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Am J Hum Genet. 2019 Jan 3;104(1):21-34. doi: 10.1016/j.ajhg.2018.11.002. Epub 2018 Dec 13.

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

Mavaddat N1, Michailidou K2, Dennis J3, Lush M3, Fachal L4, Lee A3, Tyrer JP4, Chen TH5, Wang Q3, Bolla MK3, Yang X3, Adank MA6, Ahearn T7, Aittomäki K8, Allen J3, Andrulis IL9, Anton-Culver H10, Antonenkova NN11, Arndt V12, Aronson KJ13, Auer PL14, Auvinen P15, Barrdahl M16, Beane Freeman LE7, Beckmann MW17, Behrens S16, Benitez J18, Bermisheva M19, Bernstein L20, Blomqvist C21, Bogdanova NV22, Bojesen SE23, Bonanni B24, Børresen-Dale AL25, Brauch H26, Bremer M27, Brenner H28, Brentnall A29, Brock IW30, Brooks-Wilson A31, Brucker SY32, Brüning T33, Burwinkel B34, Campa D35, Carter BD36, Castelao JE37, Chanock SJ7, Chlebowski R38, Christiansen H27, Clarke CL39, Collée JM40, Cordina-Duverger E41, Cornelissen S42, Couch FJ43, Cox A30, Cross SS44, Czene K45, Daly MB46, Devilee P47, Dörk T48, Dos-Santos-Silva I49, Dumont M50, Durcan L51, Dwek M52, Eccles DM53, Ekici AB54, Eliassen AH55, Ellberg C56, Engel C57, Eriksson M45, Evans DG58, Fasching PA59, Figueroa J60, Fletcher O61, Flyger H62, Försti A63, Fritschi L64, Gabrielson M45, Gago-Dominguez M65, Gapstur SM36, García-Sáenz JA66, Gaudet MM36, Georgoulias V67, Giles GG68, Gilyazova IR69, Glendon G70, Goldberg MS71, Goldgar DE72, González-Neira A73, Grenaker Alnæs GI74, Grip M75, Gronwald J76, Grundy A77, Guénel P41, Haeberle L17, Hahnen E78, Haiman CA79, Håkansson N80, Hamann U81, Hankinson SE82, Harkness EF83, Hart SN84, He W45, Hein A17, Heyworth J85, Hillemanns P48, Hollestelle A86, Hooning MJ86, Hoover RN7, Hopper JL87, Howell A88, Huang G81, Humphreys K45, Hunter DJ89, Jakimovska M90, Jakubowska A91, Janni W92, John EM93, Johnson N61, Jones ME94, Jukkola-Vuorinen A95, Jung A16, Kaaks R16, Kaczmarek K76, Kataja V96, Keeman R42, Kerin MJ97, Khusnutdinova E69, Kiiski JI98, Knight JA99, Ko YD100, Kosma VM101, Koutros S7, Kristensen VN25, Krüger U56, Kühl T102, Lambrechts D103, Le Marchand L104, Lee E79, Lejbkowicz F105, Lilyquist J84, Lindblom A106, Lindström S107, Lissowska J108, Lo WY109, Loibl S110, Long J111, Lubiński J76, Lux MP17, MacInnis RJ112, Maishman T51, Makalic E87, Maleva Kostovska I90, Mannermaa A101, Manoukian S113, Margolin S114, Martens JWM86, Martinez ME115, Mavroudis D67, McLean C116, Meindl A117, Menon U118, Middha P119, Miller N97, Moreno F66, Mulligan AM120, Mulot C121, Muñoz-Garzon VM122, Neuhausen SL20, Nevanlinna H98, Neven P123, Newman WG58, Nielsen SF124, Nordestgaard BG23, Norman A84, Offit K125, Olson JE84, Olsson H56, Orr N126, Pankratz VS127, Park-Simon TW48, Perez JIA128, Pérez-Barrios C129, Peterlongo P130, Peto J49, Pinchev M105, Plaseska-Karanfilska D90, Polley EC84, Prentice R131, Presneau N52, Prokofyeva D132, Purrington K133, Pylkäs K134, Rack B92, Radice P135, Rau-Murthy R136, Rennert G105, Rennert HS105, Rhenius V4, Robson M136, Romero A129, Ruddy KJ137, Ruebner M17, Saloustros E138, Sandler DP139, Sawyer EJ140, Schmidt DF141, Schmutzler RK78, Schneeweiss A142, Schoemaker MJ94, Schumacher F143, Schürmann P48, Schwentner L92, Scott C84, Scott RJ144, Seynaeve C86, Shah M4, Sherman ME145, Shrubsole MJ111, Shu XO111, Slager S84, Smeets A123, Sohn C142, Soucy P50, Southey MC146, Spinelli JJ147, Stegmaier C148, Stone J149, Swerdlow AJ150, Tamimi RM151, Tapper WJ152, Taylor JA153, Terry MB154, Thöne K102, Tollenaar RAEM155, Tomlinson I156, Truong T41, Tzardi M157, Ulmer HU158, Untch M159, Vachon CM84, van Veen EM58, Vijai J125, Weinberg CR160, Wendt C114, Whittemore AS161, Wildiers H123, Willett W162, Winqvist R134, Wolk A163, Yang XR7, Yannoukakos D164, Zhang Y12, Zheng W111, Ziogas A10; ABCTB Investigators165; kConFab/AOCS Investigators166; NBCS Collaborators167, Dunning AM4, Thompson DJ3, Chenevix-Trench G168, Chang-Claude J169, Schmidt MK170, Hall P171, Milne RL172, Pharoah PDP173, Antoniou AC3, Chatterjee N174, Kraft P175, García-Closas M7, Simard J50, Easton DF173.

Author information

1
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.
2
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.
3
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge CB1 8RN, UK.
4
Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge CB1 8RN, UK.
5
Department of Mathematics and Statistics, Laval University, Québec City, QC G1V 0A6, Canada.
6
Family Cancer Clinic, the Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Amsterdam, 1066 CX, the Netherlands.
7
Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20850, USA.
8
Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland.
9
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.
10
Department of Epidemiology, Genetic Epidemiology Research Institute, University of California Irvine, Irvine, CA 92617, USA.
11
NN Alexandrov Research Institute of Oncology and Medical Radiology, Minsk 223040, Belarus.
12
Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
13
Department of Public Health Sciences, and Cancer Research Institute, Queen's University, Kingston, ON K7L 3N6, Canada.
14
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.
15
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.
16
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
17
Department of Gynecology and Obstetrics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
18
Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain; Biomedical Network on Rare Diseases (CIBERER), Madrid 28029, Spain.
19
Institute of Biochemistry and Genetics, Ufa Scientific Center of Russian Academy of Sciences, Ufa 450054, Russia.
20
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA 91010, USA.
21
Department of Oncology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland; Department of Oncology, Örebro University Hospital, Örebro 70185, Sweden.
22
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.
23
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.
24
Division of Cancer Prevention and Genetics, IEO, European Institute of Oncology IRCCS, Milan 20141, Italy.
25
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.
26
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.
27
Department of Radiation Oncology, Hannover Medical School, Hannover 30625, Germany.
28
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.
29
Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London EC1M 6BQ, UK.
30
Sheffield Institute for Nucleic Acids (SInFoNiA), Department of Oncology and Metabolism, University of Sheffield, Sheffield S10 2TN, UK.
31
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.
32
Department of Gynecology and Obstetrics, University of Tübingen, Tübingen 72076, Germany.
33
Institute for Prevention and Occupational Medicine of the German Social Accident Insurance, Institute of the Ruhr University Bochum (IPA), Bochum 44789, Germany.
34
Department of Obstetrics and Gynecology, University of Heidelberg, Heidelberg 69120, Germany; Molecular Epidemiology Group, C080, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
35
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Department of Biology, University of Pisa, Pisa 56126, Italy.
36
Epidemiology Research Program, American Cancer Society, Atlanta, GA 30303, USA.
37
Oncology and Genetics Unit, Instituto de Investigacion Sanitaria Galicia Sur (IISGS), Xerencia de Xestion Integrada de Vigo-SERGAS, Vigo 36312, Spain.
38
Division of Medical Oncology and Hematology, University of California at Los Angeles, Los Angeles, CA 90024, USA.
39
Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
40
Department of Clinical Genetics, Erasmus University Medical Center, Rotterdam 3015 CN, the Netherlands.
41
Cancer & Environment Group, Center for Research in Epidemiology and Population Health (CESP), INSERM, University Paris-Sud, University Paris-Saclay, Villejuif 94805, France.
42
Division of Molecular Pathology, the Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam 1066 CX, the Netherlands.
43
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN 55905, USA.
44
Academic Unit of Pathology, Department of Neuroscience, University of Sheffield, Sheffield S10 2TN, UK.
45
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden.
46
Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
47
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.
48
Gynaecology Research Unit, Hannover Medical School, Hannover 30625, Germany.
49
Department of Non-Communicable Disease Epidemiology, London School of Hygiene and Tropical Medicine, London WC1E 7HT, UK.
50
Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Université Laval, Québec City, QC G1V 4G2, Canada.
51
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.
52
School of Life Sciences, University of Westminster, London W1B 2HW, UK.
53
Cancer Sciences Academic Unit, Faculty of Medicine, University of Southampton, Southampton SO17 6YD, UK.
54
Institute of Human Genetics, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Comprehensive Cancer Center Erlangen-EMN, Erlangen 91054, Germany.
55
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.
56
Department of Cancer Epidemiology, Clinical Sciences, Lund University, Lund 222 42, Sweden.
57
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.
58
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.
59
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.
60
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.
61
The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London SW7 3RP, UK.
62
Department of Breast Surgery, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev 2730, Denmark.
63
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.
64
School of Public Health, Curtin University, Perth, WA 6102, Australia.
65
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.
66
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.
67
Department of Medical Oncology, University Hospital of Heraklion, Heraklion 711 10, Greece.
68
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.
69
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.
70
Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
71
Department of Medicine, McGill University, Montréal, QC H4A 3J1, Canada; Division of Clinical Epidemiology, Royal Victoria Hospital, McGill University, Montréal, QC H4A 3J1, Canada.
72
Department of Dermatology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT 84112, USA.
73
Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid 28029, Spain.
74
Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital-Radiumhospitalet, Oslo 0379, Norway.
75
Department of Surgery, Oulu University Hospital, University of Oulu, Oulu 90220, Finland.
76
Department of Genetics and Pathology, Pomeranian Medical University, Szczecin 71-252, Poland.
77
Centre de Recherche du Centre Hospitalier de Université de Montréal (CHUM), Université de Montréal, Montréal, QC H2X 0A9, Canada.
78
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.
79
Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.
80
Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden.
81
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
82
Department of Biostatistics & Epidemiology, University of Massachusetts, Amherst, Amherst, MA 1003, USA.
83
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.
84
Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA.
85
School of Population and Global Health, University of Western Australia, Perth, WA 6009, Australia.
86
Department of Medical Oncology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam 3015 CN, the Netherlands.
87
Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC 3010, Australia.
88
Division of Cancer Sciences, University of Manchester, Manchester M13 9PL, UK.
89
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.
90
Research Centre for Genetic Engineering and Biotechnology "Georgi D. Efremov," Macedonian Academy of Sciences and Arts, Skopje 1000, Republic of Macedonia.
91
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.
92
Department of Gynecology and Obstetrics, University Hospital Ulm, Ulm 89075, Germany.
93
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA 94304, USA.
94
Division of Genetics and Epidemiology, The Institute of Cancer Research, London SM2 5NG, UK.
95
Department of Oncology, Tampere University Hospital, Tampere, Finland Box 2000, 33521 Tampere, Finland.
96
Translational Cancer Research Area, University of Eastern Finland, Kuopio 70210, Finland; Central Finland Health Care District, Jyväskylä Central Hospital, Jyväskylä 40620, Finland.
97
Surgery, School of Medicine, National University of Ireland, Galway H91TK33, Ireland.
98
Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki 00290, Finland.
99
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.
100
Department of Internal Medicine, Evangelische Kliniken Bonn gGmbH, Johanniter Krankenhaus, Bonn 53177, Germany.
101
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.
102
Cancer Epidemiology Group, University Cancer Center Hamburg (UCCH), University Medical Center Hamburg-Eppendorf, Hamburg 20246, Germany.
103
VIB Center for Cancer Biology, VIB, Leuven 3000, Belgium; Laboratory for Translational Genetics, Department of Human Genetics, University of Leuven, Leuven 3000, Belgium.
104
Epidemiology Program, University of Hawaii Cancer Center, Honolulu, HI 96813, USA.
105
Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa 35254, Israel.
106
Department of Molecular Medicine and Surgery, Karolinska Institutet, and Department of Clinical Genetics, Karolinska University Hospital, Stockholm 171 76, Sweden.
107
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.
108
Department of Cancer Epidemiology and Prevention, M Sklodowska-Curie Cancer Center - Oncology Institute, Warsaw 02-034, Poland.
109
Dr Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Stuttgart 70376, Germany; University of Tübingen, Tübingen 72074, Germany.
110
German Breast Group, GmbH, Neu Isenburg 63263, Germany.
111
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
112
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.
113
Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan 20133, Italy.
114
Department of Clinical Science and Education, Södersjukhuset, Karolinska Institutet, Stockholm 118 83, Sweden; Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden.
115
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.
116
Anatomical Pathology, The Alfred Hospital, Melbourne, VIC 3004, Australia.
117
Department of Gynecology and Obstetrics, Ludwig Maximilian University of Munich, Munich 80336, Germany.
118
MRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College London, London WC1V 6LJ, UK.
119
Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany; Faculty of Medicine, University of Heidelberg, Heidelberg 69120, Germany.
120
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.
121
Université Paris Sorbonne Cité, INSERM UMR-S1147, Paris 75270, France.
122
Radiation Oncology, Hospital Meixoeiro-XXI de Vigo, Vigo 36214, Spain.
123
Leuven Multidisciplinary Breast Center, Department of Oncology, Leuven Cancer Institute, University Hospitals Leuven, Leuven 3000, Belgium.
124
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.
125
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.
126
Centre for Cancer Research and Cell Biology, Queen's University Belfast, Belfast BT7 1NN, UK.
127
University of New Mexico Health Sciences Center, University of New Mexico, Albuquerque, NM 87131, USA.
128
Servicio de Cirugía General y Especialidades, Hospital Monte Naranco, Oviedo 33012, Spain.
129
Medical Oncology Department, Hospital Universitario Puerta de Hierro, Madrid 28222, Spain.
130
Genome Diagnostic Program, IFOM the FIRC (Italian Foundation for Cancer Research) Institute of Molecular Oncology, Milan 20139, Italy.
131
Cancer Prevention Program, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
132
Department of Genetics and Fundamental Medicine, Bashkir State University, Ufa 450076, Russia.
133
Department of Oncology, Wayne State University School of Medicine, Detroit, MI 48201, USA.
134
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.
135
Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan 20133, Italy.
136
Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
137
Department of Oncology, Mayo Clinic, Rochester, MN 55905, USA.
138
Department of Oncology, University Hospital of Larissa, Larissa 711 10, Greece.
139
Epidemiology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
140
Research Oncology, Guy's Hospital, King's College London, London SE1 9RT, UK.
141
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.
142
National Center for Tumor Diseases, University Hospital and German Cancer Research Center, Heidelberg 69120, Germany.
143
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.
144
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.
145
Department of Health Sciences Research, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
146
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.
147
Population Oncology, BC Cancer, Vancouver, BC V5Z 1G1, Canada; School of Population and Public Health, University of British Columbia, Vancouver, BC, V6T 1Z4, Canada.
148
Saarland Cancer Registry, Saarbrücken 66119, Germany.
149
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.
150
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.
151
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.
152
Faculty of Medicine, University of Southampton, Southampton SO17 1BJ, UK.
153
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.
154
Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, NY 10032, USA.
155
Department of Surgery, Leiden University Medical Center, Leiden 2333 ZA, the Netherlands.
156
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.
157
Department of Pathology, University Hospital of Heraklion, Heraklion 711 10, Greece.
158
Frauenklinik der Stadtklinik Baden-Baden, Baden-Baden 76532, Germany.
159
Department of Gynecology and Obstetrics, Helios Clinics Berlin-Buch, Berlin 13125, Germany.
160
Biostatistics and Computational Biology Branch, National Institute of Environmental Health Sciences, NIH, Research Triangle Park, NC 27709, USA.
161
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.
162
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.
163
Institute of Environmental Medicine, Karolinska Institutet, Stockholm 171 77, Sweden; Department of Surgical Sciences, Uppsala University, Uppsala 751 05, Sweden.
164
Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research "Demokritos," Athens 15310, Greece.
165
Australian Breast Cancer Tissue Bank, Westmead Institute for Medical Research, University of Sydney, Sydney, NSW 2145, Australia.
166
Peter MacCallum Cancer Center, Melbourne, VIC 3000, Australia.
167
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.
168
Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD 4006, Australia.
169
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.
170
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.
171
Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm 171 65, Sweden; Department of Oncology, Södersjukhuset, Stockholm 118 83, Sweden.
172
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.
173
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.
174
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.
175
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.

KEYWORDS:

breast; cancer; epidemiology; genetic; polygenic; prediction; risk; score; screening; stratification

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