a role in sporadic tumours.15 The VHL gene is now known to be disabled through mutation or hypermethylation in the majority of sporadic clear cell RCCs, the most common type of kidney cancer.2, 17,18

Sporadic RCC patients whose tumours carry mutations of the VHL gene do not exhibit any of the other VHL symptoms. While genes that control cell division such as TP53, RB and RAS may play a role in the development of RCC, mutations of these genes have only rarely been reported in RCC patients. 19-21

Around 5-10 per cent of sporadic kidney cancers are papillary RCCs; these often exhibit trisomy of chromosomes 7, 16 or 17, or loss of the Y chromosome.22 Mutations in c-MET have also been reported in a subset of sporadic papillary RCC patients.10

Studies in the Icelandic population indicate that renal cell carcinoma can cluster in families not affected by VHL. This suggests that there may be an inherited component to some "sporadic" cases of RCC, at least in this population.23

The identification of the VHL gene fifteen years ago has led to substantial advances in the understanding of kidney cancer.2 Continuing research is providing a better knowledge of the role of the VHL protein in normal cell growth and is unravelling the wider molecular pathways involved in the disease. This will lead to improved methods of diagnosis and treatment as well as, potentially, the development of prevention strategies for some types of kidney cancer.5-8

References for kidney cancer molecular biology and genetics

Maher, E.R., et al., Clinical features and natural history of von Hippel-Lindau disease. Q J Med, 1990. 77(283): p. 1151-63
Latif, F., et al., Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 1993. 260(5112): p. 1317-20
VHL Family Alliance.
Ong, K.R., et al., Genotype-phenotype correlations in von Hippel-Lindau disease. Hum Mutat, 2007. 28(2): p. 143-9
Kibel, A., et al., Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C. Science, 1995. 269(5229): p. 1444-6
Maxwell, P.H., et al.,The tumour suppressor protein VHL targets hypoxia-inducible factors for oxygen-dependent proteolysis. Nature, 1999. 399(6733): p. 271-5
Ohh, M., et al., Ubiquitination of hypoxia-inducible factor requires direct binding to the beta-domain of the von Hippel-Lindau protein. Nat Cell Biol, 2000. 2(7): p. 423-7
Hon, W., et al.,Structural basis for the recognition of hydroxyproline in HIF-1a by pVHL. Nature, 2002. 417: p. 975-978
Skolarikos, A.A., et al., Molecular pathogenetics of renal cancer. Am J Nephrol, 2006. 26(3): p. 218-31
Schmidt, L., et al.,Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat Genet, 1997. 16(1): p. 68-73
Zhuang, Z., et al., Trisomy 7-harbouring non-random duplication of the mutant MET allele in hereditary papillary renal carcinomas. Nat Genet, 1998. 20(1): p. 66-9
Jeffers, M., et al., Activating mutations for the met tyrosine kinase receptor in human cancer. Proc Natl Acad Sci U S A, 1997. 94(21): p. 11445-50
Launonen, V., et al., Inherited susceptibility to uterine leiomyomas and renal cell cancer. Proc Natl Acad Sci U S A, 2001. 98(6): p. 3387-92
Tomlinson, I.P., et al.,Germline mutations in FH predispose to dominantly inherited uterine fibroids, skin leiomyomata and papillary renal cell cancer. Nat Genet, 2002. 30(4): p. 406-10
Sudarshan, S., Linehan, W.M., and Neckers, L., HIF and fumarate hydratase in renal cancer. Br J Cancer, 2007. 96(3): p. 403-7
Baba, M., et al., Folliculin encoded by the BHD gene interacts with a binding protein, FNIP1, and AMPK, and is involved in AMPK and mTOR signaling. Proc Natl Acad Sci U S A, 2006. 103(42): p. 15552-7
Gnarra, J.R., et al., Mutations of the VHL tumour suppressor gene in renal carcinoma. Nat Genet, 1994. 7(1): p. 85-90
Banks, R.E., et al., Genetic and epigenetic analysis of von Hippel-Lindau (VHL) gene alterations and relationship with clinical variables in sporadic renal cancer. Cancer Res, 2006. 66(4): p. 2000-11
Uchida, T., et al., Infrequent involvement of p53 mutations and loss of heterozygosity of 17p in the tumorigenesis of renal cell carcinoma. J Urol, 1993. 150(4): p. 1298-301
Lipponen, P., Eskelinen, M., and Syrjanen, K., Expression of tumour-suppressor gene Rb, apoptosis-suppressing protein Bcl-2 and c-Myc have no independent prognostic value in renal adenocarcinoma. Br J Cancer, 1995. 71(4): p. 863-7
Nanus, D.M., et al., Infrequent ras oncogene point mutations in renal cell carcinoma. J Urol, 1990. 143(1): p. 175-8
Kovacs, G., Molecular cytogenetics of renal cell tumors. Adv Cancer Res, 1993. 62: p. 89-124
Gudbjartsson, T., et al., A population-based familial aggregation analysis indicates genetic contribution in a majority of renal cell carcinomas. Int J Cancer, 2002. 100(4): p. 476-9

Kidney cancer molecular biology and genetics

References for kidney cancer molecular biology and genetics

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