Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations
Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations
ABSTRACT We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants (P<5×10?8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes (P<2.6×10?6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution.
Kraft Peter、Lambrechts Diether、Spurdle Amanda B.、Ramus Susan J.、Kar Siddhartha P.、Siddiqui Nadeem、Campa Daniele、Chen Chu、Yu Herbert、Tomlinson Ian P. M.、Chanock Stephen J.、Easton Douglas F.、Eeles Rosalind A.、Daly Mary B.、Pharoah Paul D. P.、Lawrenson Kate、O?ˉMara Tracy A.、Chang-Claude Jenny、Ant¨?n Fernando M.、Beeghly-Fadiel Alicia、Bj?rge Line、Podgorski Agnieszka、Mieszkowska Agnieszka D.、Monteiro Alvaro N.、Permuth Jennifer B.、van Altena Anne M.、Vega-Gliemmo Ana、Vijai Joseph、Winqvist Robert、Peterlongo Paolo、Scott Rodney J.、?piewankiewicz Beata、Turnbull Clare、Carney Michael、Berchuck Andrew、Ekici Arif B.、Flanagan James M.、Giles Graham G.、Heitz Florian、Hillemanns Peter、Jensen Allan、Kannisto P?ivi、Karlan Beth Y.、Khusnutdinova Elza、Thompson Deborah J.、Goode Ellen L.、Park-Simon Tjoung-Won、Kjaer Susanne K.、Schmidt Marjanka K.、Gayther Simon A.、Kiemeney Lambertus A.、Tyrer Jonathan P.、Lindstr?m Sara、Chenevix-Trench Georgia、Burghaus Stefanie、May Taymaa、Konopka Bozena、Sieh Weiva、Hamilton Robert J.、Hildebrandt Michelle、Winham Stacey J.、Hung Rayjean J.、Klapdor R¨1diger、Usmani Nawaid、Runnebaum Ingo B.、the PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS、Muir Kenneth、Nielsen Sune F.、Moysich Kirsten、Radice Paolo、Brauch Hiltrud、Irmejs Arvids、Lophatananon Artitaya、Vierkant Robert A.、Gawelko Jan、Ewing Ailith、Huang Ruea-Yea、Zheng Wei、Odunsi Kunle、Setiawan Veronica W.、Glubb Dylan M.、Vergote Ignace、Chen Zhihua、Bodelon Clara、Lessel Davor、Jakubowska Anna、Alsulimani Ahmad G. M.、Harris Holly R.、Olsson H?kan、Kleiblova Petra、Prentice Ross、Krakstad Camilla、K?bel Martin、Titus Linda J.、Schildkraut Joellen M.、John Esther M.、Rzepecka Iwona K.、Fasching Peter、Bois Andreas du、Imaz Liher、Risch Harvey A.、Szafron Lukasz M.、Thompson Cheryl L.
Department of Epidemiology, Harvard T.H. Chan School of Public Health||Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public HealthVIB Center for Cancer Biology||Laboratory of Translational Genetics, Department of Human Genetics, University of LeuvenDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research InstituteAdult Cancer Program, Lowy Cancer Research Centre, University of New South WalesMedical Research Council Integrative Epidemiology Unit, University of Bristol||Population Health Sciences, Bristol Medical School, University of BristolDepartment of Gynaecological Oncology, Glasgow Royal InfirmaryDivision of Cancer Epidemiology||Department of Biology, University of PisaProgram in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center||Department of Epidemiology, University of WashingtonEpidemiology Program, University of Hawaii Cancer CenterEdinburgh Cancer Research Centre, University of EdinburghDivision of Cancer Epidemiology and Genetics, National Cancer InstituteCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge||Centre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeInstitute of Cancer Research||Royal Marsden NHS Foundation TrustDepartment of Clinical Genetics, Fox Chase Cancer CenterCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge||Centre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeCenter for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical Center||Women?ˉs Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research InstituteDivision of Cancer Epidemiology, German Cancer Research Center (DKFZ)||Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-EppendorfHospital Cl¨anico San CarlosDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of MedicineDepartment of Obstetrics and Gynecology, Haukeland University, Hospital||Centre for Cancer Biomarkers CCBIO, Department of Clinical Science, University of BergenDepartment of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of OncologyDepartment of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of OncologyCancer Epidemiology, H. Lee Moffitt Cancer Center and Research InstituteDepartments of Cancer Epidemiology and Gastrointestinal Oncology, Moffitt Cancer Center and Research InstituteRadboud University Medical Centre, Department of Obstetrics and GynecologyGalician Public Foundation of Genomic Medicine (FPGMX), Clinical University Hospital, Santiago de CompostelaNiehaus Center For Inherited Cancer Genomics, Memorial Sloan Kettering Cancer Center||Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center||Department of Medicine, Weill Cornell Medical CollegeBiocenter Oulu, Cancer and Translational Medicine Research Unit, Laboratory of Cancer Genetics and Tumor Biology, University of Oulu||Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre OuluGenome Diagnostics Program, IFOM-The FIRC (Italian Foundation for Cancer Research) Institute of Molecular OncologyDivision of Molecular Medicine, Pathology North, John Hunter Hospital||Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle||Hunter Medical Research Institute, John Hunter HospitalDepartment of Gynecologic Oncology, Institute of OncologyDivision of Genetics and Epidemiology, Institute of Cancer Research||Department of Clinical Genetics, Royal Marsden NHS Foundation Trust||Public Health England, National Cancer Registration and Analysis ServiceDepartment of Obstetrics and Gynecology, John A. Burns School of Medicine, University of HawaiiDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical CenterInstitute of Human Genetics, University Hospital Erlangen||Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ErlangenDepartment of Surgery and Cancer, Faculty of Medicine, Imperial College LondonCancer Epidemiology Division, Cancer Council Victoria||Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne||Precision Medicine, School of Clinical Sciences at Monash Health, Monash UniversityDepartment of Gynecology and Gynecologic Oncology, Kliniken Essen-Mitte/ Evang.||Department of Gynecology, Center for Oncologic Surgery, Charit¨| Campus Virchow-Klinikum, Universit?tsmedizin Berlin||Freie Universit?t Berlin, Humboldt-Universit?t of Berlin, and Berlin Institute of HealthDepartment of Gynecology and Obstetrics, Hannover Medical SchoolDepartment of Virus, Lifestyle and Genes, Danish Cancer Society Research CenterDepartment of Obstetrics and Gynecology, University of LundDavid Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los AngelesInstitute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of SciencesCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of CambridgeDepartment of Health Sciences ResearchDepartment of Gynecology, Hannover Medical SchoolDepartment of Virus, Lifestyle and Genes, Danish Cancer Society Research Center||Department of Gynaecology, Rigshospitalet, University of CopenhagenDivision of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital||Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek HospitalCenter for Bioinformatics and Functional Genomics, Department of Biomedical Science, Cedars-Sinai Medical CenterRadboud Institute for Health Sciences, Radboud University Medical CenterCentre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of CambridgeDepartment of Epidemiology, University of Washington School of Public Health||Public Health Sciences Division, Fred Hutchinson Cancer Research CenterDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research InstituteFrauenklinik, Universit?tsklinikum ErlangenDivision of Gynecologic Oncology, University Health Network, Princess Margaret HospitalDepartment of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of OncologyDepartment of Population Health Science and Policy, Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount SinaiDivision of Urology, Department of Surgery, Princess Margaret Cancer Centre, University Health Network, University of TorontoDepartment of Epidemiology, The University of Texas MD Anderson Cancer CenterDepartment of Health Sciences Research, Division of Biomedical Statistics and InformaticsLunenfeld-Tanenbaum Research Institute, Sinai Health System and University of TorontoDepartment of Gynecology and Obstetrics, Hannover Medical SchoolDepartment of Radiation Oncology, Cross Cancer Institute, University of AlbertaDepartment for Gynaecology and Reproductive Medicine, Jena University Hospital-Friedrich Schiller University JenaMembers from the PRACTICAL Consortium, CRUK, BPC3, CAPS and PEGASUS are provided in the Supplementmary NotesDivision of Population Health, Health Services Research and Primary Care, Faculty of Biology, Medicine and Health, Centre for Epidemiology, University of ManchesterDepartment of Clinical Biochemistry, Herlev Hospital, Copenhagen University HospitalDepartment of Cancer Prevention and Control, Roswell Park Cancer InstituteUnit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT)Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology||iFIT Cluster of Excellence, University of T¨1bingen||German Cancer Consortium (DKTK) and German Cancer Research Center (DKFZ), Partner Site T¨1bingenRiga Stradins University, Pauls Stradins Clinical University HospitalDivision of Population Health, Health Services Research and Primary Care, Faculty of Biology, Medicine and Health, Centre for Epidemiology, University of ManchesterDepartment of Health Sciences Research, Division of Biomedical Statistics and InformaticsMedical College Rzeszow UniversityMRC Human Genetics Unit, MRC Institute of Genetics and Molecular Medicine, The University of Edinburgh, Western General HospitalCenter for Immunotherapy, Roswell Park Comprehensive Cancer CenterDivision of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of MedicineCenter for Immunotherapy, Roswell Park Comprehensive Cancer Center||Department of Gynecologic Oncology, Roswell Park Comprehensive Cancer CenterDepartment of Preventive Medicine, Keck School of Medicine, University of Southern CaliforniaDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research InstituteDivision of Gynecologic Oncology, Department of Obstetrics and Gynecology, KU UniversityCancer Epidemiology, H. Lee Moffitt Cancer Center and Research InstituteDivison of Cancer Epidemiology and Genetics, National Cancer InstituteInstitute of Human Genetics, University Medical Center Hamburg-EppendorfDepartment of Genetics and Pathology, Pomeranian Medical University||Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical UniversityDepartment of Cancer Prevention and Control, Roswell Park Cancer InstituteProgram in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research CenterDivision of Oncology, Department of Clinical Sciences, Lund UniversityInstitute of Biology and Medical Genetics, First Faculty of Medicine, Charles University and General University Hospital in PragueCancer Prevention Program, Fred Hutchinson Cancer Research CenterDepartment of Obstetrics and Gynecology, Haukeland University Hospital||Centre for Cancer Biomarkers, Department of Clinical Science, University of BergenDepartment of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical CenterDepartment of Epidemiology, Geisel School of Medicine at DartmouthDepartment of Epidemiology, Rollins School of Public Health, Emory UniversityCancer Prevention Institute of California||Division of Oncology and Stanford Cancer Institute, Department of Medicine, Stanford University School of MedicineDepartment of Pathology and Laboratory Diagnostics, The Maria Sklodowska-Curie National Research Institute of OncologyDavid Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles||Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-NurembergDepartment of Gynecology and Gynecologic Oncology, Evang. Kliniken Essen-MitteMinistry of Health of the Basque Government, Public Health Division of Gipuzkoa||Biodonostia Health Research InstituteDepartment of Chronic Disease Epidemiology, Yale School of Public HealthMaria Sklodowska-Curie Memorial Cancer Center and Institute of OncologyDepartment of Population and Quantitative Health Sciences, Case Western Reserve University
肿瘤学基础医学遗传学
Kraft Peter,Lambrechts Diether,Spurdle Amanda B.,Ramus Susan J.,Kar Siddhartha P.,Siddiqui Nadeem,Campa Daniele,Chen Chu,Yu Herbert,Tomlinson Ian P. M.,Chanock Stephen J.,Easton Douglas F.,Eeles Rosalind A.,Daly Mary B.,Pharoah Paul D. P.,Lawrenson Kate,O?ˉMara Tracy A.,Chang-Claude Jenny,Ant¨?n Fernando M.,Beeghly-Fadiel Alicia,Bj?rge Line,Podgorski Agnieszka,Mieszkowska Agnieszka D.,Monteiro Alvaro N.,Permuth Jennifer B.,van Altena Anne M.,Vega-Gliemmo Ana,Vijai Joseph,Winqvist Robert,Peterlongo Paolo,Scott Rodney J.,?piewankiewicz Beata,Turnbull Clare,Carney Michael,Berchuck Andrew,Ekici Arif B.,Flanagan James M.,Giles Graham G.,Heitz Florian,Hillemanns Peter,Jensen Allan,Kannisto P?ivi,Karlan Beth Y.,Khusnutdinova Elza,Thompson Deborah J.,Goode Ellen L.,Park-Simon Tjoung-Won,Kjaer Susanne K.,Schmidt Marjanka K.,Gayther Simon A.,Kiemeney Lambertus A.,Tyrer Jonathan P.,Lindstr?m Sara,Chenevix-Trench Georgia,Burghaus Stefanie,May Taymaa,Konopka Bozena,Sieh Weiva,Hamilton Robert J.,Hildebrandt Michelle,Winham Stacey J.,Hung Rayjean J.,Klapdor R¨1diger,Usmani Nawaid,Runnebaum Ingo B.,the PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS,Muir Kenneth,Nielsen Sune F.,Moysich Kirsten,Radice Paolo,Brauch Hiltrud,Irmejs Arvids,Lophatananon Artitaya,Vierkant Robert A.,Gawelko Jan,Ewing Ailith,Huang Ruea-Yea,Zheng Wei,Odunsi Kunle,Setiawan Veronica W.,Glubb Dylan M.,Vergote Ignace,Chen Zhihua,Bodelon Clara,Lessel Davor,Jakubowska Anna,Alsulimani Ahmad G. M.,Harris Holly R.,Olsson H?kan,Kleiblova Petra,Prentice Ross,Krakstad Camilla,K?bel Martin,Titus Linda J.,Schildkraut Joellen M.,John Esther M.,Rzepecka Iwona K.,Fasching Peter,Bois Andreas du,Imaz Liher,Risch Harvey A.,Szafron Lukasz M.,Thompson Cheryl L..Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations[EB/OL].(2025-03-28)[2025-05-02].https://www.biorxiv.org/content/10.1101/2020.06.16.146803.点此复制
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