Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
About this Publication
Title
Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses.
Pubmed ID
32424353
(View this publication on the PubMed website)
Digital Object Identifier
Publication
Nat Genet. 2020 Jun; Volume 52 (Issue 6): Pages 572-581
Authors
Zhang H, Ahearn TU, Lecarpentier J, Barnes D, Beesley J, Qi G, Jiang X, O'Mara TA, Zhao N, Bolla MK, Dunning AM, Dennis J, Wang Q, Ful ZA, Aittomäki K, Andrulis IL, Anton-Culver H, Arndt V, Aronson KJ, Arun BK, ...show more Auer PL, Azzollini J, Barrowdale D, Becher H, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bialkowska K, Blanco A, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Bondavalli D, Borg A, Brauch H, Brenner H, Briceno I, Broeks A, Brucker SY, Brüning T, Burwinkel B, Buys SS, Byers H, Caldés T, Caligo MA, Calvello M, Campa D, Castelao JE, Chang-Claude J, Chanock SJ, Christiaens M, Christiansen H, Chung WK, Claes KBM, Clarke CL, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Diez O, Domchek SM, Dörk T, Dwek M, Eccles DM, Ekici AB, Evans DG, Fasching PA, Figueroa J, Foretova L, Fostira F, Friedman E, Frost D, Gago-Dominguez M, Gapstur SM, Garber J, García-Sáenz JA, Gaudet MM, Gayther SA, Giles GG, Godwin AK, Goldberg MS, Goldgar DE, González-Neira A, Greene MH, Gronwald J, Guénel P, Häberle L, Hahnen E, Haiman CA, Hake CR, Hall P, Hamann U, Harkness EF, Heemskerk-Gerritsen BAM, Hillemanns P, Hogervorst FBL, Holleczek B, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huebner H, Hulick PJ, Imyanitov EN, kConFab Investigators, ABCTB Investigators, Isaacs C, Izatt L, Jager A, Jakimovska M, Jakubowska A, James P, Janavicius R, Janni W, John EM, Jones ME, Jung A, Kaaks R, Kapoor PM, Karlan BY, Keeman R, Khan S, Khusnutdinova E, Kitahara CM, Ko YD, Konstantopoulou I, Koppert LB, Koutros S, Kristensen VN, Laenkholm AV, Lambrechts D, Larsson SC, Laurent-Puig P, Lazaro C, Lazarova E, Lejbkowicz F, Leslie G, Lesueur F, Lindblom A, Lissowska J, Lo WY, Loud JT, Lubinski J, Lukomska A, MacInnis RJ, Mannermaa A, Manoochehri M, Manoukian S, Margolin S, Martinez ME, Matricardi L, McGuffog L, McLean C, Mebirouk N, Meindl A, Menon U, Miller A, Mingazheva E, Montagna M, Mulligan AM, Mulot C, Muranen TA, Nathanson KL, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen FC, Nikitina-Zake L, Nodora J, Offit K, Olah E, Olopade OI, Olsson H, Orr N, Papi L, Papp J, Park-Simon TW, Parsons MT, Peissel B, Peixoto A, Peshkin B, Peterlongo P, Peto J, Phillips KA, Piedmonte M, Plaseska-Karanfilska D, Prajzendanc K, Prentice R, Prokofyeva D, Rack B, Radice P, Ramus SJ, Rantala J, Rashid MU, Rennert G, Rennert HS, Risch HA, Romero A, Rookus MA, Rübner M, Rüdiger T, Saloustros E, Sampson S, Sandler DP, Sawyer EJ, Scheuner MT, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schöttker B, Schürmann P, Senter L, Sharma P, Sherman ME, Shu XO, Singer CF, Smichkoska S, Soucy P, Southey MC, Spinelli JJ, Stone J, Stoppa-Lyonnet D, EMBRACE Study, GEMO Study Collaborators, Swerdlow AJ, Szabo CI, Tamimi RM, Tapper WJ, Taylor JA, Teixeira MR, Terry M, Thomassen M, Thull DL, Tischkowitz M, Toland AE, Tollenaar RAEM, Tomlinson I, Torres D, Troester MA, Truong T, Tung N, Untch M, Vachon CM, van den Ouweland AMW, van der Kolk LE, van Veen EM, vanRensburg EJ, Vega A, Wappenschmidt B, Weinberg CR, Weitzel JN, Wildiers H, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zheng W, Zorn KK, Milne RL, Kraft P, Simard J, Pharoah PDP, Michailidou K, Antoniou AC, Schmidt MK, Chenevix-Trench G, Easton DF, Chatterjee N, García-Closas M
Affiliations
- Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services, Bethesda, MD, USA.
- Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.
- Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
- Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
- Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
- Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
- Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
- Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.
- Department of Epidemiology, Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, CA, USA.
- Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Department of Public Health Sciences and Cancer Research Institute, Queen's University, Kingston, Ontario, Canada.
- Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
- Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.
- Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
- Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
- Institute of Medical Biometry and Epidemiology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
- Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University of Erlangen-Nuremberg, Erlangen, Germany.
- Division of Cancer Epidemiology, DKFZ, Heidelberg, Germany.
- Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Valencia, Spain.
- Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia.
- Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
- Molecular Medicine Unit, Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain.
- Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
- N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.
- Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.
- Division of Cancer Prevention and Genetics, European Institute of Oncology (IEO) IRCCS, Milan, Italy.
- Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
- Dr. Margarete Fischer-Bosch Institute of Clinical Pharmacology, Stuttgart, Germany.
- Bioscience Department, Faculty of Medicine, Universidad de la Sabana, Chia, Colombia.
- Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
- Department of Women's Health, University of Tübingen, Tübingen, Germany.
- Institute for Prevention and Occupational Medicine of the German Social Accident Insurance (IPA), Ruhr University Bochum, Bochum, Germany.
- Molecular Epidemiology Group (C080), DKFZ, Heidelberg, Germany.
- Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.
- Manchester 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.
- Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid, Spain.
- Section of Molecular Genetics, Department of Laboratory Medicine, University Hospital of Pisa, Pisa, Italy.
- Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.
- Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.
- Department of Radiation Oncology, Hannover Medical School, Hannover, Germany.
- Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA.
- Centre for Medical Genetics, Ghent University, Ghent, Belgium.
- Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
- Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.
- Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield, UK.
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.
- Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
- Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands.
- Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Barcelona, Spain.
- Department of Medicine, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.
- Department of Biomedical Sciences, Faculty of Science and Technology, University of Westminster, London, UK.
- Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.
- Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany.
- Usher Institute of Population Health Sciences and Informatics, University of Edinburgh Medical School, Edinburgh, UK.
- Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
- Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
- The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
- Genomic Medicine Group, Galician Foundation of Genomic Medicine, IDIS, Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain.
- Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.
- Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.
- Center for Bioinformatics and Functional Genomics and the Cedars-Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
- Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.
- Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA.
- Department of Medicine, McGill University, Montréal, Québec, Canada.
- Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
- Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
- Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
- Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University of Paris-Saclay, Paris, France.
- Department of Gynaecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center ER-EMN, Erlangen, Germany.
- Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
- Waukesha Memorial Hospital Pro Health Care, Waukesha, WI, USA.
- Molecular Genetics of Breast Cancer, DKFZ, Heidelberg, Germany.
- Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester, UK.
- Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
- Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.
- Saarland Cancer Registry, Saarbrücken, Germany.
- Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, University of Melbourne, Melbourne, Victoria, Australia.
- Division of Cancer Sciences, University of Manchester, Manchester, UK.
- Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
- N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
- Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
- Clinical Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
- Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of Macedonia.
- Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
- Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania.
- Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
- Department of Medicine, Division of Oncology, Stanford Cancer Institute, School of Medicine, Stanford University, Stanford, CA, USA.
- Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.
- David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA.
- Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
- Radiation Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
- Department of Internal Medicine, Evangelische Kliniken Bonn, Johanniter Krankenhaus, Bonn, Germany.
- Department of Surgical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.
- Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway.
- Department of Surgical Pathology, Zealand University Hospital, Slagelse, Denmark.
- VIB Center for Cancer Biology, VIB, Leuven, Belgium.
- Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.
- Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris, France.
- Molecular Diagnostic Unit, Hereditary Cancer Program, Bellvitge Biomedical Research Institute (IDIBELL), Catalan Institute of Oncology (ICO), CIBERONC, Barcelona, Spain.
- Ss. Cyril and Methodius University in Skopje, Medical Faculty, University Clinic of Radiotherapy and Oncology, Skopje, Republic of North Macedonia.
- Genetic Epidemiology of Cancer Team, INSERM U900, Paris, France.
- Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
- Department of Cancer Epidemiology and Prevention, M. Sklodowska-Curie Cancer Center, Oncology Institute, Warsaw, Poland.
- Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland.
- Department of Oncology, Södersjukhuset, Stockholm, Sweden.
- Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.
- Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV)-IRCCS, Padua, Italy.
- Department of Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia.
- Genetic Epidemiology of Cancer Team, INSERM U900, Institut Curie, PSL University, Mines ParisTech, Paris, France.
- Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich, Germany.
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK.
- NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
- Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia.
- Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.
- Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
- Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
- Latvian Biomedical Research and Study Centre, Riga, Latvia.
- Clinical Genetics Research Laboratory, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
- Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
- Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
- Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund, Sweden.
- Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast, Northern Ireland, UK.
- Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy.
- Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
- Department of Oncology, Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
- Genome Diagnostics Program, IFOM, FIRC Institute of Molecular Oncology, Milan, Italy.
- Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, INT, Milan, Italy.
- Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia.
- Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
- Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
- Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.
- Department of Epidemiology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.
- Institute of Pathology, Staedtisches Klinikum Karlsruhe, Karlsruhe, Germany.
- Department of Oncology, University Hospital of Larissa, Larissa, Greece.
- Prevent Breast Cancer Centre and Nightingale Breast Screening Centre, Manchester University NHS Foundation Trust, Manchester, UK.
- Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA.
- Research Oncology, Guy's Hospital, King's College London, London, UK.
- Cancer Genetics and Prevention Program, University of California, San Francisco, San Francisco, CA, USA.
- Molecular Biology of Breast Cancer, University Women's Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.
- Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
- Department of Internal Medicine, Division of Oncology, University of Kansas Medical Center, Westwood, Kansas City, KS, USA.
- Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL, USA.
- Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.
- Department of Obstetrics and Gynecology and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
- Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, Québec, Canada.
- Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia.
- Population Oncology, BC Cancer, Vancouver, British Columbia, Canada.
- Department of Genetics, INSERM U830, Institut Curie, Paris Descartes Sorbonne-Paris Cité University, Paris, France.
- National Human Genome Research Institute, National Cancer Institute, Bethesda, MD, USA.
- Faculty of Medicine, University of Southampton, Southampton, UK.
- Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.
- Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
- Department of Medicine, Magee-Womens Hospital, School of Medicine, University of Pittsburgh , Pittsburgh, PA, USA.
- Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada.
- Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
- Department of Surgery, Leiden University Medical Center, Leiden, the Netherlands.
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.
- Department 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.
- Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
- Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin, Germany.
- Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.
- Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.
- Department of Genetics, University of Pretoria, Pretoria, South Africa.
- Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Durham, NC, USA.
- Clinical Cancer Genomics, City of Hope, Duarte, CA, USA.
- Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland.
- Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.
- Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. nchatte2@jhu.edu.
Abstract
Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype1-3. 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 × 10-8), 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.
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