Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes
Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes
Abstract Discovery of cancer drivers has traditionally focused on the identification of protein-coding genes. Here we present a comprehensive analysis of putative cancer driver mutations in both protein-coding and non-coding genomic regions across >2,500 whole cancer genomes from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. We developed a statistically rigorous strategy for combining significance levels from multiple driver discovery methods and demonstrate that the integrated results overcome limitations of individual methods. We combined this strategy with careful filtering and applied it to protein-coding genes, promoters, untranslated regions (UTRs), distal enhancers and non-coding RNAs. These analyses redefine the landscape of non-coding driver mutations in cancer genomes, confirming a few previously reported elements and raising doubts about others, while identifying novel candidate elements across 27 cancer types. Novel recurrent events were found in the promoters or 5’UTRs of TP53, RFTN1, RNF34, and MTG2, in the 3’UTRs of NFKBIZ and TOB1, and in the non-coding RNA RMRP. We provide evidence that the previously reported non-coding RNAs NEAT1 and MALAT1 may be subject to a localized mutational process. Perhaps the most striking finding is the relative paucity of point mutations driving cancer in non-coding genes and regulatory elements. Though we have limited power to discover infrequent non-coding drivers in individual cohorts, combined analysis of promoters of known cancer genes show little excess of mutations beyond TERT.
Martincorena I?igo、Johnson Todd A.、Pedersen Jakob Skou、Abascal Federico、Tiao Grace、Hess Julian M.、Kahraman Abdullah、Park Keunchil、Rubin Mark A.、Reimand J¨1ri、Madsen Tobias、Kim Jaegil、Shuai Shimin、Lanz¨?s Andr¨|s、Amin Samirkumar B.、Diamanti Klev、Gonzalez-Perez Abel、Guo Qianyun、Isaev Keren、Juul Malene、Komorowski Jan、Kumar Sushant、Lochovsky Lucas、Tamborero David、Wadi Lina、Chakravarty Dimple、Chan Calvin W.Y.、Hamilton Mark P.、Hong Chen、Wadelius Claes、Gerstein Mark B.、Khurana Ekta、Tsunoda Tatsuhiko、Sieverling Lina、Lawrence Michael S.、Stuart Josh、Sinnott-Armstrong Nicholas A.、Pedersen Randi Istrup、Haradhvala Nicholas J.、L¨?pez-Bigas N¨2ria、Hobolth Asger、on behalf of the PCAWG Drivers and Functional Interpretation Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network、Lee Donghoon、Feuerbach Lars、Fonseca Nuno A.、Herrmann Carl、Wheeler David A.、Maruvka Yosef E.、Umer Husen M.、Lehmann Kjong-Van、Kahles Andre、Liu Eric Minwei、Dhingra Priyanka、Hornsh?j Henrik、Campbell Peter J.、Saksena Gordon、Raphael Ben、Nielsen Morten Muhlig、Uusk¨1la-Reimand Liis、Pich Oriol、Johnson Rory、Carlevaro-Fita Joana、Rheinbay Esther、Getz Gad、Mularoni Loris、Zhang Jing、Shen Ciyue、Sabarinathan Radhakrishnan、Kellis Manolis、Kim Youngwook、Sander Chris、Bertl Johanna、Stein Lincoln、Boroevich Keith A.
Wellcome Trust Sanger InstituteLaboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical SciencesDepartment of Molecular Medicine (MOMA), Aarhus University Hospital||Bioinformatics Research Centre (BiRC), Aarhus UniversityWellcome Trust Sanger InstituteThe Broad Institute of MIT and HarvardThe Broad Institute of MIT and HarvardInstitute of Molecular Life Sciences and Swiss Institute of Bioinformatics, University of ZurichSamsung Medical Center, Sungkyunkwan University School of Medicine South KoreaWeill Cornell Medicine and New York Presbyterian, Department of Pathology and Laboratory Medicine||Weill Cornell Medicine and New York Presbyterian, Caryl and Israel Englander Institute for Precision Medicine||Weill Cornell Medicine and New York Presbyterian, Sandra and Edward Meyer Cancer CenterComputational Biology Program, Ontario Institute for Cancer Research||Department of Medical Biophysics, University of TorontoDepartment of Molecular Medicine (MOMA), Aarhus University HospitalThe Broad Institute of MIT and HarvardInstitute for Computational Biomedicine, Weill Cornell Medical CollegeCentre for Genomic Regulation (CRG)||Universitat Pompeu Fabra (UPF)Department of Genomic Medicine, the University of Texas MD Anderson Cancer Center||Graduate Program in Structural and Computational Biology and Molecular Biophysics, Baylor College of MedicineComputational Biology and Bioinformatics, Department of Cell and Molecular BiologyInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology||Research Program on Biomedical Informatics, Universitat Pompeu FabraBioinformatics Research Centre (BiRC), Aarhus UniversityComputational Biology Program, Ontario Institute for Cancer Research||Department of Medical Biophysics, University of TorontoDepartment of Molecular Medicine (MOMA), Aarhus University HospitalComputational Biology and Bioinformatics, Department of Cell and Molecular Biology||Institute of Computer Science, Polish Academy of SciencesProgram in Computational Biology and Bioinformatics, Yale UniversityDepartment of Molecular Biophysics and Biochemistry, Yale UniversityInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology||Research Program on Biomedical Informatics, Universitat Pompeu FabraComputational Biology Program, Ontario Institute for Cancer ResearchDepartment of Genitourinary Medical Oncology - Research, Division of Cancer Medicine, The University of Texas MD Anderson Cancer CenterDivision of Theoretical Bioinformatics, German Cancer Research Center (DKFZ)||Faculty of Biosciences, Heidelberg UniversityDepartment of Molecular and Cellular Biology, Baylor College of MedicineDivision of Applied Bioinformatics, German Cancer Research Center||Faculty of Biosciences, Heidelberg UniversityScience for Life Laboratory, Department of Immunology, Genetics and PathologyProgram in Computational Biology and Bioinformatics, Yale University||Department of Molecular Biophysics and Biochemistry, Yale University||Department of Computer Science, Yale UniversityDepartment of Physiology and Biophysics, Weill Cornell Medicine||Institute for Computational Biomedicine, Weill Cornell Medical College||Weill Cornell Medicine and New York Presbyterian, Caryl and Israel Englander Institute for Precision Medicine||Weill Cornell Medicine and New York Presbyterian, Sandra and Edward Meyer Cancer CenterDepartment of Medical Science Mathematics, Medical Research Institute, Tokyo Medical and Dental University||Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences||CREST, Japan Science and Technology AgencyDivision of Applied Bioinformatics, German Cancer Research Center||Faculty of Biosciences, Heidelberg UniversityThe Broad Institute of MIT and Harvard||Massachusetts General Hospital, Center for Cancer ResearchCenter for Biomolecular Science and Engineering, University of California at Santa CruzDepartment of Genetics, Stanford University School of MedicineDepartment of Molecular Medicine (MOMA), Aarhus University HospitalThe Broad Institute of MIT and Harvard||Massachusetts General Hospital, Center for Cancer ResearchInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology||Research Program on Biomedical Informatics, Universitat Pompeu Fabra||Catalan Institution for Research and Advanced Studies (ICREA)Bioinformatics Research Centre (BiRC), Aarhus UniversityProgram in Computational Biology and Bioinformatics, Yale UniversityDivision of Applied Bioinformatics, German Cancer Research CenterEuropean Bioinformatics Institute. European Molecular Biology LaboratoryDivision of Theoretical Bioinformatics, German Cancer Research Center (DKFZ)||Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of HeidelbergHuman Genome Sequencing Center, Baylor College of MedicineThe Broad Institute of MIT and Harvard||Massachusetts General Hospital, Center for Cancer ResearchComputational Biology and Bioinformatics, Department of Cell and Molecular BiologyDivision of Computational Biology, Memorial Sloan Kettering Cancer CenterDivision of Computational Biology, Memorial Sloan Kettering Cancer CenterDepartment of Physiology and Biophysics, Weill Cornell Medicine||Institute for Computational Biomedicine, Weill Cornell Medical CollegeDepartment of Physiology and Biophysics, Weill Cornell Medicine||Institute for Computational Biomedicine, Weill Cornell Medical CollegeDepartment of Molecular Medicine (MOMA), Aarhus University HospitalWellcome Trust Sanger Institute||Department of Haematology, University of CambridgeThe Broad Institute of MIT and HarvardDepartment of Computer Science, Princeton UniversityDepartment of Molecular Medicine (MOMA), Aarhus University HospitalGenetics and Genome Biology Program, SickKids Research Institute||Department of Gene Technology, Tallinn University of TechnologyInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology||Research Program on Biomedical Informatics, Universitat Pompeu FabraDepartment of Medical Oncology, Inselspital, University Hospital and University of BernCentre for Genomic Regulation (CRG)||Universitat Pompeu Fabra (UPF)The Broad Institute of MIT and HarvardThe Broad Institute of MIT and Harvard||Massachusetts General Hospital, Center for Cancer Research||Harvard Medical School||Massachusetts General Hospital, Department of PathologyInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology||Research Program on Biomedical Informatics, Universitat Pompeu FabraProgram in Computational Biology and Bioinformatics, Yale UniversityDepartment of Cell Biology, Harvard Medical School||cBio Center, Dana-Farber Cancer InstituteInstitute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology||Research Program on Biomedical Informatics, Universitat Pompeu FabraThe Broad Institute of MIT and Harvard||MIT Computer Science and Artificial Intelligence LaboratorySamsung Medical Center, Sungkyunkwan University School of Medicine South KoreaDepartment of Cell Biology, Harvard Medical School||cBio Center, Dana-Farber Cancer InstituteDepartment of Molecular Medicine (MOMA), Aarhus University HospitalDepartment of Molecular Genetics, University of Toronto||Computational Biology Program, Ontario Institute for Cancer Research||Ontario Institute for Cancer ResearchLaboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences
肿瘤学基础医学分子生物学
Martincorena I?igo,Johnson Todd A.,Pedersen Jakob Skou,Abascal Federico,Tiao Grace,Hess Julian M.,Kahraman Abdullah,Park Keunchil,Rubin Mark A.,Reimand J¨1ri,Madsen Tobias,Kim Jaegil,Shuai Shimin,Lanz¨?s Andr¨|s,Amin Samirkumar B.,Diamanti Klev,Gonzalez-Perez Abel,Guo Qianyun,Isaev Keren,Juul Malene,Komorowski Jan,Kumar Sushant,Lochovsky Lucas,Tamborero David,Wadi Lina,Chakravarty Dimple,Chan Calvin W.Y.,Hamilton Mark P.,Hong Chen,Wadelius Claes,Gerstein Mark B.,Khurana Ekta,Tsunoda Tatsuhiko,Sieverling Lina,Lawrence Michael S.,Stuart Josh,Sinnott-Armstrong Nicholas A.,Pedersen Randi Istrup,Haradhvala Nicholas J.,L¨?pez-Bigas N¨2ria,Hobolth Asger,on behalf of the PCAWG Drivers and Functional Interpretation Group and the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Network,Lee Donghoon,Feuerbach Lars,Fonseca Nuno A.,Herrmann Carl,Wheeler David A.,Maruvka Yosef E.,Umer Husen M.,Lehmann Kjong-Van,Kahles Andre,Liu Eric Minwei,Dhingra Priyanka,Hornsh?j Henrik,Campbell Peter J.,Saksena Gordon,Raphael Ben,Nielsen Morten Muhlig,Uusk¨1la-Reimand Liis,Pich Oriol,Johnson Rory,Carlevaro-Fita Joana,Rheinbay Esther,Getz Gad,Mularoni Loris,Zhang Jing,Shen Ciyue,Sabarinathan Radhakrishnan,Kellis Manolis,Kim Youngwook,Sander Chris,Bertl Johanna,Stein Lincoln,Boroevich Keith A..Discovery and characterization of coding and non-coding driver mutations in more than 2,500 whole cancer genomes[EB/OL].(2025-03-28)[2025-06-07].https://www.biorxiv.org/content/10.1101/237313.点此复制
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