ArticleNature communications2015
Patterns and functional implications of rare germline variants across 12 cancer types.
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In one paragraph
Article in Nature communications, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 190 papers, 5 of them syntheses that pooled it.
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190citing papers in PubMed, 5 pooled it
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Who cites it
190 citing papers in PubMed, 5 syntheses or guidelines pooled it, 309 citations in OpenAlex.
- Germline and Somatic Genetic Variants in the p53 Pathway Interact to Affect Cancer Risk, Progression, and Drug Response.Cancer research · 2021Pooled it
- A Systematic Literature Review of Whole Exome and Genome Sequencing Population Studies of Genetic Susceptibility to Cancer.Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology · 2020Pooled it
- Summary ofGenes · 2020Pooled it
- BRIP1, RAD51C, and RAD51D mutations are associated with high susceptibility to ovarian cancer: mutation prevalence and precise risk estimates based on a pooled analysis of ~30,000 cases.Journal of ovarian research · 2020Pooled it
- A systematic review of the prevalence of DNA damage response gene mutations in prostate cancer.International journal of oncology · 2019Pooled it
- [Genetic diagnostics].Pathologie (Heidelberg, Germany) · 2026Review
- Landscape of somatic genetic alterations and PAM50 intrinsic subtypes in breast cancer associated with germline pathogenic variants in DNA-repair genes.Journal of the National Cancer Institute · 2026Article
- High-throughput evaluation of in vitro CRISPR activities enables optimized large-scale multiplex enrichment of rare variants.Nature biomedical engineering · 2026Article
- Lung squamous cell carcinoma with germline EGFR P848L mutation: a case report.Annals of medicine and surgery (2012) · 2026Article
- Risk and Survival Outcomes of Secondary Primary Malignancies in Chinese Lymphoma Patients in the Era of Modern Targeted Therapies: A Single-Center Retrospective Cohort Study.Blood and lymphatic cancer : targets and therapy · 2026Article
- Differences of clinical features, prognosis and genetic mutations in Chinese patients with malignant melanoma and additional primary tumours.Annals of medicine · 2025Article
- Germline variant spectrum of hereditary cancer susceptibility genes in a Chinese cohort.Human genomics · 2025Article
- Article
- Functional characterization of BRCA1 variants of unknown significance using homologous recombination repair assays.Breast cancer research : BCR · 2025Article
- The landscape of germline variants in breast and colorectal cancer susceptibility genes in patients with pituitary tumours.Journal of neuro-oncology · 2025Article
- The role of multi-organ cancer predisposition genes in the risk of inherited and histologically diverse gastric cancer.EBioMedicine · 2025Article
- Article
- The Prognostic and Predictive Roles of Ataxia-Telangiectasia Mutated (ATM) Expression in Patients with Metastatic Non-Small-Cell Lung Cancer Receiving Pembrolizumab Monotherapy Alone or in Combination with Chemotherapy.Diagnostics (Basel, Switzerland) · 2025Article
- Pathogenic germline variants in Chinese pancreatic adenocarcinoma patients.Nature communications · 2025Article
- Comprehensive genomic profiling of Chinese lung cancer characterizes germline-somatic mutation interactions influencing cancer risk.Journal of translational medicine · 2025Article
130 more citing papers are in PubMed but not listed here.
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
43 authors at 5 institutions in 1 country.
Charles LuThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Mingchao XieThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Michael C WendlThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Jiayin WangThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Michael D McLellanThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Mark D M LeisersonDepartment of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
Kuan-Lin HuangThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Matthew A WyczalkowskiThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Reyka JayasingheThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.ORCID http://orcid.org/0000-0003-2368-4890
Tapahsama BanerjeeThe Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Jie NingThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Piyush TripathiDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Qunyuan ZhangThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Beifang NiuThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Kai YeThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.ORCID http://orcid.org/0000-0002-2851-6741
Heather K SchmidtThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Robert S FultonThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Joshua F McMichaelThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Prag BatraThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.ORCID http://orcid.org/0000-0003-3482-0923
Cyriac KandothThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Maheetha BharadwajThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Daniel C KoboldtThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Christopher A MillerThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.ORCID http://orcid.org/0000-0003-4266-6700
Krishna L KanchiThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
James M EldredThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
David E LarsonThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.ORCID http://orcid.org/0000-0001-7934-5906
John S WelchDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Ming YouDepartment of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
Bradley A OzenbergerThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.ORCID http://orcid.org/0000-0002-2276-7013
Ramaswamy GovindanDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Matthew J WalterDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Matthew J EllisDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Elaine R MardisThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Timothy A GraubertDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
John F DipersioDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Timothy J LeyThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Richard K WilsonThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Paul J GoodfellowThe Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Benjamin J RaphaelDepartment of Computer Science, Brown University, Providence, Rhode Island 02912, USA.
Feng ChenDepartment of Medicine, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
Kimberly J JohnsonBrown School Master of Public Health Program, Washington University in St Louis, St Louis, Missouri 63130, USA.
Jeffrey D ParvinThe Ohio State University Comprehensive Cancer Center, Columbus, Ohio 43210, USA.
Li DingThe McDonnell Genome Institute, Washington University in St. Louis, Forest Park Avenue, Campus Box 8501, St Louis, Missouri 63108, USA.
James S. McDonnell Foundation · USWashington University in St. Louis · USThe Ohio State University · USBrown University · USMedical College of Wisconsin · US
Funding
Large Scale Genome SequencingU54HG003079 · NHGRI · WASHINGTON UNIVERSITY · PI DUTCHER, SUSAN K · 2004 to 2016
$445.7MTranslational Therapeutics Research Program (TT)P30CA016058 · NCI · OHIO STATE UNIVERSITY · PI Tasleem J Padamsee · 1985 to 2026
$132.3MSpecimen Acquistition and Expression ProfilingP01CA101937 · NCI · WASHINGTON UNIVERSITY · PI LEY, TIMOTHY J. · 2003 to 2023
$58.8MTRAINING PROGRAM IN CELLULAR AND MOLECULAR BIOLOGYT32GM007067 · NIGMS · WASHINGTON UNIVERSITY · PI TRUE-KROB, HEATHER L · 1985 to 2020
$20.4MMolecular Pathogenesis of Acute Myeloid LeukemiaR35CA197561 · NCI · WASHINGTON UNIVERSITY · PI Timothy J. Ley · 2015 to 2026
$11.0MINSTITUTIONAL TRAINING GRANT IN GENOMIC SCIENCET32HG000045 · NHGRI · WASHINGTON UNIVERSITY · PI MICHAEL R BRENT, Barak A Cohen · 1997 to 2026
$8.4MA Turnkey System for High-throughput Variant Discovery and InterpretationU01HG006517 · NHGRI · WASHINGTON UNIVERSITY · PI DING, LI · 2012 to 2015
$3.0MInformatics methods for identifying breast cancer control genes and proteinsR01CA141090 · NCI · OHIO STATE UNIVERSITY · PI CATALYUREK, UMIT V., HUANG, KUN · 2009 to 2013
$2.2MNFAT SIGNALING IN GLOMERULOSCLEROSISR01DK087960 · NIDDK · WASHINGTON UNIVERSITY · PI CHEN, FENG · 2010 to 2014
$1.6MCANCER SUSCEPTIBILITY VARIANT DISCOVERY IN HIGH THROUGHPUT SEQUENCING DATAR01CA180006 · NCI · WASHINGTON UNIVERSITY · PI DING, LI · 2013 to 2016
$1.1MComputational Characterization of Genetic HeterogeneityR01HG007069 · NHGRI · PRINCETON UNIVERSITY · PI RAPHAEL, BENJAMIN · 2013 to 2015
$1.1MVIRUS DISCOVERY AND CHARACTERIZATION IN LARGE-SCALE CANCER SEQUENCING DATAR01CA178383 · NCI · WASHINGTON UNIVERSITY · PI DING, LI · 2014 to 2016
$772kNCI NIH HHS P01 CA101937NCI NIH HHS P01CA101937NCI NIH HHS P30 CA016058NCI NIH HHS R01 CA141090NCI NIH HHS R01CA141090NCI NIH HHS R01 CA178383NCI NIH HHS R01CA178383NCI NIH HHS R01 CA180006NCI NIH HHS R35 CA197561NHGRI NIH HHS R01 HG007069NHGRI NIH HHS R01HG007069NHGRI NIH HHS T32 HG000045NHGRI NIH HHS U01 HG006517NHGRI NIH HHS U01HG006517NHGRI NIH HHS U54 HG003079NHGRI NIH HHS U54HG003079NIDDK NIH HHS R01 DK087960NIDDK NIH HHS R01DK087960NIGMS NIH HHS GM 007067NIGMS NIH HHS T32 GM007067
Abstract
Large-scale cancer sequencing data enable discovery of rare germline cancer susceptibility variants. Here we systematically analyse 4,034 cases from The Cancer Genome Atlas cancer cases representing 12 cancer types. We find that the frequency of rare germline truncations in 114 cancer-susceptibility-associated genes varies widely, from 4% (acute myeloid leukaemia (AML)) to 19% (ovarian cancer), with a notably high frequency of 11% in stomach cancer. Burden testing identifies 13 cancer genes with significant enrichment of rare truncations, some associated with specific cancers (for example, RAD51C, PALB2 and MSH6 in AML, stomach and endometrial cancers, respectively). Significant, tumour-specific loss of heterozygosity occurs in nine genes (ATM, BAP1, BRCA1/2, BRIP1, FANCM, PALB2 and RAD51C/D). Moreover, our homology-directed repair assay of 68 BRCA1 rare missense variants supports the utility of allelic enrichment analysis for characterizing variants of unknown significance. The scale of this analysis and the somatic-germline integration enable the detection of rare variants that may affect individual susceptibility to tumour development, a critical step toward precision medicine.
Indexed as
Genetic VariationAdolescentAdultAgedAged, 80 and overChildFemaleGenetic Predisposition to DiseaseHumansMaleMiddle AgedMutationNeoplasmsUnited StatesYoung Adult
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