PURPOSE: We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers. METHODS: Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort. RESULTS: The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation = 1.29 [95% CI 1.25-1.33], P = 3×10-72). For BRCA2, the strongest association was with overall BC PRS (HR = 1.31 [95% CI 1.27-1.36], P = 7×10-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR = 1.32 [95% CI 1.25-1.40], P = 3×10-22) and BRCA2 (HR = 1.44 [95% CI 1.30-1.60], P = 4×10-12) carriers. The associations in the prospective cohort were similar. CONCLUSION: Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

Aalborg University Department of Clinical Medicine Aalborg Denmark

Aalborg University Hospital Clinical Cancer Research Center Aalborg Denmark

Aalborg University Hospital Molecular Diagnostics Aalborg Denmark

Aarhus University Hospital Department of Clinical Medicine Aarhus Denmark

Amsterdam UMC location AMC Department of Clinical Genetics Amsterdam The Netherlands

Amsterdam UMC location VUmc Department of Clinical Genetics Amsterdam The Netherlands

Beckman Research Institute of City of Hope Department of Population Sciences Duarte CA USA

Beth Israel Deaconess Medical Center Department of Medical Oncology Boston MA USA

Birmingham Women's Hospital Healthcare NHS Trust West Midlands Regional Genetics Service Birmingham UK

Cambridge University Hospitals NHS Foundation Trust East Anglian Medical Genetics Service Cambridge UK

Campus Virchov Klinikum Charite Institute of Human Genetics Berlin Germany

Cancer Council Victoria Cancer Epidemiology Division Melbourne VIC Australia

Cancer Genetics Centre Hong Kong Hereditary Breast Cancer Family Registry Happy Valley Hong Kong

Cancer Research Malaysia Breast Cancer Research Programme Subang Jaya Selangor Malaysia

Carmel Medical Center and Technion Faculty of Medicine Clalit National Cancer Control Center Haifa Israel

Cedars Sinai Medical Center Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute Los Angeles CA USA

Centre Antoine Lacassagne Département d'Hématologie Oncologie Médicale Nice France

Centre for Cancer Genetic Epidemiology Department of Oncology University of Cambridge Cambridge UK

Centre for Cancer Genetic Epidemiology Department of Public Health and Primary Care University of Cambridge Cambridge UK

Centre François Baclesse Département de Biopathologie Caen France

Centre Georges François Leclerc Unité d'oncogénétique Centre de Lutte Contre le Cancer Dijon France

Centre Hospitalier Universitaire de Québec Université Laval Research Center Genomics Center Québec City QC Canada

Centre Léon Bérard Unité de Prévention et d'Epidémiologie Génétique Lyon France

Centro de Investigación en Red de Enfermedades Raras Madrid Spain

CH Niort Service Régional Oncogénétique Poitou Charentes Niort France

Chaim Sheba Medical Center The Susanne Levy Gertner Oncogenetics Unit Ramat Gan Israel

Chapel Allerton Hospital Yorkshire Regional Genetics Service Leeds UK

CHU de Besançon Service de Génétique Besançon France

CHU Nantes Laboratoire de genetique moleculaire Nantes France

CIBERONC Hospital Clinico San Carlos IdISSC Molecular Oncology Laboratory Madrid Spain

City of Hope Clinical Cancer Genomics Duarte CA USA

Clinical Genetics Branch Division of Cancer Epidemiology and Genetics National Cancer Institute Bethesda MD USA

Columbia University Departments of Pediatrics and Medicine New York NY USA

Dana Farber Cancer Institute Cancer Risk and Prevention Clinic Boston MA USA

Department of Gynecology and Obstetrics Medical Faculty and University Hospital Carl Gustav Carus Technische Universität Dresden Dresden Germany

Department of Life and Health Sciences PSL University Paris France

DHU Dijon Centre de Génétique Dijon France

Erasmus MC Cancer Institute Department of Medical Oncology Family Cancer Clinic Rotterdam The Netherlands

Faculty of Medicine and University Hospital Cologne University of Cologne Center for Familial Breast and Ovarian Cancer Cologne Germany

Faculty of Medicine and University Hospital Cologne University of Cologne Center for Integrated Oncology Cologne Germany

Faculty of Medicine and University Hospital Cologne University of Cologne Center for Molecular Medicine Cologne Cologne Germany

Fondazione IRCCS Istituto Nazionale dei Tumori di Milano Unit of Medical Genetics Department of Medical Oncology and Hematology Milan Italy

Fondazione IRCCS Istituto Nazionale dei Tumori Unit of Molecular Bases of Genetic Risk and Genetic Testing Department of Research Milan Italy

Fox Chase Cancer Center Department of Clinical Genetics Philadelphia PA USA

Fundación Pública Galega de Medicina Xenómica Santiago de Compostela Spain

German Cancer Research Center Molecular Genetics of Breast Cancer Heidelberg Germany

Ghent University Centre for Medical Genetics Ghent Belgium

Great Ormond Street Hospital for Children NHS Trust North East Thames Regional Genetics Service London UK

Guy's and St Thomas' NHS Foundation Trust Clinical Genetics London UK

Hannover Medical School Institute of Human Genetics Hannover Germany

Hong Kong Sanatorium and Hospital Department of Surgery Happy Valley Hong Kong

Hospices Civils de Lyon Department of Genetics Bron France

Huntsman Cancer Institute Department of Medicine Salt Lake City UT USA

Huntsman Cancer Institute University of Utah School of Medicine Department of Dermatology Salt Lake City UT USA

IDIBELL Catalan Institute of Oncology ProCURE Barcelona Spain

IEO European Institute of Oncology IRCCS Division of Cancer Prevention and Genetics Milan Italy

IFOM the FIRC Institute of Molecular Oncology Genome Diagnostics Program Milan Italy

INSERM U830 Department of Tumour Biology Paris France

Inserm U900 Genetic Epidemiology of Cancer team Paris France

Institut Curie Paris France

Institut Curie Service de Génétique Paris France

Institut de Cancérologie Strasbourg Europe ICANS Strasbourg France

Institute of Genetic Medicine International Centre for Life Northern Genetic Service Newcastle upon Tyne UK

Instituto de Investigación Sanitaria de Santiago de Compostela Complejo Hospitalario Universitario de Santiago SERGAS Santiago de Compostela Spain

Jonsson Comprehensive Cancer Centre UCLA Schools of Medicine and Public Health Division of Cancer Prevention and Control Research Los Angeles CA USA

Karolinska Institutet Clinical Genetics Stockholm Sweden

Karolinska Institutet Department of Oncology Stockholm Sweden

Klinikum rechts der Isar der Technischen Universität München Department of Gynaecology and Obstetrics Munich Germany

Landspitali University Hospital Department of Pathology Reykjavik Iceland

Latvian Biomedical Research and Study Centre Riga Latvia

Leiden University Medical Center Department of Human Genetics Leiden The Netherlands

Leiden University Medical Center Department of Pathology Leiden The Netherlands

Lombardi Comprehensive Cancer Center Georgetown University Washington DC USA

Lund University Division of Oncology and Pathology Department of Clinical Sciences Lund Lund Sweden

Lunenfeld Tanenbaum Research Institute of Mount Sinai Hospital Fred A Litwin Center for Cancer Genetics Toronto ON Canada

Lyon University UMR CNRS 5558 Lyon France

Maastricht University Medical Center Department of Clinical Genetics Maastricht The Netherlands

Magee Womens Hospital University of Pittsburgh School of Medicine Department of Medicine Pittsburgh PA USA

Magee Womens Hospital University of Pittsburgh School of Medicine Pittsburgh PA USA

Manchester Academic Health Science Centre Manchester Universities Foundation Trust St Mary's Hospital Genomic Medicine North West Genomics hub Manchester UK

Masaryk Memorial Cancer Institute Department of Cancer Epidemiology and Genetics Brno Czech Republic

Mayo Clinic Department of Laboratory Medicine and Pathology Rochester MN USA

Mayo Clinic Department of Oncology Rochester MN USA

McGill University Program in Cancer Genetics Departments of Human Genetics and Oncology Montréal QC Canada

Medical University of Vienna Dept of OB GYN and Comprehensive Cancer Center Vienna Austria

Medical University of Vienna Dept of OB GYN Vienna Austria

Memorial Sloan Kettering Cancer Center Clinical Genetics Research Lab Department of Cancer Biology and Genetics New York NY USA

Memorial Sloan Kettering Cancer Center Clinical Genetics Service Department of Medicine New York NY USA

Mines ParisTech Fontainebleau France

Monash University Precision Medicine School of Clinical Sciences at Monash Health Clayton VIC Australia

N N Petrov Institute of Oncology St Petersburg Russia

National Centre for Scientific Research 'Demokritos' Molecular Diagnostics Laboratory INRASTES Athens Greece

National Institute of Oncology Department of Molecular Genetics Budapest Hungary

NHMRC Clinical Trials ANZ GOTG Coordinating Centre Camperdown NSW Australia

NorthShore University HealthSystem Center for Medical Genetics Evanston IL USA

Odense University Hospital Department of Clinical Genetics Odense Denmark

ONCOBELL IDIBELL IDIBGI IGTP Catalan Institute of Oncology CIBERONC Hereditary Cancer Program Barcelona Spain

Oncogénétique Clinique and Aix Marseille Univ INSERM IRD SESSTIM Institut Paoli Calmettes Département d'Anticipation et de Suivi des Cancers Marseille France

Oxford University Hospitals Oxford Centre for Genomic Medicine Oxford UK

Perelman School of Medicine at the University of Pennsylvania Department of Medicine Abramson Cancer Center Philadelphia PA USA

Peter MacCallum Cancer Center Melbourne VIC Australia

Peter MacCallum Cancer Center Parkville Familial Cancer Centre Melbourne VIC Australia

Pomeranian Medical University Department of Genetics and Pathology Szczecin Poland

Pomeranian Medical University Independent Laboratory of Molecular Biology and Genetic Diagnostics Szczecin Poland

Portuguese Oncology Institute Department of Genetics Porto Portugal

Princess Anne Hospital Southampton UK

QIMR Berghofer Medical Research Institute Department of Genetics and Computational Biology Brisbane QLD Australia

Queen Elizabeth University Hospitals Department of Clinical Genetics Glasgow UK

Radboud University Medical Center Department of Human Genetics Nijmegen The Netherlands

Region of Southern Denmark Vejle Hospital Department of Clinical Genetics Vejle Denmark

Rigshospitalet Copenhagen University Hospital Center for Genomic Medicine Copenhagen Denmark

Rigshospitalet Copenhagen University Hospital Department of Clinical Genetics Copenhagen Denmark

Rigshospitalet Copenhagen University Hospital Department of Oncology Copenhagen Denmark

Roswell Park Cancer Institute NRG Oncology Statistics and Data Management Center Buffalo NY USA

Royal Devon and Exeter Hospital Department of Clinical Genetics Exeter UK

Seoul National University Cancer Research Institute Seoul Korea

Seoul National University College of Medicine Department of Preventive Medicine Seoul Korea

Seoul National University Graduate School Department of Biomedical Sciences Seoul Korea

Sheffield Children's Hospital Sheffield Clinical Genetics Service Sheffield UK

Spanish National Cancer Research Centre Human Cancer Genetics Programme Madrid Spain

St George's NHS Foundation Trust Southwest Thames Regional Genetics Service London UK

Stanford Cancer Institute Stanford University School of Medicine Department of Medicine Division of Oncology Stanford CA USA

State Research Institute Centre for Innovative Medicine Vilnius Lithuania

Tel Aviv University Sackler Faculty of Medicine Ramat Aviv Israel

The Institute of Cancer Research and Royal Marsden NHS Foundation Trust Oncogenetics Team London UK

The Kinghorn Cancer Centre Garvan Institute of Medical Research Sydney NSW Australia

The Netherlands Cancer Institute Antoni van Leeuwenhoek hospital Family Cancer Clinic Amsterdam The Netherlands

The Netherlands Cancer Institute Department of Epidemiology Amsterdam The Netherlands

The Ohio State University Clinical Cancer Genetics Program Division of Human Genetics Department of Internal Medicine The Comprehensive Cancer Center Columbus OH USA

The Ohio State University Department of Cancer Biology and Genetics Columbus OH USA

The University of Chicago Center for Clinical Cancer Genetics Chicago IL USA

The University of Chicago Pritzker School of Medicine Chicago IL USA

The University of Hong Kong Department of Surgery Pok Fu Lam Hong Kong

The University of Manchester Manchester Academic Health Science Centre Manchester Universities Foundation Trust St Mary's Hospital Genomic Medicine Division of Evolution and Genomic Sciences Manchester UK

The University of Melbourne Centre for Epidemiology and Biostatistics Melbourne School of Population and Global Health Melbourne VIC Australia

The University of Melbourne Department of Clinical Pathology Melbourne VIC Australia

The University of Melbourne Department of Medicine St Vincent's Hospital Fitzroy VIC Australia

The University of Melbourne Sir Peter MacCallum Department of Oncology Melbourne VIC Australia

Unité d'Oncogénétique Centre de Lutte contre le Cancer Paul Strauss Strasbourg France

Université de Strasbourg Laboratoire d'ImmunoRhumatologie Moléculaire Plateforme GENOMAX INSERM UMR_S 1109 LabEx TRANSPLANTEX Fédération de Médecine Translationnelle de Strasbourg Faculté de Médecine Strasbourg France

Université Paris Descartes Paris France

University Health Network Laboratory Medicine Program Toronto ON Canada

University Hospital Düsseldorf Heinrich Heine University Düsseldorf Department of Gynecology and Obstetrics Düsseldorf Germany

University Hospital Heidelberg Institute of Human Genetics Heidelberg Germany

University Hospital Leipzig Institute of Human Genetics Leipzig Germany

University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Department of Gynaecology and Obstetrics Kiel Germany

University Hospital of Schleswig Holstein Campus Kiel Christian Albrechts University Kiel Institute of Clinical Molecular Biology Kiel Germany

University Hospital of Vall d'Hebron Department of Medical Oncology Barcelona Spain

University Hospital SOD Genetica Molecolare Pisa Italy

University Hospital Ulm Department of Gynaecology and Obstetrics Ulm Germany

University Hospital Vall dHebron Clinical and Molecular Genetics Area Barcelona Spain

University Medical Center Utrecht Department of Medical Genetics Utrecht The Netherlands

University of California at Los Angeles David Geffen School of Medicine Department of Obstetrics and Gynecology Los Angeles CA USA

University of California San Francisco Cancer Genetics and Prevention Program San Francisco CA USA

University of Cambridge Department of Medical Genetics National Institute for Health Research Cambridge Biomedical Research Centre Cambridge UK

University of Florence Department of Experimental and Clinical Biomedical Sciences 'Mario Serio' Medical Genetics Unit Florence Italy

University of Helsinki Department of Clinical Genetics Helsinki University Hospital Helsinki Finland

University of Helsinki Department of Obstetrics and Gynecology Helsinki University Hospital Helsinki Finland

University of Iceland BMC Faculty of Medicine Reykjavik Iceland

University of Kansas Medical Center Department of Internal Medicine Division of Medical Oncology Westwood KS USA

University of Kansas Medical Center Department of Pathology and Laboratory Medicine Kansas City KS USA

University of Leipzig Institute for Medical Informatics Statistics and Epidemiology Leipzig Germany

University of Malaya Department of Surgery Faculty of Medicine Kuala Lumpur Malaysia

University Of Melbourne Department of Medicine Melbourne VIC Australia

University of Munich Campus Großhadern Department of Gynecology and Obstetrics Munich Germany

University of Münster Institute of Human Genetics Münster Germany

University of NSW Sydney Adult Cancer Program Lowy Cancer Research Centre Sydney NSW Australia

University of NSW Sydney School of Women's and Children's Health Faculty of Medicine Sydney NSW Australia

University of Pennsylvania Basser Center for BRCA Abramson Cancer Center Philadelphia PA USA

University of Porto Biomedical Sciences Institute Porto Portugal

University of Pretoria Department of Genetics Arcadia South Africa

University of Texas MD Anderson Cancer Center Department of Breast Medical Oncology Houston TX USA

University of Toronto Department of Laboratory Medicine and Pathobiology Toronto ON Canada

University of Toronto Department of Molecular Genetics Toronto ON Canada

University Würzburg Department of Human Genetics Würzburg Germany

Vall d'Hebron Institute of Oncology High Risk and Cancer Prevention Group Barcelona Spain

Vall dHebron Institute of Oncology Oncogenetics Group Barcelona Spain

Veneto Institute of Oncology IOV IRCCS Immunology and Molecular Oncology Unit Padua Italy

Vilnius University Hospital Santariskiu Clinics Hematology Oncology and Transfusion Medicine Center Department of Molecular and Regenerative Medicine Vilnius Lithuania

Wexner Medical Center The Ohio State University Department of Gynecology and Obstetrics Columbus OH USA

Yale School of Medicine Chronic Disease Epidemiology New Haven CT USA

Zealand University Hospital Clinical Genetic Unit Department of Paediatrics Roskilde Denmark

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Polygenic risk modeling for prediction of epithelial ovarian cancer risk

Risks of breast and ovarian cancer for women harboring pathogenic missense variants in BRCA1 and BRCA2 compared with those harboring protein truncating variants

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant