title: Mutational heterogeneity in cancer and the search for new cancer-associated genes.
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.
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Petar
authors.initials: P
authors.lastname: Stojanov
authors.affiliation: 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.
authors.forename: Paz
authors.initials: P
authors.lastname: Polak
authors.affiliation: 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.
authors.forename: Gregory V
authors.initials: GV
authors.lastname: Kryukov
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Kristian
authors.initials: K
authors.lastname: Cibulskis
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Andrey
authors.initials: A
authors.lastname: Sivachenko
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Scott L
authors.initials: SL
authors.lastname: Carter
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Chip
authors.initials: C
authors.lastname: Stewart
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Roberts
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Kiezun
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Genome Sciences, University of Washington, Seattle, WA 98195.
authors.forename: Aaron
authors.initials: A
authors.lastname: McKenna
authors.affiliation: 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.
authors.forename: Yotam
authors.initials: Y
authors.lastname: Drier
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Lihua
authors.initials: L
authors.lastname: Zou
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Alex H
authors.initials: AH
authors.lastname: Ramos
authors.affiliation: 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.
authors.forename: Trevor J
authors.initials: TJ
authors.lastname: Pugh
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Stransky
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Helman
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Jaegil
authors.initials: J
authors.lastname: Kim
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Carrie
authors.initials: C
authors.lastname: Sougnez
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Ambrogio
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Nickerson
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Erica
authors.initials: E
authors.lastname: Shefler
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Cortés
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Auclair
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Gordon
authors.initials: G
authors.lastname: Saksena
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Douglas
authors.initials: D
authors.lastname: Voet
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Noble
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: DiCara
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Pei
authors.initials: P
authors.lastname: Lin
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Lee
authors.initials: L
authors.lastname: Lichtenstein
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: David I
authors.initials: DI
authors.lastname: Heiman
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: Fennell
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Massachusetts General Hospital, Boston, MA, 02114, USA.
authors.forename: Marcin
authors.initials: M
authors.lastname: Imielinski
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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authors.initials: B
authors.lastname: Hernandez
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Eran
authors.initials: E
authors.lastname: Hodis
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Sylvan
authors.initials: S
authors.lastname: Baca
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
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authors.initials: AM
authors.lastname: Dulak
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
authors.forename: Jens
authors.initials: J
authors.lastname: Lohr
authors.affiliation: 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.
authors.forename: Dan-Avi
authors.initials: DA
authors.lastname: Landau
authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, 02215, USA.|Harvard Medical School, Boston, MA, 02115, USA.
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authors.initials: CJ
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authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico.
authors.forename: Jorge
authors.initials: J
authors.lastname: Melendez-Zajgla
authors.affiliation: Instituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico.
authors.forename: Alfredo
authors.initials: A
authors.lastname: Hidalgo-Miranda
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Harvard Medical School, Boston, MA, 02115, USA.
authors.forename: Amnon
authors.initials: A
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authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Harvard Medical School, Boston, MA, 02115, USA.
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authors.initials: SA
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authors.affiliation: Department of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
authors.forename: Jaume
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authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, 02215, USA.|Boston Children's Hospital, Boston, MA, 02115, USA.
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authors.lastname: Crompton
authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
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authors.initials: SB
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authors.affiliation: Dana-Farber Cancer Institute, Boston, MA, 02215, USA.|Harvard Medical School, Boston, MA, 02115, USA.|Boston Children's Hospital, Boston, MA, 02115, USA.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.affiliation: 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.
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authors.initials: M
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authors.affiliation: 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.
authors.forename: Todd R
authors.initials: TR
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authors.affiliation: Laboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
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authors.initials: DA
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authors.affiliation: 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.
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authors.initials: S
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authors.affiliation: 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.
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authors.initials: ES
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authors.affiliation: The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.|Massachusetts General Hospital, Boston, MA, 02114, USA.
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mesh_terms: D016477:Artifacts; D042522:DNA Replication Timing; D059472:Exome / Q000235:genetics; D005189:False Positive Reactions; D015870:Gene Expression; D018740:Genetic Heterogeneity; D015894:Genome, Human / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics; D009154:Mutation / Q000235:genetics*; D059645:Mutation Rate; D009369:Neoplasms / Q000145:classification / Q000235:genetics* / Q000473:pathology; D018307:Neoplasms, Squamous Cell / Q000235:genetics; D009857:Oncogenes / Q000235:genetics*; D015203:Reproducibility of Results; D018401:Sample Size