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    Nature genetics. 2020 May 18. doi: 10.1038/s41588-020-0609-2. pii: 10.1038/s41588-020-0609-2
    Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
    Zhang H1,  Ahearn TU2,  Lecarpentier J3,  Barnes D4,  Beesley J5,  Qi G6,  Jiang X7,  O'Mara TA8,  Zhao N9,  Bolla MK10,  Dunning AM11,  Dennis J12,  Wang Q13,  Ful ZA14,  Aittomäki K15,  Andrulis IL16,  Anton-Culver H17,  Arndt V18,  Aronson KJ19,  Arun BK20,  Auer PL21,  Azzollini J22,  Barrowdale D23,  Becher H24,  Beckmann MW25,  Behrens S26,  Benitez J27,  Bermisheva M28,  Bialkowska K29,  Blanco A30,  Blomqvist C31,  Bogdanova NV32,  Bojesen SE33,  Bonanni B34,  Bondavalli D35,  Borg A36,  Brauch H37,  Brenner H38,  Briceno I39,  Broeks A40,  Brucker SY41,  Brüning T42,  Burwinkel B43,  Buys SS44,  Byers H45,  Caldés T46,  Caligo MA47,  Calvello M48,  Campa D49,  Castelao JE50,  Chang-Claude J51,  Chanock SJ52,  Christiaens M53,  Christiansen H54,  Chung WK55,  Claes KBM56,  Clarke CL57,  Cornelissen S58,  Couch FJ59,  Cox A60,  Cross SS61,  Czene K62,  Daly MB63,  Devilee P64,  Diez O65,  Domchek SM66,  Dörk T67,  Dwek M68,  Eccles DM69,  Ekici AB70,  Evans DG71,  Fasching PA72,  Figueroa J73,  Foretova L74,  Fostira F75,  Friedman E76,  Frost D77,  Gago-Dominguez M78,  Gapstur SM79,  Garber J80,  García-Sáenz JA81,  Gaudet MM82,  Gayther SA83,  Giles GG84,  Godwin AK85,  Goldberg MS86,  Goldgar DE87,  González-Neira A88,  Greene MH89,  Gronwald J90,  Guénel P91,  Häberle L92,  Hahnen E93,  Haiman CA94,  Hake CR95,  Hall P96,  Hamann U97,  Harkness EF98,  Heemskerk-Gerritsen BAM99,  Hillemanns P100,  Hogervorst FBL101,  Holleczek B102,  Hollestelle A103,  Hooning MJ104,  Hoover RN105,  Hopper JL106,  Howell A107,  Huebner H108,  Hulick PJ109,  Imyanitov EN110,  Isaacs C111,  Izatt L112,  Jager A113,  Jakimovska M114,  Jakubowska A115,  James P116,  Janavicius R117,  Janni W118,  John EM119,  Jones ME120,  Jung A121,  Kaaks R122,  Kapoor PM123,  Karlan BY124,  Keeman R125,  Khan S126,  Khusnutdinova E127,  Kitahara CM128,  Ko YD129,  Konstantopoulou I130,  Koppert LB131,  Koutros S132,  Kristensen VN133,  Laenkholm AV134,  Lambrechts D135,  Larsson SC136,  Laurent-Puig P137,  Lazaro C138,  Lazarova E139,  Lejbkowicz F140,  Leslie G141,  Lesueur F142,  Lindblom A143,  Lissowska J144,  Lo WY145,  Loud JT146,  Lubinski J147,  Lukomska A148,  MacInnis RJ149,  Mannermaa A150,  Manoochehri M151,  Manoukian S152,  Margolin S153,  Martinez ME154,  Matricardi L155,  McGuffog L156,  McLean C157,  Mebirouk N158,  Meindl A159,  Menon U160,  Miller A161,  Mingazheva E162,  Montagna M163,  Mulligan AM164,  Mulot C165,  Muranen TA166,  Nathanson KL167,  Neuhausen SL168,  Nevanlinna H169,  Neven P170,  Newman WG171,  Nielsen FC172,  Nikitina-Zake L173,  Nodora J174,  Offit K175,  Olah E176,  Olopade OI177,  Olsson H178,  Orr N179,  Papi L180,  Papp J181,  Park-Simon TW182,  Parsons MT183,  Peissel B184,  Peixoto A185,  Peshkin B186,  Peterlongo P187,  Peto J188,  Phillips KA189,  Piedmonte M190,  Plaseska-Karanfilska D191,  Prajzendanc K192,  Prentice R193,  Prokofyeva D194,  Rack B195,  Radice P196,  Ramus SJ197,  Rantala J198,  Rashid MU199,  Rennert G200,  Rennert HS201,  Risch HA202,  Romero A203,  Rookus MA204,  Rübner M205,  Rüdiger T206,  Saloustros E207,  Sampson S208,  Sandler DP209,  Sawyer EJ210,  Scheuner MT211,  Schmutzler RK212,  Schneeweiss A213,  Schoemaker MJ214,  Schöttker B215,  Schürmann P216,  Senter L217,  Sharma P218,  Sherman ME219,  Shu XO220,  Singer CF221,  Smichkoska S222,  Soucy P223,  Southey MC224,  Spinelli JJ225,  Stone J226,  Stoppa-Lyonnet D227,  Swerdlow AJ228,  Szabo CI229,  Tamimi RM230,  Tapper WJ231,  Taylor JA232,  Teixeira MR233,  Terry M234,  Thomassen M235,  Thull DL236,  Tischkowitz M237,  Toland AE238,  Tollenaar RAEM239,  Tomlinson I240,  Torres D241,  Troester MA242,  Truong T243,  Tung N244,  Untch M245,  Vachon CM246,  van den Ouweland AMW247,  van der Kolk LE248,  van Veen EM249,  vanRensburg EJ250,  Vega A251,  Wappenschmidt B252,  Weinberg CR253,  Weitzel JN254,  Wildiers H255,  Winqvist R256,  Wolk A257,  Yang XR258,  Yannoukakos D259,  Zheng W260,  Zorn KK261,  Milne RL262,  Kraft P263,  Simard J264,  Pharoah PDP265,  Michailidou K266,  Antoniou AC267,  Schmidt MK268,  Chenevix-Trench G269,  Easton DF270,  Chatterjee N271,  García-Closas M272
    Author information
    1Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    2Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    3Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    4Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    5Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
    6Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
    7Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    8Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
    9Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
    10Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    11Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    12Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    13Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    14Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    15Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    16Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
    17Department of Epidemiology, Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, CA, USA.
    18Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    19Department of Public Health Sciences and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
    20Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    21Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    22Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    23Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
    24Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
    25Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
    26Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
    27Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
    28Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
    29Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    30Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
    31Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    32N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
    33Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
    34Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy.
    35Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy.
    36Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
    37Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
    38Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    39Bioscience Department, Faculty of Medicine, Universidad de la Sabana, Chia, Colombia.
    40Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
    41Department of Women's Health, University of Tübingen, Tübingen, Germany.
    42Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Ruhr University Bochum, Bochum, Germany.
    43Molecular Epidemiology Group (C080), DKFZ, Heidelberg, Germany.
    44Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.
    45Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
    46Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
    47Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
    48Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy.
    49Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
    50Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
    51Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
    52Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    53Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
    54Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
    55Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA.
    56Centre for Medical Genetics, Ghent University, Ghent, Belgium.
    57Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
    58Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
    59Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
    60Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
    61Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
    62Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    63Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
    64Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
    65Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
    66Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
    67Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
    68Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
    69Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
    70Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany.
    71Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
    72Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
    73Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Edinburgh, UK.
    74Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    75Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
    76The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
    77Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
    78Genomic Medicine Group, Galician Foundation of Genomic Medicine, IDIS, Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
    79Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
    80Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.
    81Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
    82Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
    83Center for Bioinformatics and Functional Genomics and the Cedars-Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
    84Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
    85Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA.
    86Department of Medicine, McGill University, Montréal, Québec, Canada.
    87Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
    88Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
    89Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    90Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    91Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University of Paris-Saclay, Paris, France.
    92Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany.
    93Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    94Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
    95Waukesha Memorial Hospital Pro Health Care, Waukesha, WI, USA.
    96Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
    97Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany.
    98Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
    99Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
    100Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
    101Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
    102Saarland Cancer Registry, Saarbrücken, Germany.
    103Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
    104Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
    105Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    106Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
    107Division of Cancer Sciences, University of Manchester, Manchester, UK.
    108Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
    109Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
    110N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
    111Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
    112Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
    113Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
    114Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
    115Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    116Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
    117Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania.
    118Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
    119Department of Medicine, Division of Oncology, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA.
    120Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
    121Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
    122Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
    123Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
    124David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA.
    125Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
    126Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    127Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
    128Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    129Department of Internal Medicine, Evangelische Kliniken Bonn, Johanniter Krankenhaus, Bonn, Germany.
    130Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
    131Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
    132Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    133Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
    134Department of Surgical Pathology, Zealand University Hospital, Slagelse, Denmark.
    135VIB Center for Cancer Biology, VIB, Leuven, Belgium.
    136Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
    137Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris, France.
    138Molecular Diagnostic Unit, Hereditary Cancer Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), CIBERONC, Barcelona, Spain.
    139Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia.
    140Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    141Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    142Genetic Epidemiology of Cancer Team, INSERM U900, Paris, France.
    143Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
    144Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland.
    145Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
    146Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    147Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    148Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    149Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
    150Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
    151Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany.
    152Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    153Department of Oncology, Södersjukhuset, Stockholm, Sweden.
    154Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
    155Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy.
    156Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    157Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia.
    158Genetic Epidemiology of Cancer Team, INSERM U900, Institut Curie, PSL University, Mines ParisTech, Paris, France.
    159Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany.
    160MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
    161NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
    162Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia.
    163Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy.
    164Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
    165Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris, France.
    166Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    167Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
    168Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    169Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    170Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
    171Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
    172Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    173Latvian Biomedical Research and Study Centre, Riga, Latvia.
    174Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
    175Clinical Genetics Research Laboratory, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    176Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    177Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
    178Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
    179Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
    180Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
    181Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    182Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
    183Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
    184Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    185Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    186Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
    187Genome Diagnostics Program, IFOM, FIRC Institute of Molecular Oncology, Milan, Italy.
    188Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    189Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
    190NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
    191Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
    192Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    193Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
    194Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia.
    195Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
    196Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, INT, Milan, Italy.
    197Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
    198Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
    199Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany.
    200Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    201Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    202Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
    203Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
    204Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
    205Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany.
    206Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
    207Department of Oncology, University Hospital of Larissa, Larissa, Greece.
    208Prevent Breast Cancer Centre and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust, Manchester, UK.
    209Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA.
    210Research Oncology, Guy's Hospital, King's College London, London, UK.
    211Cancer Genetics and Prevention Program, University of California, San Francisco, San Francisco, CA, USA.
    212Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    213Molecular Biology of Breast Cancer, University Women's Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
    214Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
    215Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    216Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
    217Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
    218Department of Internal Medicine, Division of Oncology, University of Kansas Medical Center, Westwood, Kansas City, KS, USA.
    219Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
    220Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
    221Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    222Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia.
    223Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, Québec, Canada.
    224Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia.
    225Population Oncology, BC Cancer, Vancouver, British Columbia, Canada.
    226Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
    227Department of Genetics, INSERM U830, Institut Curie, Paris Descartes Sorbonne-Paris Cité University, Paris, France.
    228Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
    229National Human Genome Research Institute, National Cancer Institute, Bethesda, MD, USA.
    230Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    231Faculty of Medicine, University of Southampton, Southampton, UK.
    232Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA.
    233Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    234Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
    235Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
    236Department of Medicine, Magee-Womens Hospital, School of Medicine, University of Pittsburgh , Pittsburgh, PA, USA.
    237Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada.
    238Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
    239Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
    240Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
    241Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany.
    242Department of Epidemiology, Gillings School of Global Public Health and UNC Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
    243Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University of Paris-Saclay, Paris, France.
    244Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
    245Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
    246Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
    247Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
    248Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
    249Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester NIHR Biomedical Research Centre, Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
    250Department of Genetics, University of Pretoria, Pretoria, South Africa.
    251Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
    252Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    253Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA.
    254Clinical Cancer Genomics, City of Hope, Duarte, CA, USA.
    255Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
    256Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
    257Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
    258Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    259Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
    260Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
    261Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    262Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
    263Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
    264Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, Québec, Canada.
    265Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    266Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    267Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    268Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
    269Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
    270Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
    271Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. nchatte2@jhu.edu.
    272Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
    Abstract

    Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 × 10), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.


    Publikations ID: 32424353
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