ArticleNature2013
Mutational heterogeneity in cancer and the search for new cancer-associated genes.
3 registry-linked trialsOpen access · greenAbstract read
In one paragraph
Article in Nature, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to 3 registered trials, which are not on this map. Cited by 3,267 papers, 2 of them syntheses that pooled it.
0numbers the graph read from it
0cells of the map it votes in
3,267citing papers in PubMed, 2 pooled it
146.7field-weighted citation impact, top 1% of its field
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
A Randomized Phase II Study Evaluating Pembrolizumab vs Topotecan in the Second-Line Treatment of Patients With Small Cell Lung Cancer
Cabozantinib Plus Durvalumab in Patients With Advanced and Chemotherapy-treated Bladder Carcinoma, of Urothelial and Non-urothelial Histology: an Open-label, Single-centre, Phase 2, Single-arm Proof-of-concept Trial: ARCADIA Study
Molecular Classification in Relation to Prevention of Endometrial Cancer Recurrence and Lifestyle Factors
Who cites it
3,267 citing papers in PubMed, 2 syntheses or guidelines pooled it, 5,657 citations in OpenAlex.
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3,207 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
64 authors at 12 institutions in 4 countries.
Michael S Lawrence *The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Petar Stojanov *The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Paz Polak *The Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Gregory V KryukovThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Kristian CibulskisThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Andrey SivachenkoThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Scott L CarterThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Chip StewartThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Craig H MermelThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Steven A RobertsLaboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
Adam KiezunThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Peter S HammermanThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Aaron McKennaThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Yotam DrierThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Lihua ZouThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Alex H RamosThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Trevor J PughThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Nicolas StranskyThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Elena HelmanThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Jaegil KimThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Carrie SougnezThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Lauren AmbrogioThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Elizabeth NickersonThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Erica SheflerThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Maria L CortésThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Daniel AuclairThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Gordon SaksenaThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Douglas VoetThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Michael NobleThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Daniel DiCaraThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Pei LinThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Lee LichtensteinThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
David I HeimanThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Timothy FennellThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Marcin ImielinskiThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Bryan HernandezThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Eran HodisThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Sylvan BacaThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Austin M DulakThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Jens LohrThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Dan-Avi LandauThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Catherine J WuDana-Farber Cancer Institute, Boston, MA, 02215, USA.
Jorge Melendez-ZajglaInstituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico.
Alfredo Hidalgo-MirandaInstituto Nacional de Medicina Genómica, Mexico City, 14610, Mexico.
Amnon KorenThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Steven A McCarrollThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Jaume MoraDepartment of Pediatric Oncology, Hospital Sant Joan de Déu, Barcelona, Spain.
Brian CromptonDana-Farber Cancer Institute, Boston, MA, 02215, USA.
Robert OnofrioThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Melissa ParkinThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Wendy WincklerThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Kristin ArdlieThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Stacey B GabrielThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Charles W M RobertsDana-Farber Cancer Institute, Boston, MA, 02215, USA.
Jaclyn A BiegelChildren's Hospital, Philadelphia, PA, 19104, USA.
Kimberly StegmaierThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Adam J BassThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Levi A GarrawayThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Matthew MeyersonThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Todd R GolubThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Dmitry A GordeninLaboratory of Molecular Genetics, National Institute of Environmental Health Sciences, NIH, DHHS, Durham, NC 27709, USA.
Shamil SunyaevThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Eric S LanderThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Gad GetzThe Broad Institute of MIT and Harvard, Cambridge, MA, 02141, USA.
Broad Institute · USDana-Farber Cancer Institute · USHarvard University · USMassachusetts General Hospital · USNational Institute of Environmental Health Sciences · USNational Institute of Genomic Medicine · MXBoston Children's Hospital · USBrigham and Women's Hospital · USChildren's Hospital of Philadelphia · USHospital Sant Joan de Déu Barcelona · ESHoward Hughes Medical Institute · USMassachusetts Institute of Technology · US
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MMedical Scientist Training ProgramT32GM007753 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI WALENSKY, LOREN DAVID · 1985 to 2021
$50.0MPhysician Scientist Training in Cancer ResearchT32CA009172 · NCI · DANA-FARBER CANCER INSTITUTE · PI Jennifer R Brown, James A. DeCaprio · 1985 to 2026
$17.1MThe Cancer Genome Atlas Data Analysis CenterU24CA143845 · NCI · BROAD INSTITUTE, INC. · PI CHIN, LYNDA, GETZ, GAD A · 2009 to 2016
$16.0MMOLECULAR IMMUNOLOGY AND TUMOR BIOLOGYT32CA009216 · NCI · MASSACHUSETTS GENERAL HOSPITAL · PI David Michael Langenau · 1985 to 2026
$10.6MMechanisms Of Genome InstabilityZIAES065073 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI RESNICK, MICHAEL A · 2009 to 2014
$9.3MMOLECULAR MECHANISMS OF DNA REPAIR AND RECOMBINATION IN YEASTZ01ES065073 · NIEHS · NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES · PI RESNICK, MICHAEL A · 1991 to 2008
$2.8MHoward Hughes Medical InstituteIntramural NIH HHS Z01 ES065073NCI NIH HHS T32 CA009172NCI NIH HHS T32 CA009216NCI NIH HHS U24 CA143845NHGRI NIH HHS U54 HG003067NIGMS NIH HHS T32 GM007753
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.
Indexed as
Genetic HeterogeneityArtifactsDNA Replication TimingExomeFalse Positive ReactionsGene ExpressionGenome, HumanHumansLung NeoplasmsMutationMutation RateNeoplasmsNeoplasms, Squamous CellOncogenesReproducibility of ResultsSample Size
Identifiers
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.