ArticleCell2018
Pathogenic Germline Variants in 10,389 Adult Cancers.
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Article in Cell, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 520 papers.
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520citing papers in PubMed
38.0field-weighted citation impact, top 1% of its field
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Who cites it
520 citing papers in PubMed, 866 citations in OpenAlex.
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- Pervasive chromosomal instability drives the karyotypic evolution of hypodiploid tumours.Genome medicine · 2026Article
460 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
48 authors at 13 institutions in 4 countries.
Kuan-Lin HuangDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
R Jay MashlDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Yige WuDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Deborah I RitterBaylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.
Jiayin WangSchool of Management, Xi'an Jiaotong University, Xi'an, Shanxi, China.
Clara OhDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Marta PaczkowskaComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Sheila ReynoldsInstitute for Systems Biology, Seattle, WA 98109, USA.
Matthew A WyczalkowskiDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Ninad OakDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Adam D ScottDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Michal KrassowskiComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Andrew D CherniackThe Broad Institute, Cambridge, MA 02142, USA.
Kathleen E HoulahanComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Reyka JayasingheDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Liang-Bo WangDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Daniel Cui ZhouDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Di LiuDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Song CaoDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Young Won KimDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Amanda KoireDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Joshua F McMichaelMcDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Vishwanathan HucthagowderClinical Cytogenetics at Molecular Pathology Laboratory Network, Inc., Maryville, TN 37804, USA.
Tae-Beom KimDepartments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Abigail HahnInstitute for Systems Biology, Seattle, WA 98109, USA.
Chen WangDepartment of Health Sciences Research and Department of Obstetrics and Gynecology, Mayo Clinic College of Medicine, Rochester, MN 55905 USA.
Michael D McLellanMcDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Fahd Al-MullaDasman Diabetes Institute and Molecular Pathology Laboratory, Kuwait University, Kuwait.
Kimberly J JohnsonBrown School Master of Public Health Program, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Cancer Genome Atlas Research Network
Olivier LichtargeDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Paul C BoutrosComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Benjamin RaphaelLewis-Sigler Institute, Princeton University, Princeton, NJ 08544, USA.
Alexander J LazarDepartments of Pathology and Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Wei ZhangDepartment of Cancer Biology and Center for Genomics and Personalized Medicine Research, Wake Forest School of Medicine, Winston Salem, NC 27157 USA.
Michael C WendlMcDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, Saint Louis, MO 63108, USA; Department of Mathematics, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Ramaswamy GovindanDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Sanjay JainDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA.
David WheelerDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Shashikant KulkarniDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Baylor Genetics, Houston, TX 77021, USA.
John F DipersioDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University in St. Louis, Saint Louis, MO 63108, USA.
Jüri ReimandComputational Biology Program, Ontario Institute for Cancer Research, Toronto, Ontario, Canada; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Funda Meric-BernstamDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ken ChenDepartments of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Ilya ShmulevichInstitute for Systems Biology, Seattle, WA 98109, USA.
Sharon E PlonDepartment of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA.
Feng ChenDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University in St. Louis, Saint Louis, MO 63108, USA. Electronic address: fchen@wustl.edu.
Li DingDepartment of Medicine, Washington University in St. Louis, Saint Louis, MO 63108, USA; McDonnell Genome Institute, Washington University in St. Louis, Saint Louis, MO 63108, USA; Department of Genetics, Washington University in St. Louis, Saint Louis, MO 63108, USA; Siteman Cancer Center, Washington University in St. Louis, Saint Louis, MO 63108, USA. Electronic address: lding@wustl.edu.
James S. McDonnell Foundation · USWashington University in St. Louis · USBaylor College of Medicine · USOntario Institute for Cancer Research · CAThe University of Texas MD Anderson Cancer Center · USWake Forest University · USInstitute for Systems Biology · USMayo Clinic · USBroad Institute · USMolecular Pathology Laboratory Network (United States) · USPrinceton University · USXi'an Jiaotong University · CNKuwait University · KW
Funding
Large Scale Sequencing and Analysis of GenomesU54HG003067 · NHGRI · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · PI GABRIEL, STACEY, LANDER, ERIC S · 2004 to 2015
$568.6MLarge Scale Genome SequencingU54HG003079 · NHGRI · WASHINGTON UNIVERSITY · PI DUTCHER, SUSAN K · 2004 to 2016
$445.7MThe Human Genome Sequencing CenterU54HG003273 · NHGRI · BAYLOR COLLEGE OF MEDICINE · PI GIBBS, RICHARD A · 2004 to 2015
$341.3MGene Expression Patterns in Human Tumors Identified Using Transcript SequencingU24CA143848 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI HAYES, DAVID N, PEROU, CHARLES M · 2009 to 2016
$20.8MGenome Characterization Center (GCC)U24CA143867 · NCI · BROAD INSTITUTE, INC. · PI GABRIEL, STACEY, MEYERSON, MATTHEW L. · 2009 to 2016
$17.0MThe Cancer Genome Atlas Data Analysis CenterU24CA143845 · NCI · BROAD INSTITUTE, INC. · PI CHIN, LYNDA, GETZ, GAD A · 2009 to 2016
$16.0MHarvard Genome Characterization CenterU24CA144025 · NCI · BRIGHAM AND WOMEN'S HOSPITAL · PI KUCHERLAPATI, RAJU S. · 2009 to 2016
$14.0MThe USC-JHU Cancer Epigenome Characterization CenterU24CA143882 · NCI · UNIVERSITY OF SOUTHERN CALIFORNIA · PI BAYLIN, STEPHEN B., WEISENBERGER, DANIEL JOSEPH · 2009 to 2016
$13.3MMSKCC Center for Translational Cancer Genomic AnalysisU24CA143840 · NCI · SLOAN-KETTERING INST CAN RESEARCH · PI LADANYI, MARC, SANDER, CHRIS · 2009 to 2016
$11.5MCancer transcriptome characterization using massively parallel DNA sequencingU24CA143866 · NCI · BRITISH COLUMBIA CANCER AGENCY · PI MARRA, MARCO ANTONIO · 2009 to 2015
$10.9MIntegrative Pipeline for Analysis & Translational Application of TCGA Data (GDAC)U24CA143883 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI AKBANI, REHAN, MILLS, GORDON B. · 2009 to 2016
$10.6MCenter for Systems Analysis of the Cancer RegulomeU24CA143835 · NCI · INSTITUTE FOR SYSTEMS BIOLOGY · PI SHMULEVICH, ILYA · 2009 to 2016
$10.6MNCI NIH HHS R01 CA163722NCI NIH HHS R01 CA178383NCI NIH HHS R01 CA180006NCI NIH HHS U24 CA143799NCI NIH HHS U24 CA143835NCI NIH HHS U24 CA143840NCI NIH HHS U24 CA143843NCI NIH HHS U24 CA143845NCI NIH HHS U24 CA143848NCI NIH HHS U24 CA143858NCI NIH HHS U24 CA143866NCI NIH HHS U24 CA143867NCI NIH HHS U24 CA143882NCI NIH HHS U24 CA143883NCI NIH HHS U24 CA144025NCI NIH HHS U24 CA210949NCI NIH HHS U24 CA210950NCI NIH HHS U24 CA210957NCI NIH HHS U24 CA210969NCI NIH HHS U24 CA210972NCI NIH HHS U24 CA210988NCI NIH HHS U24 CA210990NCI NIH HHS U24 CA211000NCI NIH HHS U24 CA211006NHGRI NIH HHS R01 HG009711NHGRI NIH HHS U54 HG003067NHGRI NIH HHS U54 HG003079NHGRI NIH HHS U54 HG003273NIDDK NIH HHS R01 DK102520NIGMS NIH HHS K12 GM084897NIGMS NIH HHS R01 GM079656
Abstract
We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.
Indexed as
Databases, GeneticDNA Copy Number VariationsGene DeletionGene FrequencyGenetic Predisposition to DiseaseGenotypeGerm CellsGerm-Line MutationHumansLoss of HeterozygosityMutation, MissenseNeoplasmsPolymorphism, Single NucleotideProto-Oncogene Proteins c-metProto-Oncogene Proteins c-retTumor Suppressor ProteinsProto-Oncogene Proteins c-metProto-Oncogene Proteins c-retTumor Suppressor Proteinscancer predispositiongermline and somatic genomesLOHvariant pathogenicity
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