Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101...

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Published in:	Nature (London) 2010-01, Vol.463 (7279), p.360-363
Main Authors:	Teh, Bin Tean, Stratton, Michael R, Futreal, P. Andrew, Dalgliesh, Gillian L, Furge, Kyle, Greenman, Chris, Chen, Lina, Bignell, Graham, Butler, Adam, Davies, Helen, Edkins, Sarah, Hardy, Claire, Latimer, Calli, Teague, Jon, Andrews, Jenny, Barthorpe, Syd, Beare, Dave, Buck, Gemma, Campbell, Peter J, Forbes, Simon, Jia, Mingming, Jones, David, Knott, Henry, Kok, Chai Yin, Lau, King Wai, Leroy, Catherine, Lin, Meng-Lay, McBride, David J, Maddison, Mark, Maguire, Simon, McLay, Kirsten, Menzies, Andrew, Mironenko, Tatiana, Mulderrig, Lee, Mudie, Laura, O'Meara, Sarah, Pleasance, Erin, Rajasingham, Arjunan, Shepherd, Rebecca, Smith, Raffaella, Stebbings, Lucy, Stephens, Philip, Tang, Gurpreet, Tarpey, Patrick S, Turrell, Kelly, Dykema, Karl J, Khoo, Sok Kean, Petillo, David, Wondergem, Bill, Anema, John, Kahnoski, Richard J
Format:	Article
Language:	eng
Subjects:	Biological and medical sciences Cancer Carcinoma, Renal cell Carcinoma, Renal Cell - genetics Carcinoma, Renal Cell - pathology Cell Hypoxia - genetics Chromatin - metabolism Deoxyribonucleic acid DNA Gene Expression Regulation, Neoplastic Genes Genes, Neurofibromatosis 2 Genetic aspects Genetic testing Genetics Genotype & phenotype Heterogeneity Histone Demethylases Histone-Lysine N-Methyltransferase - genetics Histones Histones - metabolism Human Humans Hypoxia Kidney Neoplasms - genetics Kidney Neoplasms - pathology Kidneys Kinases Lysine Medical sciences Mutation - genetics Mutations Nephrology. Urinary tract diseases Nuclear Proteins - genetics Oxidoreductases, N-Demethylating - genetics Physiological aspects Risk factors Sequence Analysis, DNA Studies Tumors of the urinary system
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Summary:	Clear cell renal cell carcinoma (ccRCC) is the most common form of adult kidney cancer, characterized by the presence of inactivating mutations in the VHL gene in most cases, and by infrequent somatic mutations in known cancer genes. To determine further the genetics of ccRCC, we have sequenced 101 cases through 3,544 protein-coding genes. Here we report the identification of inactivating mutations in two genes encoding enzymes involved in histone modification-SETD2, a histone H3 lysine 36 methyltransferase, and JARID1C (also known as KDM5C), a histone H3 lysine 4 demethylase-as well as mutations in the histone H3 lysine 27 demethylase, UTX (KMD6A), that we recently reported. The results highlight the role of mutations in components of the chromatin modification machinery in human cancer. Furthermore, NF2 mutations were found in non-VHL mutated ccRCC, and several other probable cancer genes were identified. These results indicate that substantial genetic heterogeneity exists in a cancer type dominated by mutations in a single gene, and that systematic screens will be key to fully determining the somatic genetic architecture of cancer.
ISSN:	0028-0836 1476-4687