Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers
Karoline B. Kuchenbaecker; Lesley McGuffog; Daniel Barrowdale; Andrew Lee; Penny Soucy; Sue Healey; Joe Dennis; Michael Lush; Mark Robson; Amanda B. Spurdle; Susan J. Ramus; Nasim Mavaddat; Mary Beth Terry; Susan L. Neuhausen; Ute Hamann; Melissa Southey; Esther M. John; Wendy K. Chung; Mary B. Daly; Saundra S. Buys; David E. Goldgar; Cecilia M. Dorfling; Elizabeth J. van Rensburg; Yuan Chun Ding; Bent Ejlertsen; Anne-Marie Gerdes; Thomas V. O. Hansen; Susan Slager; Emily Hallberg; Javier Benitez; Ana Osorio; Nancy Cohen; William Lawler; Jeffrey N. Weitzel; Paolo Peterlongo; Valeria Pensotti; Riccardo Dolcetti; Monica Barile; Bernardo Bonanni; Jacopo Azzollini; Siranoush Manoukian; Bernard Peissel; Paolo Radice; Antonella Savarese; Laura Papi; Giuseppe Giannini; Florentia Fostira; Irene Konstantopoulou; Julian Adlard; Carole Brewer; Jackie Cook; Rosemarie Davidson; Diana Eccles; Ros Eeles; Steve Ellis; Debra Frost; Shirley Hodgson; Louise Izatt; Fiona Lalloo; Kai-ren Ong; Andrew K. Godwin; Norbert Arnold; Bernd Dworniczak; Christoph Engel; Andrea Gehrig; Eric Hahnen; Jan Hauke; Karin Kast; Alfons Meindl; Dieter Niederacher; Rita Katharina Schmutzler; Raymonda Varon-Mateeva; Shan Wang-Gohrke; Barbara Wappenschmidt; Laure Barjhoux; Marie-Agnès Collonge-Rame; Camille Elan; Lisa Golmard; Emmanuelle Barouk-Simonet; Fabienne Lesueur; Sylvie Mazoyer; Joanna Sokolowska; Dominique Stoppa-Lyonnet; Claudine Isaacs; Kathleen B. M. Claes; Bruce Poppe; Miguel de la Hoya; Vanesa Garcia-Barberan; Kristiina Aittomäki; Heli Nevanlinna; Margreet G. E. M. Ausems; J. L. de Lange; Encarna B. Gómez Garcia; Frans B. L. Hogervorst; Carolien M. Kets; Hanne E. J. Meijers-Heijboer; Jan C. Oosterwijk; Matti A. Rookus; Christi J. van Asperen; Ans M. W. van den Ouweland; Helena C. van Doorn; Theo A. M. van Os; Ava Kwong; Edith Olah; Orland Diez; Joan Brunet; Conxi Lazaro; Alex Teulé; Jacek Gronwald; Anna Jakubowska; Katarzyna Kaczmarek; Jan Lubinski; Grzegorz Sukiennicki; Rosa B. Barkardottir; Jocelyne Chiquette; Simona Agata; Marco Montagna; Manuel R. Teixeira; Sue Kyung Park; Curtis Olswold; Marc Tischkowitz; Lenka Foretova; Pragna Gaddam; Joseph Vijai; Georg Pfeiler; Christine Rappaport-Fuerhauser; Christian F. Singer; Muy-Kheng M. Tea; Mark H. Greene; Jennifer T. Loud; Gad Rennert; Evgeny N. Imyanitov; Peter J. Hulick; John L. Hays; Marion Piedmonte; Gustavo C. Rodriguez; Julie Martyn; Gord Glendon; Anna Marie Mulligan; Irene L. Andrulis; Amanda Ewart Toland; Uffe Birk Jensen; Torben A. Kruse; Inge Sokilde Pedersen; Mads Thomassen; Maria A. Caligo; Soo-Hwang Teo; Raanan Berger; Eitan Friedman; Yael Laitman; Brita Arver; Ake Borg; Hans Ehrencrona; Johanna Rantala; Olufunmilayo I. Olopade; Patricia A. Ganz; Robert L. Nussbaum; Angela R. Bradbury; Susan M. Domchek; Katherine L. Nathanson; Banu K. Arun; Paul James; Beth Y. Karlan; Jenny Lester; Jacques Simard; Paul D. P. Pharoah; Kenneth Offit; Fergus J. Couch; Georgia Chenevix-Trench; Douglas F. Easton; Antonis C. Antoniou
Author Information: The Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge, UK (KBK); Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK (KBK, LM, DB, AL, JD, ML, NM, DFE, ACA); Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, Quebec City, Quebec, Canada (PS, JSi); Department of Genetics, QIMR Berghofer Medical Research Institute, Brisbane, Australia (SHe); Clinical Genetics, Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (MR); Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Australia (ABS, GCT); Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA (SJR); Department of Epidemiology, Columbia University, New York, NY (MBT); Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA (SLN, YCD); Molecular Genetics of Breast Cancer, German Cancer Research Center, Heidelberg, Germany (UH); Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, VIC, Australia (MS); Department of Epidemiology, Cancer Prevention Institute of California, Fremont, CA (EMJ); Departments of Pediatrics and Medicine, Columbia University, New York, NY (WKC); Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA (MBD); Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT (SSB); Department of Dermatology, University of Utah School of Medicine, Salt Lake City, UT (DEG); Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Arcadia, South Africa (CMD); Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Arcadia, South Africa (EJvR); Department of Oncology (BE), Department of Clincial Genetics (AMG), and Center for Genomic Medicine (TVOH), Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Department of Health Sciences Research, Mayo Clinic, Rochester, MN (SS, EHal, CO); Human Genetics Group (JBe, AO) and Human Genotyping Unit, Human Cancer Genetics Program (JBe), Spanish National Cancer Centre , Madrid, Spain; Biomedical Network on Rare Diseases, CIBERER, Madrid, Spain (JBe, AO); City of Hope Clinical Cancer Genomics Community Research Network, Duarte, CA (NC, WL); Clinical Cancer Genetics, City of Hope, Duarte, California (JNW); IFOM, Institute of Molecular Oncology, Italian Foundation for Cancer Research, Milan, Italy (PP, VP); Cogentech Cancer Genetic Test Laboratory, Milan, Italy (VP); Centro di Riferimento Oncologico, IRCCS, Aviano, Italy (RDo); University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia (RDo); Division of Cancer Prevention and Genetics, Istituto Europeo di Oncologia, Milan, Italy (MB, BB); Unit of Medical Genetics (JAz, SMan, BPe) and Unit of Molecular Bases of Genetic Risk and Genetic Testing (PR), Department of Preventive and Predictive Medicine, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milan, Italy;Unit of Genetic Counselling, Medical Oncology Department, Istituto Nazionale Tumori Regina Elena, Rome, Italy (AS); Unit of Medical Genetics, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Florence, Italy (LP); Department of Molecular Medicine, University La Sapienza, Rome, Italy (GGi); Molecular Diagnostics Laboratory, Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research Demokritos, Aghia Paraskevi Attikis, Athens, Greece (FF, IK); Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK (JAd); Department of Clinical Genetics, Royal Devon and Exeter Hospital, Exeter, UK (CB); Sheffield Clinical Genetics Service, Sheffield Children’s Hospital, Sheffield, UK (JCo); Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK (RDa); University of Southampton Faculty of Medicine, Southampton University Hospitals NHS Trust, Southampton, UK (DE); Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London UK (RE); Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Cambridge, UK (SE, EMBRACE, DF); Medical Genetics Unit, St George's, University of London, London, UK (SHo); Clinical Genetics, Guy’s and St. Thomas’ NHS Foundation Trust, London, UK (LI); Genetic Medicine, Manchester Academic Health Sciences Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK (FLa); West Midlands Regional Genetics Service, Birmingham Women’s Hospital Healthcare NHS Trust, Edgbaston, Birmingham, UK (KrO); Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS (AKG); Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Germany (NA); Institute of Human Genetics, University of Münster, Münster, Germany (BD); Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Germany (CEn); Centre of Familial Breast and Ovarian Cancer, Department of Medical Genetics, Institute of Human Genetics, University Würzburg, Germany (AG); Center of Familial Breast and Ovarian Cancer, Centre for Integrated Oncology, Center for Molecular Medicine Cologne, University Hospital Cologne, Medical Faculty, Cologne, Germany (EHah, JH, RKS, BW); Department of Gynaecology and Obstetrics, University Hospital Carl Gustav Carus, Technical University Dresden, Germany (KKas); Department of Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum Rechts der Isar, Technical University Munich, Germany (AM); Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Germany (DN); Institute of Human Genetics, Campus Virchov Klinikum, Charite Berlin, Germany (RVM); Department of Gynaecology and Obstetrics, University Hospital Ulm, Germany (SWG); Bâtiment Cheney D, Centre Léon Bérard, Lyon, France (LB); Lyon Neuroscience Research Center- CRNL, Inserm U1028, CNRS UMR5292, University of Lyon, Lyon, France (SMaz); Service de Génétique Biologique, CHU de Besançon, Besançon, France (ACR); Service de Génétique, Institut Curie, Paris, France (CEl, LG); Institut Curie, Department of Tumour Biology, Paris, France (GEMO, DSL); Institut Curie, INSERM U830, Paris, France (GEMO, DSL); Université Paris Descartes, Sorbonne Paris Cité, France (GEMO, DSL); Oncogénétique, Institut Bergonié, Bordeaux, France (EBS); Genetic Epidemiology of Cancer team, Inserm U900, Paris, France (FLe); Institut Curie, Paris, France (FLe); Mines ParisTech, Fontainebleau, France (FLe); Laboratoire de Génétique Médicale, Nancy Université, Centre Hospitalier Régional et Universitaire, Vandoeuvre-les-Nancy, France (JSo); Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (CI); Center for Medical Genetics, Ghent University, Gent, Belgium (KBMC, BPo); Molecular Oncology Laboratory, Hospital Clinico San Carlos, El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos, Madrid, Spain (MdlH, VGB); Department of Clinical Genetics, Helsinki University Hospital, HUS, Finland (KA); Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, HUS, Finland (HN); Department of Medical Genetics, University Medical Center Utrecht, Utrecht, the Netherlands (MGEMA); Department of Epidemiology (JLdL) and Coordinating Center, Hereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON), Netherlands Cancer Institute, Amsterdam, the Netherlands (JLdL); Department of Clinical Genetics and GROW, School for Oncology and Developmental Biology, MUMC, Maastricht, the Netherlands (EBGG); Family Cancer Clinic, Netherlands Cancer Institute, Amsterdam, the Netherlands (FBLH); Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands (CMK); Department of Clinical Genetics, VU University Medical Centre, Amsterdam, the Netherlands (HEJMH); Department of Genetics, University Medical Center, Groningen University, Groningen, the Netherlands (JCO); Department of Epidemiology, Netherlands Cancer Institute, Amsterdam, the Netherlands (MAR); Department of Clinical Genetics Leiden University Medical Center Leiden, Leiden, the Netherlands (CJvA); Department of Clinical Genetics, Family Cancer Clinic, Erasmus University Medical Center, Rotterdam, the Netherlands (AMWvdO); Department of Gynaecology, Family Cancer Clinic, Erasmus MC Cancer Institute, Rotterdam, the Netherlands (HCvD); Department of Clinical Genetics, Academic Medical Center, Amsterdam, the Netherlands (TAMvO); Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong (AK); Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong (AK); Department of Surgery, The University of Hong Kong, Hong Kong (AK); Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary (EO); Oncogenetics Group, Vall d’Hebron Institute of Oncology (VHIO), Universitat Autònoma de Barcelona, Vall d’Hebron University Hospital, Barcelona, Spain (OD); Genetic Counseling Unit, Hereditary Cancer Program, Institut d'Investigació Biomèdica de Girona, Catalan Institute of Oncology, Girona, Spain (JBr); Molecular Diagnostic Unit (CL) and Genetic Counseling Unit (AT), Hereditary Cancer Program, Bellvitge Biomedical Research Institute, Catalan Institute of Oncology, L'Hospitalet, Barcelona, Spain; Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland (JG, AJ, KKac, JLu, GS); Laboratory of Cell Biology, Department of Pathology, Reykjavik, Iceland (RBB); Biomedical Centre, Faculty of Medicine, University of Iceland, Reykjavik, Iceland (RBB); Unité de Recherche en Santé des Populations, Centre des Maladies du Sein Deschênes-Fabia, Hôpital du Saint-Sacrement, Québec, Canada (JCh); Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy (SA, MM); Department of Genetics, Portuguese Oncology Institute of Porto, Porto, Portugal (MRT); Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal (MRT); Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia (KConFab); Department of Preventive Medicine, Department of Biomedical Science, and Cancer Research Institute, Seoul National University, Seoul, Korea (SKP); Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada (MTi); Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic (LF); Clinical Cancer Genetics Laboratory, Memorial Sloan Kettering Cancer Center, New York, NY (PG); Clinical Genetics Research Laboratory, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY (JV); Department of Gynecology and Gynecological Oncology, Comprehensive Cancer Center (GP), and Department of OB/GYN (CRF, CFS, MKMT), Medical University of Vienna, Vienna, Austria; Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Rockville, MD (MHG, JTL); Clalit National Israeli Cancer Control Center and Department of Community Medicine and Epidemiology, Carmel Medical Center and B. Rappaport Faculty of Medicine, Haifa, Israel (GR); N. N. Petrov Institute of Oncology, St. Petersburg, Russia (ENI); Center for Medical Genetics, NorthShore University HealthSystem, University of Chicago Pritzker School of Medicine, Evanston, IL (PJH); The Ohio State University Comprehensive Cancer Center Arthur C. James Cancer Hospital and Richard J. Solove Research Institute Biomedical Research Tower, Columbus, OH (JLH); NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY (MP); Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL (GCR); ANZGOG, NHMRC Clinical Trials Centre, Camperdown, Australia (JM); Ontario Cancer Genetics Network, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (GGl); Laboratory Medicine Program, University Health Network, Toronto, Ontario, Canada (AMM); Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada (AMM); Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, Canada (ILA); Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada (ILA); Division of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, Columbus, OH (AET); Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark (UBJ); Department of Clinical Genetics, Odense University Hospital, Odense C, Denmark (TAK, MTh); Section of Molecular Diagnostics, Clinical Biochemistry, Aalborg University Hospital, Aalborg, Denmark (ISP); Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa Italy (MAC); Cancer Research Initiatives Foundation, Sime Darby Medical Centre, Subang Jaya, Malaysia (SHT); University Malaya Cancer Research Institute, University Malaya, Kuala Lumpur, Malaysia (SHT); The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, Israel (RB); The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, Israel (EF); Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, Israel (EF); The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, Israel (YL); Department of Oncology, Karolinska University Hospital, Stockholm, Sweden (BA); Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden (AB); Department of Clinical Genetics, Lund University Hospital, Lund, Sweden (HE); Department of Clinical Genetics, Karolinska University Hospital L5:03, Stockholm, Sweden (JR); University of Chicago Medical Center, Chicago, IL (OIO); UCLA Schools of Medicine and Public Health, Division of Cancer Prevention and Control Research, Jonsson Comprehensive Cancer Center, Los Angeles, CA (PAG); Medical Sciences, University of California, San Francisco, San Francisco, CA (RLN); Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA (ARB, SMD, KLN); Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Andersson Cancer Center, Houston, TX (BKA); Familial Cancer Centre, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia (PJ); Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA (BYK, JLe); Department of Oncology, University of Cambridge, Cambridge, UK (PDPP); Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10044 (KO); Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, Rochester, MN (FJC)
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Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.
Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]–positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.
Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10−53). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10−20). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.
Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.