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Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.

About this Publication
Title
Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.
Pubmed ID
30554720 (View this publication on the PubMed website)
Digital Object Identifier
Publication
Am J Hum Genet. 2019 Jan 3; Volume 104 (Issue 1): Pages 21-34
Authors
Mavaddat N, Michailidou K, Dennis J, Lush M, Fachal L, Lee A, Tyrer JP, Chen TH, Wang Q, Bolla MK, Yang X, Adank MA, Ahearn T, Aittomäki K, Allen J, Andrulis IL, Anton-Culver H, Antonenkova NN, Arndt V, Aronson KJ, ...show more Auer PL, Auvinen P, Barrdahl M, Beane Freeman LE, Beckmann MW, Behrens S, Benitez J, Bermisheva M, Bernstein L, Blomqvist C, Bogdanova NV, Bojesen SE, Bonanni B, Børresen-Dale AL, Brauch H, Bremer M, Brenner H, Brentnall A, Brock IW, Brooks-Wilson A, Brucker SY, Brüning T, Burwinkel B, Campa D, Carter BD, Castelao JE, Chanock SJ, Chlebowski R, Christiansen H, Clarke CL, Collée JM, Cordina-Duverger E, Cornelissen S, Couch FJ, Cox A, Cross SS, Czene K, Daly MB, Devilee P, Dörk T, Dos-Santos-Silva I, Dumont M, Durcan L, Dwek M, Eccles DM, Ekici AB, Eliassen AH, Ellberg C, Engel C, Eriksson M, Evans DG, Fasching PA, Figueroa J, Fletcher O, Flyger H, Försti A, Fritschi L, Gabrielson M, Gago-Dominguez M, Gapstur SM, García-Sáenz JA, Gaudet MM, Georgoulias V, Giles GG, Gilyazova IR, Glendon G, Goldberg MS, Goldgar DE, González-Neira A, Grenaker Alnæs GI, Grip M, Gronwald J, Grundy A, Guénel P, Haeberle L, Hahnen E, Haiman CA, Håkansson N, Hamann U, Hankinson SE, Harkness EF, Hart SN, He W, Hein A, Heyworth J, Hillemanns P, Hollestelle A, Hooning MJ, Hoover RN, Hopper JL, Howell A, Huang G, Humphreys K, Hunter DJ, Jakimovska M, Jakubowska A, Janni W, John EM, Johnson N, Jones ME, Jukkola-Vuorinen A, Jung A, Kaaks R, Kaczmarek K, Kataja V, Keeman R, Kerin MJ, Khusnutdinova E, Kiiski JI, Knight JA, Ko YD, Kosma VM, Koutros S, Kristensen VN, Krüger U, Kühl T, Lambrechts D, Le Marchand L, Lee E, Lejbkowicz F, Lilyquist J, Lindblom A, Lindström S, Lissowska J, Lo WY, Loibl S, Long J, Lubiński J, Lux MP, MacInnis RJ, Maishman T, Makalic E, Maleva Kostovska I, Mannermaa A, Manoukian S, Margolin S, Martens JWM, Martinez ME, Mavroudis D, McLean C, Meindl A, Menon U, Middha P, Miller N, Moreno F, Mulligan AM, Mulot C, Muñoz-Garzon VM, Neuhausen SL, Nevanlinna H, Neven P, Newman WG, Nielsen SF, Nordestgaard BG, Norman A, Offit K, Olson JE, Olsson H, Orr N, Pankratz VS, Park-Simon TW, Perez JIA, Pérez-Barrios C, Peterlongo P, Peto J, Pinchev M, Plaseska-Karanfilska D, Polley EC, Prentice R, Presneau N, Prokofyeva D, Purrington K, Pylkäs K, Rack B, Radice P, Rau-Murthy R, Rennert G, Rennert HS, Rhenius V, Robson M, Romero A, Ruddy KJ, Ruebner M, Saloustros E, Sandler DP, Sawyer EJ, Schmidt DF, Schmutzler RK, Schneeweiss A, Schoemaker MJ, Schumacher F, Schürmann P, Schwentner L, Scott C, Scott RJ, Seynaeve C, Shah M, Sherman ME, Shrubsole MJ, Shu XO, Slager S, Smeets A, Sohn C, Soucy P, Southey MC, Spinelli JJ, Stegmaier C, Stone J, Swerdlow AJ, Tamimi RM, Tapper WJ, Taylor JA, Terry MB, Thöne K, Tollenaar RAEM, Tomlinson I, Truong T, Tzardi M, Ulmer HU, Untch M, Vachon CM, van Veen EM, Vijai J, Weinberg CR, Wendt C, Whittemore AS, Wildiers H, Willett W, Winqvist R, Wolk A, Yang XR, Yannoukakos D, Zhang Y, Zheng W, Ziogas A, ABCTB Investigators, kConFab/AOCS Investigators, NBCS Collaborators, Dunning AM, Thompson DJ, Chenevix-Trench G, Chang-Claude J, Schmidt MK, Hall P, Milne RL, Pharoah PDP, Antoniou AC, Chatterjee N, Kraft P, García-Closas M, Simard J, Easton DF
Affiliations
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK. Electronic address: nm274@medschl.cam.ac.uk.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Department of Electron Microscopy/Molecular Pathology, The Cyprus Institute of Neurology and Genetics, 1683 Nicosia, Cyprus.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
  • Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
  • Department of Mathematics and Statistics, Laval University, Québec City, QC G1V 0A6, Canada.
  • Family Cancer Clinic, the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, the Netherlands.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA.
  • Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
  • Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92617, USA.
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  • NN Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Zilber School of Public Health, University of Wisconsin-Milwaukee, Milwaukee, WI 53205, USA.
  • Cancer Center, Kuopio University Hospital, Kuopio 70210, Finland; Institute of Clinical Medicine, Oncology, University of Eastern Finland, Kuopio 70210, Finland; Translational Cancer Research Area, University of Eastern Finland, Kuopio 70210, Finland.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
  • Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
  • Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa 450054, Russia.
  • Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
  • Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland; Department of Oncology, Örebro University Hospital, Örebro 70185, Sweden.
  • NN Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus; Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany; Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark; Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen 2200, Denmark.
  • Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0450, Norway.
  • Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany; University of Tübingen, Tübingen 72074, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany.
  • Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Division of Preventive Oncology, German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Heidelberg 69120, Germany.
  • Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
  • Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2TN, UK.
  • Genome Sciences Centre, BC Cancer Agency, Vancouver, BC V5Z 1L3, Canada; Department of Biomedical Physiology and Kinesiology, Simon Fraser University, Burnaby, BC V5A 1S6, Canada.
  • Department of Gynecology and Obstetrics, University of Tübingen, Tübingen 72076, Germany.
  • Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum 44789, Germany.
  • Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany; Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Biology, University of Pisa, Pisa 56126, Italy.
  • Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.
  • Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo 36312, Spain.
  • Division of Medical Oncology and Hematology, University of California at Los Angeles, Los Angeles, CA 90024, USA.
  • Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
  • Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.
  • Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif 94805, France.
  • Division of Molecular Pathology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands.
  • Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
  • Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden.
  • Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
  • Department of Pathology, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands; Department of Human Genetics, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
  • Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
  • Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Université Laval, Québec City, QC G1V 4G2, Canada.
  • Southampton Clinical Trials Unit, Faculty of Medicine, University of Southampton, Southampton SO17 6YD, UK; Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 6YD, UK.
  • School of Life Sciences, University of Westminster, London W1B 2HW, UK.
  • Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 6YD, UK.
  • Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
  • Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund 222 42, Sweden.
  • Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig 04107, Germany; LIFE - Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig 04103, Germany.
  • Division of Evolution and Genomic Sciences, School of Biological Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9WL, UK; North West Genomic Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
  • Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany; David Geffen School of Medicine, Department of Medicine Division of Hematology and Oncology, University of California at Los Angeles, Los Angeles, CA 90095, USA.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA; Usher Institute of Population Health Sciences and Informatics, The University of Edinburgh Medical School, Edinburgh EH16 4TJ, UK; Cancer Research UK Edinburgh Centre, Edinburgh EH4 2XR, UK.
  • The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK.
  • Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark.
  • Division of Molecular Genetic Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Center for Primary Health Care Research, Clinical Research Center, Lund University, Malmö 205 02, Sweden.
  • School of Public Health, Curtin University, Perth, WA 6102, Australia.
  • 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 15706, Spain; Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA.
  • Medical Oncology Department, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria San Carlos (IdISSC), Centro Investigación Biomédica en Red de Cáncer (CIBERONC), Madrid 28040, Spain.
  • Department of Medical Oncology, University Hospital of Heraklion, Heraklion 711 10, Greece.
  • Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, VIC 3004, Australia.
  • Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa 450054, Russia; Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa 450076, Russia.
  • Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
  • Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC H4A 3J1, Canada.
  • Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
  • Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway.
  • Department of Surgery, Oulu University Hospital, University of Oulu, Oulu 90220, Finland.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland.
  • Centre de Recherche du Centre Hospitalier de Université de Montréal (CHUM), Université de Montréal, Montréal, QC H2X 0A9, Canada.
  • Center for Hereditary Breast and Ovarian Cancer, University Hospital of Cologne, Cologne 50937, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne 50931, Germany.
  • Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
  • Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, Amherst, MA 1003, USA.
  • Division of Informatics, Imaging and Data Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester Academic Health Science Centre, Manchester M13 9PT, UK; Nightingale Breast Screening Centre, Wythenshawe Hospital, Manchester University NHS Foundation Trust, Manchester M23 9LT, UK; NIHR Manchester Biomedical Research Centre, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
  • Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
  • School of Population and Global Health, University of Western Australia, Perth, WA 6009, Australia.
  • Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam 3015 CN, the Netherlands.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK.
  • Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Nuffield Department of Population Health, University of Oxford, Oxford OX3 7LF, UK.
  • Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov," Macedonian Academy of Sciences and Arts, Skopje 1000, Republic of Macedonia.
  • Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin 71-252, Poland.
  • Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm 89075, Germany.
  • Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
  • Department of Oncology, Tampere University Hospital, Tampere, Finland Box 2000, 33521 Tampere, Finland.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio 70210, Finland; Central Finland Health Care District, Jyväskylä Central Hospital, Jyväskylä 40620, Finland.
  • Surgery, School of Medicine, National University of Ireland, Galway H91TK33, Ireland.
  • Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland.
  • Prosserman Centre for Population Health Research, Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON M5T 3L9, Canada; Division of Epidemiology, Dalla Lana School of Public Health, University of Toronto, Toronto, ON M5T 3M7, Canada.
  • Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn 53177, Germany.
  • Translational Cancer Research Area, University of Eastern Finland, Kuopio 70210, Finland; Institute of Clinical Medicine, Pathology and Forensic Medicine, University of Eastern Finland, Kuopio 70210, Finland; Imaging Center, Department of Clinical Pathology, Kuopio University Hospital, Kuopio 70210, Finland.
  • Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
  • VIB Center for Cancer Biology, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven 3000, Belgium.
  • Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
  • Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa 35254, Israel.
  • Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden.
  • Department of Epidemiology, University of Washington School of Public Health, Seattle, WA 98195, USA; Public Health Sciences Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Department of Cancer Epidemiology and Prevention, M Sklodowska-Curie Cancer Center - Oncology Institute, Warsaw 02-034, Poland.
  • Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany; University of Tübingen, Tübingen 72074, Germany.
  • German Breast Group, GmbH, Neu Isenburg 63263, Germany.
  • Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan 20133, Italy.
  • Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm 118 83, Sweden; Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden.
  • Moores Cancer Center, University of California San Diego, La Jolla, CA 92093, USA; Department of Family Medicine and Public Health, University of California San Diego, La Jolla, CA 92093, USA.
  • Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
  • Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich 80336, Germany.
  • MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London WC1V 6LJ, UK.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Faculty of Medicine, University of Heidelberg, Heidelberg 69120, Germany.
  • Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON M5S 1A8, Canada; Laboratory Medicine Program, University Health Network, Toronto, ON M5G 2C4, Canada.
  • Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris 75270, France.
  • Radiation Oncology, Hospital Meixoeiro-XXI de Vigo, Vigo 36214, Spain.
  • Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven 3000, Belgium.
  • Copenhagen General Population Study, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark; Department of Clinical Biochemistry, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark.
  • Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT7 1NN, UK.
  • University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131, USA.
  • Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo 33012, Spain.
  • Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid 28222, Spain.
  • Genome Diagnostic Program, IFOM the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan 20139, Italy.
  • Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  • Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa 450076, Russia.
  • Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
  • Laboratory of Cancer Genetics and Tumor Biology, Cancer and Translational Medicine Research Unit, Biocenter Oulu, University of Oulu, Oulu 90220, Finland; Laboratory of Cancer Genetics and Tumor Biology, Northern Finland Laboratory Centre Oulu, Oulu 90220, Finland.
  • Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan 20133, Italy.
  • Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
  • Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
  • Department of Oncology, University Hospital of Larissa, Larissa 711 10, Greece.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Faculty of Information Technology, Monash University, Melbourne, VIC 3800, Australia.
  • National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg 69120, Germany.
  • Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
  • Division of Molecular Medicine, Pathology North, John Hunter Hospital, Newcastle, NSW 2305, Australia; Discipline of Medical Genetics, School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Callaghan, NSW 2308, Australia; Hunter Medical Research Institute, John Hunter Hospital, Newcastle, NSW 2305, Australia.
  • Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
  • Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia; Department of Clinical Pathology, The University of Melbourne, Melbourne, VIC 3010, Australia.
  • Population Oncology, BC Cancer, Vancouver, BC V5Z 1G1, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
  • Saarland Cancer Registry, Saarbrücken 66119, Germany.
  • Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; The Curtin UWA Centre for Genetic Origins of Health and Disease, Curtin University and University of Western Australia, Perth, WA 6000, Australia.
  • Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK; Division of Breast Cancer Research, The Institute of Cancer Research, London SW7 3RP, UK.
  • Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
  • Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
  • Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA; Epigenetic and Stem Cell Biology Laboratory, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
  • Department of Surgery, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
  • Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham B15 2TT, UK; Wellcome Trust Centre for Human Genetics and Oxford NIHR Biomedical Research Centre, University of Oxford, Oxford OX3 7BN, UK.
  • Department of Pathology, University Hospital of Heraklion, Heraklion 711 10, Greece.
  • Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden 76532, Germany.
  • Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin 13125, Germany.
  • Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
  • Department of Health Research and Policy - Epidemiology, Stanford University School of Medicine, Stanford, CA 94305, USA; Department of Biomedical Data Science, Stanford University School of Medicine, Stanford, CA 94305, USA.
  • Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Department of Nutrition, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Channing Division of Network Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
  • Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala 751 05, Sweden.
  • Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos," Athens 15310, Greece.
  • Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
  • Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia.
  • Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; Institute of Clinical Medicine, Faculty of Medicine, University of Oslo, Oslo 0450, Norway; Department of Research, Vestre Viken Hospital, Drammen 3019, Norway; Department of Cancer Genetics, Vestre Viken Hospital, Drammen 3019, Norway; Section for Breast and Endocrine Surgery, Department of Cancer, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Ullevål, Oslo 0450, Norway; Department of Radiology and Nuclear Medicine, Oslo University Hospital, Oslo 0379, Norway; Department of Pathology, Akershus University Hospital, Lørenskog 1478, Norway; Department of Tumor Biology, Institute for Cancer Research, Oslo University Hospital, Oslo 0379, Norway; Department of Oncology, Division of Surgery, Cancer and Transplantation Medicine, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; National Advisory Unit on Late Effects after Cancer Treatment, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway; Department of Oncology, Akershus University Hospital, Lørenskog 1478, Norway; Breast Cancer Research Consortium, Oslo University Hospital, Oslo 0379, Norway.
  • Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
  • Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
  • Division of Molecular Pathology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands; Division of Psychosocial Research and Epidemiology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam 1066 CX, the Netherlands.
  • Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden; Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden.
  • Cancer Epidemiology & Intelligence Division, Cancer Council Victoria, Melbourne, VIC 3004, Australia; Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia; Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, VIC 3168, Australia.
  • Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
  • Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA; Department of Biostatistics, Bloomberg School of Public Health, John Hopkins University, Baltimore, MD 21205, USA; Department of Oncology, School of Medicine, John Hopkins University, Baltimore, MD 21205, USA.
  • Department of Epidemiology, Harvard TH Chan School of Public Health, Boston, MA 02115, USA; Program in Genetic Epidemiology and Statistical Genetics, Harvard TH Chan School of Public Health, Boston, MA 02115, USA.
Abstract

Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.

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