Mutational heterogeneity in cancer and the search for new cancer-associated genes

Michael S Lawrence; Petar Stojanov; Paz Polak; Gregory V Kryukov; Kristian Cibulskis; Andrey Sivachenko; Scott L Carter; Chip Stewart; Craig H Mermel; Steven A Roberts; Adam Kiezun; Peter S Hammerman; Aaron McKenna; Yotam Drier; Lihua Zou; Alex H Ramos; Trevor J Pugh; Nicolas Stransky; Elena Helman; Jaegil Kim; Carrie Sougnez; Lauren Ambrogio; Elizabeth Nickerson; Erica Shefler; Maria L Cortés; Daniel Auclair; Gordon Saksena; Douglas Voet; Michael Noble; Daniel DiCara; Pei Lin; Lee Lichtenstein; David I Heiman; Timothy Fennell; Marcin Imielinski; Bryan Hernandez; Eran Hodis; Sylvan Baca; Austin M Dulak; Jens Lohr; Dan-Avi Landau; Catherine J Wu; Jorge Melendez-Zajgla; Alfredo Hidalgo-Miranda; Amnon Koren; Steven A McCarroll; Jaume Mora; Brian Crompton; Robert Onofrio; Melissa Parkin; Wendy Winckler; Kristin Ardlie; Stacey B Gabriel; Charles W M Roberts; Jaclyn A Biegel; Kimberly Stegmaier; Adam J Bass; Levi A Garraway; Matthew Meyerson; Todd R Golub; Dmitry A Gordenin; Shamil Sunyaev; Eric S Lander; Gad Getz

doi:10.1038/nature12213

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Mutational heterogeneity in cancer and the search for new cancer-associated genes

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Mutational heterogeneity in cancer and the search for new cancer-associated genes

Michael S Lawrence, Petar Stojanov, Paz Polak, Gregory V Kryukov, Kristian Cibulskis, Andrey Sivachenko, Scott L Carter, Chip Stewart, Craig H Mermel, Steven A Roberts, …

Nature (London), Vol.499(7457), pp.214-218

07/11/2013

DOI: https://doi.org/10.1038/nature12213

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https://hdl.handle.net/2376/107731

PMID: 23770567

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Abstract

Lung Neoplasms - genetics

Oncogenes - genetics

Gene Expression

Reproducibility of Results

Humans

Mutation Rate

Neoplasms - classification

False Positive Reactions

Mutation - genetics

Genetic Heterogeneity

Genome, Human - genetics

Artifacts

Exome - genetics

Sample Size

Neoplasms - genetics

Neoplasms, Squamous Cell - genetics

DNA Replication Timing

Neoplasms - pathology

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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Title: Mutational heterogeneity in cancer and the search for new cancer-associated genes
Creators: Michael S Lawrence - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Petar Stojanov - Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Paz Polak - Brigham and Women's Hospital, Boston, MA, 02115, USA
Gregory V Kryukov - Brigham and Women's Hospital, Boston, MA, 02115, USA
Kristian Cibulskis - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Andrey Sivachenko - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Scott L Carter - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Chip Stewart - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Craig H Mermel - Massachusetts General Hospital, Boston, MA, 02114, USA
Steven A Roberts - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA
Adam Kiezun - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Peter S Hammerman - Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Aaron McKenna - Genome Sciences, University of Washington, Seattle, WA 98195
Yotam Drier - Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100, Israel
Lihua Zou - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Alex H Ramos - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Trevor J Pugh - Harvard Medical School, Boston, MA, 02115, USA
Nicolas Stransky - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Elena Helman - Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
Jaegil Kim - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Carrie Sougnez - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Lauren Ambrogio - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Elizabeth Nickerson - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Erica Shefler - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Maria L Cortés - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Daniel Auclair - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Gordon Saksena - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Douglas Voet - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Michael Noble - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Daniel DiCara - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Pei Lin - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Lee Lichtenstein - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
David I Heiman - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Timothy Fennell - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Marcin Imielinski - Massachusetts General Hospital, Boston, MA, 02114, USA
Bryan Hernandez - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Eran Hodis - Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Sylvan Baca - Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Austin M Dulak - Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Jens Lohr - Dana-Farber Cancer Institute, Boston, MA, 02215, USA
Dan-Avi Landau - Yale Cancer Center, Department of Hematology, New Haven, CT
Catherine J Wu - Harvard Medical School, Boston, MA, 02115, USA
Jorge Melendez-Zajgla - Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico
Alfredo Hidalgo-Miranda - Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico
Amnon Koren - Harvard Medical School, Boston, MA, 02115, USA
Steven A McCarroll - Harvard Medical School, Boston, MA, 02115, USA
Jaume Mora - Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain
Brian Crompton - Boston Children's Hospital, Boston, MA, 02115, USA
Robert Onofrio - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Melissa Parkin - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Wendy Winckler - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Kristin Ardlie - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Stacey B Gabriel - The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA
Charles W M Roberts - Boston Children's Hospital, Boston, MA, 02115, USA
Jaclyn A Biegel - Children's Hospital, Philadelphia, PA, 19104, USA
Kimberly Stegmaier - Boston Children's Hospital, Boston, MA, 02115, USA
Adam J Bass - Harvard Medical School, Boston, MA, 02115, USA
Levi A Garraway - Harvard Medical School, Boston, MA, 02115, USA
Matthew Meyerson - Harvard Medical School, Boston, MA, 02115, USA
Todd R Golub - Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA
Dmitry A Gordenin - Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA
Shamil Sunyaev - Brigham and Women's Hospital, Boston, MA, 02115, USA
Eric S Lander - Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
Gad Getz - Massachusetts General Hospital, Boston, MA, 02114, USA
Publication Details: Nature (London), Vol.499(7457), pp.214-218
Academic Unit: Molecular Biosciences, School of
Publisher: England
Grant note: Howard Hughes Medical Institute T32 CA009172 / NCI NIH HHS Z01 ES065073 / Intramural NIH HHS T32 GM007753 / NIGMS NIH HHS T32 CA009216 / NCI NIH HHS U54 HG003067 / NHGRI NIH HHS U24 CA143845 / NCI NIH HHS
Identifiers: 99900547204401842
Language: English
Resource Type: Journal article