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Mutational heterogeneity in cancer and the search for new cancer-associated genes.
Lawrence, Michael S; Stojanov, Petar; Polak, Paz; Kryukov, Gregory V; Cibulskis, Kristian; Sivachenko, Andrey; Carter, Scott L; Stewart, Chip; Mermel, Craig H; Roberts, Steven A; Kiezun, Adam; Hammerman, Peter S; McKenna, Aaron; Drier, Yotam; Zou, Lihua; Ramos, Alex H; Pugh, Trevor J; Stransky, Nicolas; Helman, Elena; Kim, Jaegil; Sougnez, Carrie; Ambrogio, Lauren; Nickerson, Elizabeth; Shefler, Erica; Cortés, Maria L; Auclair, Daniel; Saksena, Gordon; Voet, Douglas; Noble, Michael; DiCara, Daniel; Lin, Pei; Lichtenstein, Lee; Heiman, David I; Fennell, Timothy; Imielinski, Marcin; Hernandez, Bryan; Hodis, Eran; Baca, Sylvan; Dulak, Austin M; Lohr, Jens; Landau, Dan-Avi; Wu, Catherine J; Melendez-Zajgla, Jorge; Hidalgo-Miranda, Alfredo; Koren, Amnon; McCarroll, Steven A; Mora, Jaume; Crompton, Brian; Onofrio, Robert; Parkin, Melissa.
Afiliación
  • Lawrence MS; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Stojanov P; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Polak P; Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Kryukov GV; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Cibulskis K; Harvard Medical School, Boston, MA, 02115, USA.
  • Sivachenko A; Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • Carter SL; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Stewart C; Harvard Medical School, Boston, MA, 02115, USA.
  • Mermel CH; Brigham and Women's Hospital, Boston, MA, 02115, USA.
  • Roberts SA; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Kiezun A; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Hammerman PS; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • McKenna A; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Drier Y; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Zou L; Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Ramos AH; Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
  • Pugh TJ; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Stransky N; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Helman E; Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Kim J; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Sougnez C; Genome Sciences, University of Washington, Seattle, WA 98195.
  • Ambrogio L; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Nickerson E; Harvard Medical School, Boston, MA, 02115, USA.
  • Shefler E; Massachusetts General Hospital, Boston, MA, 02114, USA.
  • Cortés ML; Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
  • Auclair D; Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100, Israel.
  • Saksena G; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Voet D; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Noble M; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • DiCara D; Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
  • Lin P; Harvard Medical School, Boston, MA, 02115, USA.
  • Lichtenstein L; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Heiman DI; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Fennell T; Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
  • Imielinski M; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Hernandez B; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Hodis E; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Baca S; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Dulak AM; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Lohr J; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Landau DA; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Wu CJ; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Melendez-Zajgla J; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Hidalgo-Miranda A; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Koren A; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • McCarroll SA; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Mora J; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Crompton B; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Onofrio R; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
  • Parkin M; The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Nature ; 499(7457): 214-218, 2013 Jul 11.
Article en En | MEDLINE | ID: mdl-23770567
ABSTRACT
Major international projects are underway that are aimed at creating a comprehensive catalogue of all the genes responsible for the initiation and progression of cancer. These studies involve the sequencing of matched tumour-normal samples followed by mathematical analysis to identify those genes in which mutations occur more frequently than expected by random chance. Here we describe a fundamental problem with cancer genome studies as the sample size increases, the list of putatively significant genes produced by current analytical methods burgeons into the hundreds. The list includes many implausible genes (such as those encoding olfactory receptors and the muscle protein titin), suggesting extensive false-positive findings that overshadow true driver events. We show that this problem stems largely from mutational heterogeneity and provide a novel analytical methodology, MutSigCV, for resolving the problem. We apply MutSigCV to exome sequences from 3,083 tumour-normal pairs and discover extraordinary variation in mutation frequency and spectrum within cancer types, which sheds light on mutational processes and disease aetiology, and in mutation frequency across the genome, which is strongly correlated with DNA replication timing and also with transcriptional activity. By incorporating mutational heterogeneity into the analyses, MutSigCV is able to eliminate most of the apparent artefactual findings and enable the identification of genes truly associated with cancer.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oncogenes / Heterogeneidad Genética / Mutación / Neoplasias Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Nature Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Oncogenes / Heterogeneidad Genética / Mutación / Neoplasias Tipo de estudio: Prognostic_studies / Risk_factors_studies Límite: Humans Idioma: En Revista: Nature Año: 2013 Tipo del documento: Article País de afiliación: Estados Unidos