Year: 2018
Type: article
Study design: Observational Study
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.
Authors: Nasim Mavaddat, Kyriaki Michailidou, Joe Dennis, Michael Lush, Laura Fachal, Andrew Lee, Jonathan P. Tyrer, Ting-Huei Chen, Qin Wang, Manjeet K. Bolla, Xin Yang, Muriel A. Adank, Thomas Ahearn, Kristiina Aittomäki, Jamie Allen, Irene L. Andrulis, Hoda Anton-Culver, Natalia N. Antonenkova, Volker Arndt, Kristan J. Aronson, Paul L. Auer, Päivi Auvinen, Myrto Barrdahl, Laura E. Beane Freeman, Matthias W. Beckmann, Sabine Behrens, Javier Benitez, Marina Bermisheva, Leslie Bernstein, Carl Blomqvist, Natalia V. Bogdanova, Stig E. Bojesen, Bernardo Bonanni, Anne-Lise Børresen-Dale, Hiltrud Brauch, Michael Bremer, Hermann Brenner, Adam Brentnall, Ian W. Brock, Angela Brooks-Wilson, Sara Y. Brucker, Thomas Brüning, Barbara Burwinkel, Daniele Campa, Brian D. Carter, Jose E. Castelao, Stephen J. Chanock, Rowan Chlebowski, Hans Christiansen, Christine L. Clarke, J. Margriet Collée, Emilie Cordina-Duverger, Sten Cornelissen, Fergus J. Couch, Angela Cox, Simon S. Cross, Kamila Czene, Mary B. Daly, Peter Devilee, Thilo Dörk, Isabel dos-Santos-Silva, Martine Dumont, Lorraine Durcan, Miriam Dwek, Diana M. Eccles, Arif B. Ekici, A. Heather Eliassen, Carolina Ellberg, Christoph Engel, Mikael Eriksson, D. Gareth Evans, Peter A. Fasching, Jonine Figueroa, Olivia Fletcher, Henrik Flyger, Asta Försti, Lin Fritschi, Marike Gabrielson, Manuela Gago-Dominguez, Susan M. Gapstur, José A. García-Sáenz, Mia M. Gaudet, Vassilios Georgoulias, Graham G. Giles, Irina R. Gilyazova, Gord Glendon, Mark S. Goldberg, David E. Goldgar, Anna González-Neira, Grethe I. Grenaker Alnæs, Mervi Grip, Jacek Gronwald, Anne Grundy, Pascal Guénel, Lothar Haeberle, Eric Hahnen, Christopher A. Haiman, Niclas Håkansson, Ute Hamann, Susan E. Hankinson, Elaine F. Harkness, Steven N. Hart, Wei He, Alexander Hein, Jane Heyworth, Peter Hillemanns, Antoinette Hollestelle, Maartje J. Hooning, Robert N. Hoover, John L. Hopper, Anthony Howell, Guanmengqian Huang, Keith Humphreys, David J. Hunter, Milena Jakimovska, Anna Jakubowska, Wolfgang Janni, Esther M. John, Nichola Johnson, Michael E. Jones, Arja Jukkola-Vuorinen, Audrey Jung, Rudolf Kaaks, Katarzyna Kaczmarek, Vesa Kataja, Renske Keeman, Michael J. Kerin, Elza Khusnutdinova, Johanna I. Kiiski, Julia A. Knight, Yon-Dschun Ko, Veli-Matti Kosma, Stella Koutros, Vessela N. Kristensen, Ute Krüger, Tabea Kühl, Diether Lambrechts, Loic Le Marchand, Eunjung Lee, Flavio Lejbkowicz, Jenna Lilyquist, Annika Lindblom, Sara Lindström, Jolanta Lissowska, Wing-Yee Lo, Sibylle Loibl, Jirong Long, Jan Lubiński, Michael P. Lux, Robert J. MacInnis, Tom Maishman, Enes Makalic, Ivana Maleva Kostovska, Arto Mannermaa, Siranoush Manoukian, Sara Margolin, John W.M. Martens, Maria Elena Martinez, Dimitrios Mavroudis, Catriona McLean, Alfons Meindl, Usha Menon, Pooja Middha, Nicola Miller, Fernando Moreno, Anna Marie Mulligan, Claire Mulot, Victor M. Muñoz-Garzon, Susan L. Neuhausen, Heli Nevanlinna, Patrick Neven, William G. Newman, Sune F. Nielsen, Børge G. Nordestgaard, Aaron Norman, Kenneth Offit, Janet E. Olson, Håkan Olsson, Nick Orr, V. Shane Pankratz, Tjoung-Won Park-Simon, Jose I.A. Perez, Clara Pérez-Barrios, Paolo Peterlongo, Julian Peto, Mila Pinchev, Dijana Plaseska-Karanfilska, Eric C. Polley, Ross Prentice, Nadege Presneau, Darya Prokofyeva, Kristen Purrington, Katri Pylkäs, Brigitte Rack, Paolo Radice, Rohini Rau-Murthy, Gad Rennert, Hedy S. Rennert, Valerie Rhenius, Mark Robson, Atocha Romero, Kathryn J. Ruddy, Matthias Ruebner, Emmanouil Saloustros, Dale P. Sandler, Elinor J. Sawyer, Daniel F. Schmidt, Rita K. Schmutzler, Andreas Schneeweiss, Minouk J. Schoemaker, Fredrick Schumacher, Peter Schürmann, Lukas Schwentner, Christopher Scott, Rodney J. Scott, Caroline Seynaeve, Mitul Shah, Mark E. Sherman, Martha J. Shrubsole, Xiao-Ou Shu, Susan Slager, Ann Smeets, Christof Sohn, Penny Soucy, Melissa C. Southey, John J. Spinelli, Christa Stegmaier, Jennifer Stone, Anthony J. Swerdlow, Rulla M. Tamimi, William J. Tapper, Jack A. Taylor, Mary Beth Terry, Kathrin Thöne, Rob A.E.M. Tollenaar, Ian Tomlinson, Thérèse Truong, Maria Tzardi, Hans-Ulrich Ulmer, Michael Untch, Celine M. Vachon, Elke M. van Veen, Joseph Vijai, Clarice R. Weinberg, Camilla Wendt, Alice S. Whittemore, Hans Wildiers, Walter Willett, Robert Winqvist, Alicja Wolk, Xiaohong R. Yang, Drakoulis Yannoukakos, Yan Zhang, Wei Zheng, Argyrios Ziogas, Alison M. Dunning, Deborah J. Thompson, Georgia Chenevix-Trench, Jenny Chang-Claude, Marjanka K. Schmidt, Per Hall, Roger L. Milne, Paul D.P. Pharoah, Antonis C. Antoniou, Nilanjan Chatterjee, Peter Kraft, Montserrat García-Closas, Jacques Simard, Douglas F. Easton
Institutions: University of Cambridge, Cyprus Institute of Neurology and Genetics, Université Laval, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics, The Netherlands Cancer Institute, University of Helsinki, Helsinki University Hospital, Mount Sinai Hospital, University of Toronto, Lunenfeld-Tanenbaum Research Institute, University of California, Irvine, N.N. Alexandrov National Cancer Centre, German Cancer Research Center, Queen's University, Fred Hutch Cancer Center, University of Wisconsin–Milwaukee, University of Eastern Finland, Kuopio University Hospital, Friedrich-Alexander-Universität Erlangen-Nürnberg, Universitätsklinikum Erlangen, Comprehensive Cancer Center Erlangen, Spanish National Cancer Research Centre, Centre for Biomedical Network Research on Rare Diseases, Russian Academy of Sciences, Institute of Biochemistry and Genetics of Ufa Scientific Centre, City of Hope, Beckman Research Institute, Örebro University Hospital, Medizinische Hochschule Hannover, University of Copenhagen, Herlev Hospital, Copenhagen University Hospital, Gentofte Hospital, European Institute of Oncology, Oslo University Hospital, University of Oslo, Dr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology, Deutsches Konsortium für Translationale Krebsforschung, University of Tübingen, National Center for Tumor Diseases, Queen Mary University of London, University of Sheffield, BC Cancer Agency, Simon Fraser University, Institute for Prevention and Occupational Medicine, Heidelberg University, University of Pisa, American Cancer Society, Servicio Gallego de Salud, University of California, Los Angeles, The University of Sydney, Westmead Institute for Medical Research, Erasmus MC, Inserm, Université Paris-Saclay, Centre de recherche en Epidémiologie et Santé des Populations, Mayo Clinic, Karolinska Institutet, Fox Chase Cancer Center, Leiden University Medical Center, London School of Hygiene & Tropical Medicine, Centre hospitalier universitaire de Québec, University of Southampton, University of Westminster, Brigham and Women's Hospital, Harvard University, Lund University, Leipzig University, Manchester Academic Health Science Centre, University of Manchester, St Mary's Hospital, Manchester University NHS Foundation Trust, Edinburgh Cancer Research, University of Edinburgh, Institute of Cancer Research, Breast Cancer Now, Curtin University, University of California San Diego, Complejo Hospitalario Universitario de Santiago, Fundación Pública Galega de Medicina Xenómica, Instituto de Investigación Sanitaria de Santiago, Moores Cancer Center, Hospital Clínico San Carlos, Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Centro de Investigación Biomédica en Red de Cáncer, University Hospital of Heraklion, The University of Melbourne, Cancer Council Victoria, Monash University, Bashkir State University, Royal Victoria Hospital, McGill University, University of Utah, Huntsman Cancer Institute, Oulu University Hospital, University of Oulu, Pomeranian Medical University, Centre Hospitalier de l’Université de Montréal, Université de Montréal, University of Cologne, University Hospital Cologne, University of Southern California, University of Massachusetts Amherst, Wythenshawe Hospital, NIHR Manchester Biomedical Research Centre, The University of Western Australia, Erasmus MC Cancer Institute, University of Oxford, Macedonian Academy of Sciences and Arts, University Hospital Ulm, Stanford Medicine, Stanford Cancer Institute, Stanford University, Tampere University Hospital, Central Finland Health Care District, Ollscoil na Gaillimhe – University of Galway, Sinai Health System, Johanniter-Krankenhaus Bonn, University Medical Center Hamburg-Eppendorf, University Cancer Center Hamburg, VIB-KU Leuven Center for Cancer Biology, KU Leuven, University of Hawaii Cancer Center, Technion – Israel Institute of Technology, Carmel Medical Center, Karolinska University Hospital, University of Washington, The Maria Sklodowska-Curie National Research Institute of Oncology, German Breast Group, Vanderbilt University, Vanderbilt-Ingram Cancer Center, Fondazione IRCCS Istituto Nazionale dei Tumori, Stockholm South General Hospital, The Alfred Hospital, Ludwig-Maximilians-Universität München, MRC Clinical Trials Unit at UCL, University College London, University Health Network, Universitair Ziekenhuis Leuven, Memorial Sloan Kettering Cancer Center, Queen's University Belfast, University of New Mexico, University of New Mexico Health Sciences Center, Hospital Monte Naranco, Hospital Universitario Puerta de Hierro Majadahonda, IFOM, Wayne State University, NordLab, University Hospital of Larissa, National Institute of Environmental Health Sciences, Guy's Hospital, King's College London, Case Western Reserve University, John Hunter Hospital, Hunter Medical Research Institute, University of Newcastle Australia, Mayo Clinic in Florida, Monash Health, University of British Columbia, Krebsregister Saarland, Columbia University, Centre for Human Genetics, University of Birmingham, Klinikum Mittelbaden, Helios Kliniken, Helios Hospital Berlin-Buch, Uppsala University, National Centre of Scientific Research "Demokritos", QIMR Berghofer Medical Research Institute, Johns Hopkins University, Johns Hopkins Medicine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $5,150
Funders: Wayne State University, Memorial Sloan-Kettering Cancer Center, Case Western Reserve University, Deutsches Krebsforschungszentrum, Genome Canada, Wellcome Trust, Ministère du Développement Économique, de l’Innovation et de l’Exportation, Génome Québec, Ministère de l'Économie, de la Science et de l'Innovation - Québec, Fondation du cancer du sein du Québec, Government of Canada, Cancer Research UK, National Institute for Health and Care Research, University of Southampton, King's College London, University College London, University of Oxford, European Commission, Queen's University Belfast, Hunter Medical Research Institute, Universität Heidelberg, Institut National de la Santé et de la Recherche Médicale, Universiteit Leiden, Monash University, University of Melbourne, Curtin University of Technology, Queen's University, University of Toronto, Karolinska Institutet, Leids Universitair Medisch Centrum, Oulun Yliopisto, Fondazione Italiana per la Ricerca sul Cancro, Ministero dello Sviluppo Economico, National Institutes of Health, University of California, San Diego, Horizon 2020 Framework Programme, Seventh Framework Programme, Health Sciences Center, University of New Mexico, Canadian Institutes of Health Research, Medical Research Council, Biocenter, University of Oulu, National Cancer Institute, Mailman School of Public Health, Columbia University
Awards: G1030720477, G1059790086, G1110316427, G1119724336, G1147136077, G1161123863, G116534467, G1203839305, G1278116854, G1290754221, G1378522051, G1389895161, G1431566694, G1614944260, G1698450043, G1767914659, G1791794685, G1802616407, G183579924, G1867524959, G1873219037, G1951867125, G197189410, G2004299919, G2041911762, G2130574937, G2188863825, G236237718, G2373099447, G2381291417, G2395980551, Breast CAncer STratification: understanding the determinants of risk and prognosis of molecular subtypes, G2439210756, G2453522775, G2487849073, Improvement in risk prediction, early detection and prevention of breast cancer, Discovery, Biology and Risk of Inherited Variants in Breast Cancer, G2620578876, G266684566, G2708997719, G271288088, G2718683818, G2736957817, G2858663470, G2895881997, G2899816875, G2953759644, G2969180462, G306657136, G3097030853, G31326158, G3185473129, G3284250915, G3312385442, G3385934250, G348382531, G3488400535, G3499900790, G3545110800, G3636195520, G3649983604, G3695342494, G3714974232, Breast Cancer Risk after Diagnostic Gene Sequencing (BRIDGES), G3807225764, G3830541857, G4074224340, G4098640521, G4168635842, G4181489317, G4197410787, G4268494590, G4321622477, G4339904293, G434337789, G4350737453, G4359338489, G4409261390, G4409649582, G443747538, G4662672464, G4715308887, G4758570167, G476489484, G494830712, G4970236007, G5045046497, G5052768465, G507516432, G5101459226, G5181373253, G5338223732, G5498801985, G5553985549, G5566577447, G5585565996, G5717853834, NIHR Senior Investigator Award, G5850737185, G5865683244, G6004621315, G6140938529, G6195211026, G622191773, G6229591247, G6283257732, G6370857267, G6402876381, G6413938271, G6558636245, G6628312008, G6654466364, G6678499502, G672110866, G6744381054, G6971553973, G6990806275, G7209176259, G7223051280, G7238947055, G7294807324, G7356174861, G7383316951, G7400312528, G7445271619, G7501896692, G7510707455, G751661945, Providing breast cancer risk information as part of national breast cancer screening programme: building an evidence base on benefits and harms to inform a decision to implement., G7625083360, G7635722955, G7663583697, G7787200052, G790382466, G7931532932, G7973277461, G7983258154, G8114829475, G8166097299, G8181826844, G829717837, G8385826287, G8392881711, Collaborative Oncological Gene-environment Study, G8419603088, G8490523267, G8668082143, G87018399, G872696599, G880611044, G8841081573, G8959936493, G8987248239, G9000025899, G9000200580, Cancer Center Support Grant
OpenAlex ID: W2901952863