Nature | Letter Diverse somatic mutation patterns and pathway alterations in human cancers * Zhengyan Kan1, 2 Search for this author in: * NPG journals * PubMed * Google Scholar * Bijay S. Jaiswal1 Search for this author in: * NPG journals * PubMed * Google Scholar * Jeremy Stinson1 Search for this author in: * NPG journals * PubMed * Google Scholar * Vasantharajan Janakiraman1 Search for this author in: * NPG journals * PubMed * Google Scholar * Deepali Bhatt1 Search for this author in: * NPG journals * PubMed * Google Scholar * Howard M. Stern3 Search for this author in: * NPG journals * PubMed * Google Scholar * Peng Yue2 Search for this author in: * NPG journals * PubMed * Google Scholar * Peter M. Haverty2 Search for this author in: * NPG journals * PubMed * Google Scholar * Richard Bourgon2 Search for this author in: * NPG journals * PubMed * Google Scholar * Jianbiao Zheng4 Search for this author in: * NPG journals * PubMed * Google Scholar * Martin Moorhead4 Search for this author in: * NPG journals * PubMed * Google Scholar * Subhra Chaudhuri1 Search for this author in: * NPG journals * PubMed * Google Scholar * Lynn P. Tomsho5 Search for this author in: * NPG journals * PubMed * Google Scholar * Brock A. Peters1 Search for this author in: * NPG journals * PubMed * Google Scholar * Kanan Pujara1 Search for this author in: * NPG journals * PubMed * Google Scholar * Shaun Cordes1 Search for this author in: * NPG journals * PubMed * Google Scholar * David P. Davis1 Search for this author in: * NPG journals * PubMed * Google Scholar * Victoria E. H. Carlton4 Search for this author in: * NPG journals * PubMed * Google Scholar * Wenlin Yuan1 Search for this author in: * NPG journals * PubMed * Google Scholar * Li Li2 Search for this author in: * NPG journals * PubMed * Google Scholar * Weiru Wang6 Search for this author in: * NPG journals * PubMed * Google Scholar * Charles Eigenbrot6 Search for this author in: * NPG journals * PubMed * Google Scholar * Joshua S. Kaminker2 Search for this author in: * NPG journals * PubMed * Google Scholar * David A. Eberhard3 Search for this author in: * NPG journals * PubMed * Google Scholar * Paul Waring3 Search for this author in: * NPG journals * PubMed * Google Scholar * Stephan C. Schuster5 Search for this author in: * NPG journals * PubMed * Google Scholar * Zora Modrusan1 Search for this author in: * NPG journals * PubMed * Google Scholar * Zemin Zhang2 Search for this author in: * NPG journals * PubMed * Google Scholar * David Stokoe1 Search for this author in: * NPG journals * PubMed * Google Scholar * Frederic J. de Sauvage1 Search for this author in: * NPG journals * PubMed * Google Scholar * Malek Faham4 Search for this author in: * NPG journals * PubMed * Google Scholar * Somasekar Seshagiri1 Search for this author in: * NPG journals * PubMed * Google Scholar * Affiliations * Contributions * Corresponding authorJournal name:NatureVolume:466,Pages:869–873Date published:(12 August 2010)DOI:doi:10.1038/nature09208Received23 July 2009Accepted27 May 2010Published online28 July 2010 Article tools * Full text * 日本語要約 * Print * Email * Download PDF * Download citation * Order reprints * Rights and permissions * Share/bookmark * Connotea * CiteULike * Facebook * Twitter * Delicious * Digg 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. View full text Subject terms: * Careers * Genetics * Molecular biology * Genomics Figures at a glance * Figure 1: Diverse patterns of significantly mutated genes across cancer subtypes. Each solid circle represents a gene and the size of the circle is proportional to the mutation count for that gene. The genes are represented in alphabetical order from left to right on the x axis. Selected genes with significant q-scores are labelled. * Figure 2: GRM and BAI are frequently mutated gene families. , , Positional distribution of somatic mutations across GRM8 () and BAI3 () proteins. Somatic mutations in additional GRM and BAI family members mapped onto GRM8 or BAI3, respectively, based on sequence alignment are depicted. Atrial natriuretic factor (ANF) receptor domain, thrombospondin 1 (TSP) domain, hormone receptor (HRM) domain, G-protein receptor proteolytic (GPS) domain, and 7 transmembrane (7TM) domain are depicted. Previously published data (indicated by a yellow triangle) are from refs 3, 7, 8. The dagger indicates mutations identified in the prevalence screen. * Figure 3: Integrated analysis of somatic mutations and copy number alterations. , Relative frequency of copy number gain versus loss reveals potential oncogenic or tumour-suppressor roles of 112 candidate cancer genes. Frequency is the percentage of tumour samples that show copy number gain or loss. Putative oncogenes and tumour suppressors based on this analysis are shown. , , GNAS, a G-protein α subunit, is mutated and amplified in cancers. The mutations are mapped on to the GNAS structure (Protein Data Bank 1CS4) (). The blue dots in represent GTP contact sites in GNAS. Switch I and switch II regions in are represented by yellow and maroon boxes, respectively. Samples with copy number gains in GNAS show elevated expression levels as measured by exon array (). PR, prostate tumour. –, A representative image depicting the anchorage-independent growth () of human mammary epithelial cells stably expressing Flag-tagged GNAO1 () and the number of colonies formed (). WT, wild type. Data shown in are mean ± s.e.m. (*P < 0.05; **P < 0.01). * Figure 4: Integrated analysis of signalling pathways reveals a role for MAP2K4 mutations in cancer. , Genetic alterations in RTK/RAS and GPCR signalling pathways in ovarian cancers. ECM, extracellular matrix. Numbers indicate per cent sample altered. , MAP2K4 somatic mutations identified in this study and others from refs 4, 13, 24, 25 (indicated in parentheses). Nonsense and frameshift mutations are shown below. fs, frameshift. Asterisk represents a nonsense mutation. –, A representative image showing anchorage-independent growth () and the number of colonies formed by NIH3T3 cells () stably expressing MAP2K4 somatic mutants (). , MAP2K4 somatic mutants, immunoprecipitated from cell lines stably expressing them, show impaired kinase activity towards MBP or JNK used as a substrate. EV, empty vector. Data shown in are mean ± s.e.m. (*P < 0.05 and **P < 0.01). Accession codes * Accession codes * Author information * Supplementary information * Comments Primary accessions Gene Expression Omnibus * GSE20393 Protein Data Bank * 1CS4 * 1CS4 Author information * Accession codes * Author information * Supplementary information * Comments Affiliations * Department of Molecular Biology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA * Zhengyan Kan, * Bijay S. Jaiswal, * Jeremy Stinson, * Vasantharajan Janakiraman, * Deepali Bhatt, * Subhra Chaudhuri, * Brock A. Peters, * Kanan Pujara, * Shaun Cordes, * David P. Davis, * Wenlin Yuan, * Zora Modrusan, * David Stokoe, * Frederic J. de Sauvage & * Somasekar Seshagiri * Department of Bioinformatics, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA * Zhengyan Kan, * Peng Yue, * Peter M. Haverty, * Richard Bourgon, * Li Li, * Joshua S. Kaminker & * Zemin Zhang * Department of Pathology, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA * Howard M. Stern, * David A. Eberhard & * Paul Waring * Affymetrix Inc, 3420 Central Expressway, Santa Clara, California 95051, USA * Jianbiao Zheng, * Martin Moorhead, * Victoria E. H. Carlton & * Malek Faham * Pennsylvania State University, Center for Comparative Genomics and Bioinformatics, 310 Wartik Lab, University Park, Pennsylvania 16802, USA * Lynn P. Tomsho & * Stephan C. Schuster * Department of Protein Engineering, Genentech Inc., 1 DNA Way, South San Francisco, California 94080, USA * Weiru Wang & * Charles Eigenbrot Contributions Bioinformatics analysis: Z.K., P.Y., P.M.H., R.B., B.A.P., M.M., V.E.H.C., J.S.K., L.L., Z.Z., D.S. and S.S. MRD planning and sorting: J.Z. and M.F. Mutation validation: Z.K., J.S., D.B., W.Y., L.P.T., S.C.S. and K.P. CGH, sequencing and microarray studies: Z.M. and P.M.H. Biological studies: B.S.J., V.J., S.Ch., S.Co., D.P.D., D.S. and S.S. Structural predictions: W.W. and C.E. Pathology support: H.M.S., D.A.E. and P.W. Project conception, scientific oversight and input: F.J.d.S. and S.S. Manuscript preparation: Z.K. and S.S. Competing financial interests Most of the authors are either employees of Genentech Inc. or Affymetrix Inc. Corresponding author Correspondence to: * Somasekar Seshagiri (sekar@gene.com) The CGH microarray data has been submitted to the GEO database under the accession number GSE20393. Supplementary information * Accession codes * Author information * Supplementary information * Comments Excel files * Supplementary Tables (6.1M) This file contains Supplementary Tables 1-10. PDF files * Supplementary Figures (4.6M) This file contains Supplementary Figures 1-13 with legends Additional data

DOI: 10.1038/nature09208
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