Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Gillian L. Dalgliesh, Kyle Furge, Chris Greenman, Lina Chen, Graham Bignell, Adam Butler, Helen Davies, Sarah Edkins, Claire Hardy, Calli Latimer, Jon Teague, Jenny Andrews, Syd Barthorpe, Dave Beare, Gemma Buck, Peter J. Campbell, Simon Forbes, Mingming Jia, David Jones, Henry KnottChai Yin Kok, King Wai Lau, Catherine Leroy, Meng-Lay Lin, David J. McBride, Mark Maddison, Simon Maguire, Kirsten McLay, Andrew Menzies, Tatiana Mironenko, Lee Mulderrig, Laura Mudie, Sarah O'Meara, Erin Pleasance, Aarjunan Rajasingham, Rebecca Shepherd, Raffaella Smith, Lucy Stebbings, Philip Stephens, Gurpreet Tang, Patrick S. Tarpey, Kelly Turrell, Karl J. Dykema, Sok Kean Khoo, David Petillo, Bill Wondergem, John Anema, Richard J. Kahnoski, Bin Tean Teh, Michael R. Stratton, P. Andrew Futreal

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Abstract

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.
Original languageEnglish
Pages (from-to)360-363
Number of pages4
JournalNature
Volume463
Issue number7279
DOIs
Publication statusPublished - 21 Jan 2010

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