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Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes.
Nat Genet 2020; 52(1):56-73NGen

Abstract

Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes.

Authors+Show Affiliations

Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Centre de Bioinformatique Biostatistique et Biologie Intégrative (C3BI), Institut Pasteur, Paris, France. Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. Department of Electron Microscopy/Molecular Pathology and The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA.Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Québec City, Québec, Canada.Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Québec City, Québec, Canada.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.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. UK Dementia Research Institute, Imperial College London, London, UK.Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV), IRCCS, Padua, Italy.Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.Human Genotyping-CEGEN Unit, Human Cancer Genetic Program, Spanish National Cancer Research Centre, Madrid, Spain.Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.Department of Epidemiology, Genetic Epidemiology Research Institute, University of California, Irvine, Irvine, CA, USA.N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus.Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland. BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.Division of Clinical Epidemiology and Aging Research (C070), 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.Institute of Human Genetics, Hannover Medical School, Hannover, Germany.Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA. Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.High Risk and Cancer Prevention Group, Vall Hebron Institute of Oncology, Barcelona, Spain. Department of Medical Oncology, Vall Hebron University Hospital, Barcelona, Spain.Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland. BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.Centro de Investigación en Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, 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.Cancer Genetics and Prevention Program, University of California, San Francisco, San Francisco, CA, USA.Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland. Department of Oncology, Örebro University Hospital, Örebro, Sweden.Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA. International Epidemiology Institute, Rockville, MD, USA.N.N. Alexandrov Research Institute of Oncology and Medical Radiology, Minsk, Belarus. Department of Radiation Oncology, Hannover Medical School, Hannover, Germany. Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark. Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.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.Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany. iFIT Cluster of Excellence, University of Tuebingen, Tuebingen, Germany. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany. Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg, Germany.Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia. Medical Faculty, Universidad de La Sabana, Bogota, Colombia.Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.Genome Sciences Centre, BC Cancer Agency, Vancouver, British Columbia, Canada. Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, British Columbia, Canada.Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum, Germany.Molecular Epidemiology Group (C080), German Cancer Research Center (DKFZ), Heidelberg, Germany. Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany.Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.SOD Genetica Molecolare, University Hospital, Pisa, Italy.Department of Internal Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.Research Department, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia. Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.Genomic Epidemiology Group, German Cancer Research Center (DKFZ), Heidelberg, Germany.Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo, Spain.Axe Oncologie, Centre de Recherche, Centre Hospitalier Universitaire de Québec, Université Laval, Québec, Québec, Canada.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.No affiliation info availableNo affiliation info availableDepartment of Clinical Genetics, Erasmus University Medical Center, Rotterdam, the Netherlands.Division of Molecular Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.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 Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands.Oncogenetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain. Clinical and Molecular Genetics Area, Vall Hebron University Hospital, Barcelona, Spain.Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Québec City, Québec, Canada. Département de Médecine Moléculaire, Faculté de Médecine, Centre de Recherche, Centre Hospitalier Universitaire de Québec, Laval University, Québec City, Québec, Canada.Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Québec City, Québec, Canada.Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Québec City, Québec, Canada.Cáncer Hereditario, Instituto de Biología y Genética Molecular (IBGM), Universidad de Valladolid Centro Superior de Investigaciones Científicas (UVA-CSIC), Valladolid, Spain.Southampton Clinical Trials Unit, Faculty of Medicine, University of Southampton, Southampton, UK. Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.School of Life Sciences, University of Westminster, London, UK.Faculty of Medicine, University of Southampton, Southampton, UK.Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester Academic Health Science Centre, Manchester, UK. North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.David Geffen School of Medicine, Department of Medicine, Division of Hematology and Oncology, University of California, Los Angeles, Los Angeles, CA, USA. Department of Gynecology and Obstetrics, Comprehensive Cancer Center ER-EMN, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen, Germany.Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark.Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada.The Suzanne Levy-Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel. Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel.School of Public Health, Curtin University, Perth, Western Australia, Australia.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.Genomic Medicine Group, Galician Foundation of Genomic Medicine, Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), Complejo Hospitalario Universitario de Santiago, SERGAS, Santiago de Compostela, Spain. Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA.SOD Genetica Molecolare, University Hospital, Pisa, Italy.Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Centre, University of California, Los Angeles, Los Angeles, CA, USA.Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.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.Behavioral and Epidemiology Research Group, American Cancer Society, Atlanta, GA, USA.Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia.Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada.Department of Pathology and Laboratory Medicine, Kansas University Medical Center, Kansas City, KS, USA.Department of Medicine, McGill University, Montréal, Québec, Canada. Division of Clinical Epidemiology, Royal Victoria Hospital, 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.U.O. Anatomia Patologica Ospedale di Circolo, ASST Settelaghi, Varese, Italy.Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.Department of Surgery, Oulu University Hospital, University of Oulu, Oulu, Finland.Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CHUM), Université de Montréal, Montréal, Québec, Canada.Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Paris, France.Center for Hereditary Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. 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.Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. Department of Oncology, Södersjukhuset, Stockholm, Sweden.Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.Saw Swee Hock School of Public Health, National University of Singapore, Singapore, Singapore. Department of Surgery, National University Health System, Singapore, Singapore.Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.School of Population and Global Health, The University of Western Australia, Perth, Western Australia, Australia.Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.Division of Cancer Sciences, University of Manchester, Manchester, UK.Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA. The University of Chicago Pritzker School of Medicine, Chicago, IL, USA.N.N. Petrov Institute of Oncology, St. Petersburg, Russia.No affiliation info availableNo affiliation info availableNo affiliation info availableLombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.Division of Epidemiology, Center for Public Health Sciences, National Cancer Center, Tokyo, Japan.Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of North Macedonia.Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland.Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia. 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. State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.Department of Medicine, Division of Hematology/Oncology, UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, UK.Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Department of Oncology, Tampere University Hospital, Tampere University and Tampere Cancer Center, Tampere, Finland.Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. Cancer Research Institute, Seoul National University, Seoul, Korea.Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Faculty of Medicine, University of Heidelberg, Heidelberg, Germany.David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.Division of Molecular Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.Surgery, School of Medicine, National University of Ireland, Galway, Ireland.Institute of Biochemistry and Genetics, Ufa Federal Research Centre of the Russian Academy of Sciences, Ufa, Russia. Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia.Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.Familial Cancer Service, Weatmead Hospital, Sydney, New South Wales, Australia.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.Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.Department of Histopathology and Cytology, Clinical Hospital 'Acibadem Sistina', Skopje, Republic of North Macedonia.Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong. Department of Surgery, The University of Hong Kong, Pok Fu Lam, Hong Kong. Department of Surgery, Hong Kong Sanatorium and Hospital, Happy Valley, Hong Kong.Department of Electron Microscopy/Molecular Pathology and The Cyprus School of Molecular Medicine, The Cyprus Institute of Neurology and Genetics, Nicosia, Cyprus.The Suzanne Levy-Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.VIB Center for Cancer Biology, VIB, Leuven, Belgium. Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven, Belgium.Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California, Los Angeles, Los Angeles, CA, USA. Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.Institut Curie, Paris, France. Mines ParisTech, Paris, France. Genetic Epidemiology of Cancer Team, INSERM U900, Paris, France.Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden.Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart, Germany.Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia.Southampton Clinical Trials Unit, Faculty of Medicine, University of Southampton, Southampton, UK. Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton, UK.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia.Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio, Finland. Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio, Finland.Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.Department of Oncology, Södersjukhuset, Stockholm, Sweden. Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA. Department of Family Medicine and Public Health, University of California, San Diego, La Jolla, CA, USA.Division of Cancer Epidemiology and Prevention, Aichi Cancer Center Research Institute, Nagoya, Japan. Division of Cancer Epidemiology, Nagoya University Graduate School of Medicine, Nagoya, Japan.Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Department of Medical Oncology, University Hospital of Heraklion, Heraklion, Greece.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Anatomical Pathology, The Alfred Hospital, Melbourne, Victoria, Australia.Institut Curie, Paris, France. Mines ParisTech, Paris, France. Department of Tumour Biology, INSERM U830, Paris, France.Department of Gynecology and Obstetrics, University of Munich, Munich, Germany.NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA.Surgery, School of Medicine, National University of Ireland, Galway, Ireland.Immunology and Molecular Oncology Unit, Veneto Institute of Oncology (IOV), IRCCS, Padua, Italy.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.Division of Population Health, Health Services Research and Primary Care, School of Health Sciences, Faculty of Biology, Medicine and Health, The University of Manchester, Manchester, UK.Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada.Radiation Oncology, Hospital Meixoeiro-XXI de Vigo, Vigo, Spain.Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.Women's College Research Institute, University of Toronto, Toronto, Ontario, Canada.Department of Pathology, School of Medicine, Umm Al-Qura University, Holy Makkah, Saudi Arabia.Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.Center for Genomic Medicine at Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.Latvian Biomedical Research and Study Centre, Riga, Latvia.Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.Clinical Genetics Research Laboratory, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Clinical Genetics Service, Department of Medicine, 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, UK.Centro de Investigación en Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM, USA.Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea. Department of Biomedical Sciences, Seoul National University Graduate School, Seoul, Korea. Cancer Research Institute, Seoul National University, Seoul, Korea.Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Cancer Research UK Clinical Trials Unit, Institute of Cancer Sciences, University of Glasgow, Glasgow, UK.Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark. Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark. Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.Genome Diagnostics Program, IFOM-the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan, Italy.Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London, UK.Research Centre for Genetic Engineering and Biotechnology 'Georgi D. Efremov', Macedonian Academy of Sciences and Arts, Skopje, Republic of North Macedonia.Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA, USA.School of Life Sciences, University of Westminster, London, UK.Department of Genetics and Fundamental Medicine, Bashkir State Medical University, Ufa, Russia.ProCURE, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain.Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.School of Women's and Children's Health, Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia. The Kinghorn Cancer Centre, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Clalit National Israeli Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.Center for Genomic Medicine at Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.Department of Oncology, University Hospital of Larissa, Larissa, Greece.Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid, Spain.Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.Centro de Investigación en Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. Fundación Pública Galega de Medicina Xenómica, Santiago de Compostela, Spain. Instituto de Investigación Sanitaria de Santiago de Compostela, Santiago de Compostela, Spain.School of Medicine, University of Western Australia, Perth, Western Australia, Australia.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.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Faculty of Information Technology, Monash University, Melbourne, Victoria, Australia.Center for Hereditary Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.Molecular Biology of Breast Cancer, University Womens Clinic Heidelberg, University of Heidelberg, Heidelberg, Germany. National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg, Germany.Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Heidelberg, Germany. Network Aging Research, University of Heidelberg, Heidelberg, Germany.Gynaecology Research Unit, Hannover Medical School, Hannover, Germany.Department of Health Sciences Research, Mayo Clinic, Rochester, MN, USA.Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, New South Wales, Australia. Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, New South Wales, Australia. Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales, Australia.Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA.Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan. School of Public Health, China Medical University, Taichung, Taiwan.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.Clinical Cancer Genomics, City of Hope, Duarte, CA, USA.University Clinic of Radiotherapy and Oncology, Medical Faculty, Ss. Cyril and Methodius University in Skopje, Skopje, Republic of North Macedonia.Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia. Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.Population Oncology, BC Cancer, Vancouver, British Columbia, Canada. School of Population and Public Health, University of British Columbia, Vancouver, British Columbia, Canada.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, Western Australia, Australia.Department of Tumour Biology, INSERM U830, Paris, France. Service de Génétique, Institut Curie, Paris, France. Université Paris Descartes, Paris, France.Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK. Division of Breast Cancer Research, The Institute of Cancer Research, London, UK.Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA, USA.Department of Obstetrics and Gynecology, Medical University of Vienna, Vienna, Austria.Faculty of Medicine, University of Southampton, Southampton, UK.Epidemiology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA. Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC, USA.Department of Genetics, Portuguese Oncology Institute, Porto, Portugal. Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.Translational Cancer Research Area, University of Eastern Finland, Kuopio, Finland. Cancer Center, Kuopio University Hospital, Kuopio, Finland. Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio, Finland.Breast Cancer Research Programme, Cancer Research Malaysia, Kuala Lumpur, Malaysia. Department of Surgery, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia.Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY, USA.Hereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.Department of Clinical Genetics, Odense University Hospital, Odence, Denmark.Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, Québec, Canada. Department of Medical Genetics, University of Cambridge, Cambridge, UK.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. Wellcome Trust Centre for Human Genetics and NIHR Oxford Biomedical Research Centre, University of Oxford, Oxford, UK.Institute of Human Genetics, Pontificia Universidad Javeriana, Bogota, Colombia. Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.Center for Population Health Research, National Institute of Public Health, Cuernavaca, Mexico.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.Cancer and Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Paris, France.Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.Department of Pathology, University Hospital of Heraklion, Heraklion, Greece.Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden, Germany.Department of Health Science Research, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA.Department of Clinical Genetics, Leiden University Medical Center, Leiden, the Netherlands.Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.Department of Genetics, University of Pretoria, Pretoria, South Africa.Fundación Pública Galega de Medicina Xenómica-SERGAS, Grupo de Medicina Xenómica-USC, CIBERER, IDIS, Santiago de Compostela, Spain.Division of Functional Onco-genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.Clinical Genetics Research Laboratory, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA. Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.Family Cancer Clinic, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Center for Hereditary Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany. Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, USA.Clinical Cancer Genomics, City of Hope, Duarte, CA, USA.Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm, Sweden.Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven, Belgium.Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu, Finland. Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu, Finland.Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden. Department of Surgical Sciences, Uppsala University, Uppsala, Sweden.Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.Division of Clinical Epidemiology and Aging Research (C070), German Cancer Research Center (DKFZ), Heidelberg, Germany. German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany.Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA.Nuffield Department of Population Health, University of Oxford, Oxford, UK.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany. Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg, Germany.Division of Cancer Epidemiology and Genetics, Department of Health and Human Services, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. Division of Genetics and Epidemiology, Institute of Cancer Research, London, UK.Division of Molecular Pathology, Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands.Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, Victoria, Australia. Cancer Epidemiology Division, Cancer Council Victoria, Melbourne, Victoria, Australia. Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Melbourne, Victoria, Australia.Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo, Norway. Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo, Norway. The Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON) Coordinating Center, The Netherlands Cancer Institute, Amsterdam, the Netherlands. Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, New South Wales, Australia.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.Genomics Center, Centre Hospitalier Universitaire de Québec, Université Laval Research Center, Québec City, Québec, Canada.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.Program in Genetic Epidemiology and Statistical Genetics, Harvard T.H. Chan School of Public Health, Boston, MA, USA. pkraft@hsph.harvard.edu. Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA. pkraft@hsph.harvard.edu.Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK. amd24@medschl.cam.ac.uk.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31911677

Citation

Fachal, Laura, et al. "Fine-mapping of 150 Breast Cancer Risk Regions Identifies 191 Likely Target Genes." Nature Genetics, vol. 52, no. 1, 2020, pp. 56-73.
Fachal L, Aschard H, Beesley J, et al. Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nat Genet. 2020;52(1):56-73.
Fachal, L., Aschard, H., Beesley, J., Barnes, D. R., Allen, J., Kar, S., ... Dunning, A. M. (2020). Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. Nature Genetics, 52(1), pp. 56-73. doi:10.1038/s41588-019-0537-1.
Fachal L, et al. Fine-mapping of 150 Breast Cancer Risk Regions Identifies 191 Likely Target Genes. Nat Genet. 2020;52(1):56-73. PubMed PMID: 31911677.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Fine-mapping of 150 breast cancer risk regions identifies 191 likely target genes. AU - Fachal,Laura, AU - Aschard,Hugues, AU - Beesley,Jonathan, AU - Barnes,Daniel R, AU - Allen,Jamie, AU - Kar,Siddhartha, AU - Pooley,Karen A, AU - Dennis,Joe, AU - Michailidou,Kyriaki, AU - Turman,Constance, AU - Soucy,Penny, AU - Lemaçon,Audrey, AU - Lush,Michael, AU - Tyrer,Jonathan P, AU - Ghoussaini,Maya, AU - Moradi Marjaneh,Mahdi, AU - Jiang,Xia, AU - Agata,Simona, AU - Aittomäki,Kristiina, AU - Alonso,M Rosario, AU - Andrulis,Irene L, AU - Anton-Culver,Hoda, AU - Antonenkova,Natalia N, AU - Arason,Adalgeir, AU - Arndt,Volker, AU - Aronson,Kristan J, AU - Arun,Banu K, AU - Auber,Bernd, AU - Auer,Paul L, AU - Azzollini,Jacopo, AU - Balmaña,Judith, AU - Barkardottir,Rosa B, AU - Barrowdale,Daniel, AU - Beeghly-Fadiel,Alicia, AU - Benitez,Javier, AU - Bermisheva,Marina, AU - Białkowska,Katarzyna, AU - Blanco,Amie M, AU - Blomqvist,Carl, AU - Blot,William, AU - Bogdanova,Natalia V, AU - Bojesen,Stig E, AU - Bolla,Manjeet K, AU - Bonanni,Bernardo, AU - Borg,Ake, AU - Bosse,Kristin, AU - Brauch,Hiltrud, AU - Brenner,Hermann, AU - Briceno,Ignacio, AU - Brock,Ian W, AU - Brooks-Wilson,Angela, AU - Brüning,Thomas, AU - Burwinkel,Barbara, AU - Buys,Saundra S, AU - Cai,Qiuyin, AU - Caldés,Trinidad, AU - Caligo,Maria A, AU - Camp,Nicola J, AU - Campbell,Ian, AU - Canzian,Federico, AU - Carroll,Jason S, AU - Carter,Brian D, AU - Castelao,Jose E, AU - Chiquette,Jocelyne, AU - Christiansen,Hans, AU - Chung,Wendy K, AU - Claes,Kathleen B M, AU - Clarke,Christine L, AU - ,, AU - ,, AU - Collée,J Margriet, AU - Cornelissen,Sten, AU - Couch,Fergus J, AU - Cox,Angela, AU - Cross,Simon S, AU - Cybulski,Cezary, AU - Czene,Kamila, AU - Daly,Mary B, AU - de la Hoya,Miguel, AU - Devilee,Peter, AU - Diez,Orland, AU - Ding,Yuan Chun, AU - Dite,Gillian S, AU - Domchek,Susan M, AU - Dörk,Thilo, AU - Dos-Santos-Silva,Isabel, AU - Droit,Arnaud, AU - Dubois,Stéphane, AU - Dumont,Martine, AU - Duran,Mercedes, AU - Durcan,Lorraine, AU - Dwek,Miriam, AU - Eccles,Diana M, AU - Engel,Christoph, AU - Eriksson,Mikael, AU - Evans,D Gareth, AU - Fasching,Peter A, AU - Fletcher,Olivia, AU - Floris,Giuseppe, AU - Flyger,Henrik, AU - Foretova,Lenka, AU - Foulkes,William D, AU - Friedman,Eitan, AU - Fritschi,Lin, AU - Frost,Debra, AU - Gabrielson,Marike, AU - Gago-Dominguez,Manuela, AU - Gambino,Gaetana, AU - Ganz,Patricia A, AU - Gapstur,Susan M, AU - Garber,Judy, AU - García-Sáenz,José A, AU - Gaudet,Mia M, AU - Georgoulias,Vassilios, AU - Giles,Graham G, AU - Glendon,Gord, AU - Godwin,Andrew K, AU - Goldberg,Mark S, AU - Goldgar,David E, AU - González-Neira,Anna, AU - Tibiletti,Maria Grazia, AU - Greene,Mark H, AU - Grip,Mervi, AU - Gronwald,Jacek, AU - Grundy,Anne, AU - Guénel,Pascal, AU - Hahnen,Eric, AU - Haiman,Christopher A, AU - Håkansson,Niclas, AU - Hall,Per, AU - Hamann,Ute, AU - Harrington,Patricia A, AU - Hartikainen,Jaana M, AU - Hartman,Mikael, AU - He,Wei, AU - Healey,Catherine S, AU - Heemskerk-Gerritsen,Bernadette A M, AU - Heyworth,Jane, AU - Hillemanns,Peter, AU - Hogervorst,Frans B L, AU - Hollestelle,Antoinette, AU - Hooning,Maartje J, AU - Hopper,John L, AU - Howell,Anthony, AU - Huang,Guanmengqian, AU - Hulick,Peter J, AU - Imyanitov,Evgeny N, AU - ,, AU - ,, AU - ,, AU - Isaacs,Claudine, AU - Iwasaki,Motoki, AU - Jager,Agnes, AU - Jakimovska,Milena, AU - Jakubowska,Anna, AU - James,Paul A, AU - Janavicius,Ramunas, AU - Jankowitz,Rachel C, AU - John,Esther M, AU - Johnson,Nichola, AU - Jones,Michael E, AU - Jukkola-Vuorinen,Arja, AU - Jung,Audrey, AU - Kaaks,Rudolf, AU - Kang,Daehee, AU - Kapoor,Pooja Middha, AU - Karlan,Beth Y, AU - Keeman,Renske, AU - Kerin,Michael J, AU - Khusnutdinova,Elza, AU - Kiiski,Johanna I, AU - Kirk,Judy, AU - Kitahara,Cari M, AU - Ko,Yon-Dschun, AU - Konstantopoulou,Irene, AU - Kosma,Veli-Matti, AU - Koutros,Stella, AU - Kubelka-Sabit,Katerina, AU - Kwong,Ava, AU - Kyriacou,Kyriacos, AU - Laitman,Yael, AU - Lambrechts,Diether, AU - Lee,Eunjung, AU - Leslie,Goska, AU - Lester,Jenny, AU - Lesueur,Fabienne, AU - Lindblom,Annika, AU - Lo,Wing-Yee, AU - Long,Jirong, AU - Lophatananon,Artitaya, AU - Loud,Jennifer T, AU - Lubiński,Jan, AU - MacInnis,Robert J, AU - Maishman,Tom, AU - Makalic,Enes, AU - Mannermaa,Arto, AU - Manoochehri,Mehdi, AU - Manoukian,Siranoush, AU - Margolin,Sara, AU - Martinez,Maria Elena, AU - Matsuo,Keitaro, AU - Maurer,Tabea, AU - Mavroudis,Dimitrios, AU - Mayes,Rebecca, AU - McGuffog,Lesley, AU - McLean,Catriona, AU - Mebirouk,Noura, AU - Meindl,Alfons, AU - Miller,Austin, AU - Miller,Nicola, AU - Montagna,Marco, AU - Moreno,Fernando, AU - Muir,Kenneth, AU - Mulligan,Anna Marie, AU - Muñoz-Garzon,Victor M, AU - Muranen,Taru A, AU - Narod,Steven A, AU - Nassir,Rami, AU - Nathanson,Katherine L, AU - Neuhausen,Susan L, AU - Nevanlinna,Heli, AU - Neven,Patrick, AU - Nielsen,Finn C, AU - Nikitina-Zake,Liene, AU - Norman,Aaron, AU - Offit,Kenneth, AU - Olah,Edith, AU - Olopade,Olufunmilayo I, AU - Olsson,Håkan, AU - Orr,Nick, AU - Osorio,Ana, AU - Pankratz,V Shane, AU - Papp,Janos, AU - Park,Sue K, AU - Park-Simon,Tjoung-Won, AU - Parsons,Michael T, AU - Paul,James, AU - Pedersen,Inge Sokilde, AU - Peissel,Bernard, AU - Peshkin,Beth, AU - Peterlongo,Paolo, AU - Peto,Julian, AU - Plaseska-Karanfilska,Dijana, AU - Prajzendanc,Karolina, AU - Prentice,Ross, AU - Presneau,Nadege, AU - Prokofyeva,Darya, AU - Pujana,Miquel Angel, AU - Pylkäs,Katri, AU - Radice,Paolo, AU - Ramus,Susan J, AU - Rantala,Johanna, AU - Rau-Murthy,Rohini, AU - Rennert,Gad, AU - Risch,Harvey A, AU - Robson,Mark, AU - Romero,Atocha, AU - Rossing,Maria, AU - Saloustros,Emmanouil, AU - Sánchez-Herrero,Estela, AU - Sandler,Dale P, AU - Santamariña,Marta, AU - Saunders,Christobel, AU - Sawyer,Elinor J, AU - Scheuner,Maren T, AU - Schmidt,Daniel F, AU - Schmutzler,Rita K, AU - Schneeweiss,Andreas, AU - Schoemaker,Minouk J, AU - Schöttker,Ben, AU - Schürmann,Peter, AU - Scott,Christopher, AU - Scott,Rodney J, AU - Senter,Leigha, AU - Seynaeve,Caroline M, AU - Shah,Mitul, AU - Sharma,Priyanka, AU - Shen,Chen-Yang, AU - Shu,Xiao-Ou, AU - Singer,Christian F, AU - Slavin,Thomas P, AU - Smichkoska,Snezhana, AU - Southey,Melissa C, AU - Spinelli,John J, AU - Spurdle,Amanda B, AU - Stone,Jennifer, AU - Stoppa-Lyonnet,Dominique, AU - Sutter,Christian, AU - Swerdlow,Anthony J, AU - Tamimi,Rulla M, AU - Tan,Yen Yen, AU - Tapper,William J, AU - Taylor,Jack A, AU - Teixeira,Manuel R, AU - Tengström,Maria, AU - Teo,Soo Hwang, AU - Terry,Mary Beth, AU - Teulé,Alex, AU - Thomassen,Mads, AU - Thull,Darcy L, AU - Tischkowitz,Marc, AU - Toland,Amanda E, AU - Tollenaar,Rob A E M, AU - Tomlinson,Ian, AU - Torres,Diana, AU - Torres-Mejía,Gabriela, AU - Troester,Melissa A, AU - Truong,Thérèse, AU - Tung,Nadine, AU - Tzardi,Maria, AU - Ulmer,Hans-Ulrich, AU - Vachon,Celine M, AU - van Asperen,Christi J, AU - van der Kolk,Lizet E, AU - van Rensburg,Elizabeth J, AU - Vega,Ana, AU - Viel,Alessandra, AU - Vijai,Joseph, AU - Vogel,Maartje J, AU - Wang,Qin, AU - Wappenschmidt,Barbara, AU - Weinberg,Clarice R, AU - Weitzel,Jeffrey N, AU - Wendt,Camilla, AU - Wildiers,Hans, AU - Winqvist,Robert, AU - Wolk,Alicja, AU - Wu,Anna H, AU - Yannoukakos,Drakoulis, AU - Zhang,Yan, AU - Zheng,Wei, AU - Hunter,David, AU - Pharoah,Paul D P, AU - Chang-Claude,Jenny, AU - García-Closas,Montserrat, AU - Schmidt,Marjanka K, AU - Milne,Roger L, AU - Kristensen,Vessela N, AU - French,Juliet D, AU - Edwards,Stacey L, AU - Antoniou,Antonis C, AU - Chenevix-Trench,Georgia, AU - Simard,Jacques, AU - Easton,Douglas F, AU - Kraft,Peter, AU - Dunning,Alison M, Y1 - 2020/01/07/ PY - 2018/12/13/received PY - 2019/10/24/accepted PY - 2020/07/07/pmc-release PY - 2020/1/9/pubmed PY - 2020/1/9/medline PY - 2020/1/9/entrez SP - 56 EP - 73 JF - Nature genetics JO - Nat. Genet. VL - 52 IS - 1 N2 - Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT pipeline for prioritizing genes as targets of those potentially causal variants, using gene expression (expression quantitative trait loci), chromatin interaction and functional annotations. Known cancer drivers, transcription factors and genes in the developmental, apoptosis, immune system and DNA integrity checkpoint gene ontology pathways were over-represented among the highest-confidence target genes. SN - 1546-1718 UR - https://www.unboundmedicine.com/medline/citation/31911677/Fine-mapping_of_150_breast_cancer_risk_regions_identifies_191_likely_target_genes L2 - http://dx.doi.org/10.1038/s41588-019-0537-1 DB - PRIME DP - Unbound Medicine ER -