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PMID: 23770567 Published · ppublish English Journal Article Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't

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

Nature ·Vol. 499 ·No. 7457 ·2013-07-11 ·Pages 214-218

Lawrence MS, Stojanov P, Polak P, Kryukov GV, Cibulskis K, Sivachenko A, Carter SL, Stewart C, Mermel CH, Roberts SA, Kiezun A, Hammerman PS, McKenna A, Drier Y, Zou L, Ramos AH, Pugh TJ, Stransky N, Helman E, Kim J, Sougnez C, Ambrogio L, Nickerson E, Shefler E, Cortés ML, Auclair D, Saksena G, Voet D, Noble M, DiCara D, Lin P, Lichtenstein L, Heiman DI, Fennell T, Imielinski M, Hernandez B, Hodis E, Baca S, Dulak AM, Lohr J, Landau DA, Wu CJ, Melendez-Zajgla J, Hidalgo-Miranda A, Koren A, McCarroll SA, Mora J, Crompton B, Onofrio R, Parkin M, Winckler W, Ardlie K, Gabriel SB, Roberts CWM, Biegel JA, Stegmaier K, Bass AJ, Garraway LA, Meyerson M, Golub TR, Gordenin DA, Sunyaev S, Lander ES, Getz G

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.

MeSH Terms
Artifacts DNA Replication Timing Exome/genetics False Positive Reactions Gene Expression Genetic Heterogeneity Genome, Human/genetics Humans Lung Neoplasms/genetics Mutation/genetics Mutation Rate Neoplasms/classification,genetics,pathology Neoplasms, Squamous Cell/genetics Oncogenes/genetics Reproducibility of Results Sample Size
Authors & Affiliations
64 authors, click to expand affiliations / ORCID
Lawrence Michael S
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Stojanov Petar
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Polak Paz
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Brigham and Women's Hospital, Boston, MA, 02115, USA.
Kryukov Gregory V
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Brigham and Women's Hospital, Boston, MA, 02115, USA.
Cibulskis Kristian
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Sivachenko Andrey
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Carter Scott L
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Stewart Chip
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Mermel Craig H
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Massachusetts General Hospital, Boston, MA, 02114, USA.
Roberts Steven A
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
Kiezun Adam
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Hammerman Peter S
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
McKenna Aaron
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Genome Sciences, University of Washington, Seattle, WA 98195.
Drier Yotam
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Massachusetts General Hospital, Boston, MA, 02114, USA. | Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA. | Department of Physics of Complex Systems, Weizmann Institute of Science, Rehovot, 76100, Israel.
Zou Lihua
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Ramos Alex H
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Pugh Trevor J
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA.
Stransky Nicolas
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Helman Elena
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Kim Jaegil
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Sougnez Carrie
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Ambrogio Lauren
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Nickerson Elizabeth
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Shefler Erica
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Cortés Maria L
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Auclair Daniel
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Saksena Gordon
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Voet Douglas
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Noble Michael
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
DiCara Daniel
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Lin Pei
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Lichtenstein Lee
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Heiman David I
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Fennell Timothy
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Imielinski Marcin
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Massachusetts General Hospital, Boston, MA, 02114, USA.
Hernandez Bryan
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Hodis Eran
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Baca Sylvan
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Dulak Austin M
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Lohr Jens
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
Landau Dan-Avi
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Yale Cancer Center, Department of Hematology, New Haven, CT.
Wu Catherine J
Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA.
Melendez-Zajgla Jorge
Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico.
Hidalgo-Miranda Alfredo
Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico.
Koren Amnon
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA.
McCarroll Steven A
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA.
Mora Jaume
Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
Crompton Brian
Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Boston Children's Hospital, Boston, MA, 02115, USA.
Onofrio Robert
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Parkin Melissa
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Winckler Wendy
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Ardlie Kristin
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Gabriel Stacey B
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Roberts Charles W M
Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Boston Children's Hospital, Boston, MA, 02115, USA.
Biegel Jaclyn A
Children's Hospital, Philadelphia, PA, 19104, USA.
Stegmaier Kimberly
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Boston Children's Hospital, Boston, MA, 02115, USA.
Bass Adam J
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA.
Garraway Levi A
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA.
Meyerson Matthew
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA.
Golub Todd R
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Dana-Farber Cancer Institute, Boston, MA, 02215, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Howard Hughes Medical Institute, Chevy Chase, MD, 20815, USA.
Gordenin Dmitry A
Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
Sunyaev Shamil
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Brigham and Women's Hospital, Boston, MA, 02115, USA.
Lander Eric S
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Harvard Medical School, Boston, MA, 02115, USA. | Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
Getz Gad
The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA. | Massachusetts General Hospital, Boston, MA, 02114, USA.
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Article Info
Journal
Nature
Abbr.
Nature
ISSN
1476-4687
DOI
10.1038/nature12213
Published
2013-07-11
Epub
2013-00-16
Pages
214-218
Language
English
Region
England
NLM ID
0410462
PMCID
PMC3919509
Subset
IM
Grants
NHGRI NIH HHS · U54 HG003067 · United States
Intramural NIH HHS · Z01 ES065073 · United States
Howard Hughes Medical Institute · United States
NCI NIH HHS · U24 CA143845 · United States
NIGMS NIH HHS · T32 GM007753 · United States
NCI NIH HHS · T32 CA009172 · United States
NCI NIH HHS · T32 CA009216 · United States
Corrections
CommentIn
PMID: 24104755
External Links
PubMed source DOI: 10.1038/nature12213 PMC Full Text View journal details
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