Systematic sequencing of renal carcinoma reveals inactivation of histone modifying genes

Cancer Genome Project

Gillian L. Dalgliesh1, Kyle Furge2, Chris Greenman1, Lina Chen1, Graham Bignell1, Adam Butler1, Helen Davies1, Sarah Edkins1, Claire Hardy1, Calli Latimer1, Jon Teague1, Jenny Andrews1, Syd Barthorpe1, Dave Beare1, Gemma Buck1, Peter J. Campbell1, Simon Forbes1, Mingming Jia1, David Jones1, Henry Knott1, Chai Yin Kok1, King Wai Lau1, Catherine Leroy1, Meng-Lay Lin1, David J. McBride1, Mark Maddison1, Simon Maguire1, Kirsten McLay1, Andrew Menzies1, Tatiana Mironenko1, Lee Mulderrig1, Laura Mudie1, Sarah O’Meara1, Erin Pleasance1, Arjunan Rajasingham1, Rebecca Shepherd1, Raffaella Smith1, Lucy Stebbings1, Philip Stephens1, Gurpreet Tang1, Patrick S. Tarpey1, Kelly Turrell1, Karl J. Dykema2, Sok Kean Khoo3, David Petillo3, Bill Wondergem2, John Anema4, Richard J. Kahnoski4, Bin Tean Teh3,5, Michael R. Stratton1,6 & P. Andrew Futreal1

Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK
Laboratory of Computational Biology,
Laboratory of Cancer Genertics, Van Andel Research Institute, Grand Rapids, Michigan 49503, USA
Department of Urology, Spectrum Health Hospital, Grand Rapids, Michigan 49503, USA
NCCS-VARI Translational Cancer Research Laboratory, National Cancer Centre, 169610 Singapore
Institute of Cancer Research, Sutton, Surrey SM2 5NG, UK
Correspondence to: Bin Tean Teh3,5Michael R. Stratton1,6P. Andrew Futreal1 Correspondence and requests for materials should be addressed to B.T.T. (Email: Bin.Teh@vai.org), M.R.S. (Email: mrs@sanger.ac.uk) or P.A.F. (Email: paf@sanger.ac.uk).

Top of pageClear 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 cases1, 2, 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 reported3. 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.

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