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2007年11月29日木曜日
Laura D.Woodの大腸癌遺伝子解析
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Letter
Nature advance online publication 28 July 2010 |Received 23 July 2009; Accepted 27 May 2010; Published online 28 July 2010
Diverse somatic mutation patterns and pathway alterations in human cancers
Zhengyan Kan1,2, Bijay S. Jaiswal1, Jeremy Stinson1, Vasantharajan Janakiraman1, Deepali Bhatt1, Howard M. Stern3, Peng Yue2, Peter M. Haverty2, Richard Bourgon2, Jianbiao Zheng4, Martin Moorhead4, Subhra Chaudhuri1, Lynn P. Tomsho5, Brock A. Peters1, Kanan Pujara1, Shaun Cordes1, David P. Davis1, Victoria E. H. Carlton4, Wenlin Yuan1, Li Li2, Weiru Wang6, Charles Eigenbrot6, Joshua S. Kaminker2, David A. Eberhard3, Paul Waring3, Stephan C. Schuster5, Zora Modrusan1, Zemin Zhang2, David Stokoe1, Frederic J. de Sauvage1, Malek Faham4 & Somasekar Seshagiri1
- Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA
- Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA
- Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA
- Affymetrix Inc, 3420 Central Expressway, Santa Clara, California 95051, USA
- Pennsylvania State University, Center for Comparative Genomics and Bioinformatics, 310 Wartik Lab, University Park, Pennsylvania 16802, USA
- Department of Protein Engineering, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA
Correspondence to: Somasekar Seshagiri1 Email: sekar@gene.com
Abstract
The systematic characterization of somatic mutations in cancer genomes is essential for understanding the disease and for developing targeted therapeutics1. Here we report the identification of 2,576 somatic mutations across ~1,800 megabases of DNA representing 1,507 coding genes from 441 tumours comprising breast, lung, ovarian and prostate cancer types and subtypes. We found that mutation rates and the sets of mutated genes varied substantially across tumour types and subtypes. Statistical analysis identified 77 significantly mutated genes including protein kinases, G-protein-coupled receptors such as GRM8, BAI3, AGTRL1 (also called APLNR) and LPHN3, and other druggable targets. Integrated analysis of somatic mutations and copy number alterations identified another 35 significantly altered genes including GNAS, indicating an expanded role for Gα subunits in multiple cancer types. Furthermore, our experimental analyses demonstrate the functional roles of mutant GNAO1 (a Gα subunit) and mutant MAP2K4 (a member of the JNK signalling pathway) in oncogenesis. Our study provides an overview of the mutational spectra across major human cancers and identifies several potential therapeutic targets.
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