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Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants

Barnes DR 1 , Rookus MA 2 , McGuffog L 3 , Leslie G 3 , Mooij TM 2 , Dennis J 3 Show all authors , Mavaddat N 3 , Adlard J 4 , Ahmed M 5 , Aittomäki K 6 , Andrieu N 7 , Andrulis IL 8 , Arnold N 9 , Arun BK 10 , Azzollini J 11 , Balmaña J 12 , Barkardottir RB 13 , Barrowdale D 3 , Benitez J 14 , Berthet P 15 , Białkowska K 16 , Blanco AM 17 , Blok MJ 18 , Bonanni B 19 , Boonen SE 20 , Borg Å 21 , Bozsik A 22 , Bradbury AR 23 , Brennan P 24 , Brewer C 25 , Brunet J 26 , Buys SS 27 , Caldés T 28 , Caligo MA 29 , Campbell I 30 , Christensen LL 31 , Chung WK 32 , Claes KBM 33 , Colas C 34 , GEMO Study Collaborators , EMBRACE Collaborators , Collonge-Rame MA 35 , Cook J 36 , Daly MB 37 , Davidson R 38 , de la Hoya M 28 , de Putter R 33 , Delnatte C 39 , Devilee P 40 , Diez O 41 , Ding YC 42 , Domchek SM 43 , Dorfling CM 44 , Dumont M 45 , Eeles R 46 , Ejlertsen B 47 , Engel C 48 , Evans DG 49 , Faivre L 50 , Foretova L 51 , Fostira F 52 , Friedlander M 53 , Friedman E 54 , Frost D 3 , Ganz PA 55 , Garber J 56 , Gehrig A 57 , Gerdes AM 58 , Gesta P 59 , Giraud S 60 , Glendon G 8 , Godwin AK 61 , Goldgar DE 62 , González-Neira A 63 , Greene MH 64 , Gschwantler-Kaulich D 65 , Hahnen E 66 , Hamann U 67 , Hanson H 68 , Hentschel J 69 , Hogervorst FBL 70 , Hooning MJ 71 , Horvath J 72 , Hu C 73 , Hulick PJ 74 , Imyanitov EN 75 , kConFab Investigators , HEBON Investigators , GENEPSO Investigators , Isaacs C 76 , Izatt L 77 , Izquierdo A 26 , Jakubowska A 16 , James PA 78 , Janavicius R 79 , John EM 80 , Joseph V 81 , Karlan BY 82 , Kast K 83 , Koudijs M 84 , Kruse TA 85 , Kwong A 86 , Laitman Y 54 , Lasset C 87 , Lazaro C 26 , Lester J 82 , Lesueur F 7 , Liljegren A 88 , Loud JT 64 , Lubiński J 16 , Mai PL 89 , Manoukian S 11 , Mari V 90 , Mebirouk N 7 , Meijers-Heijboer HEJ 91 , Meindl A 92 , Mensenkamp AR 93 , Miller A 94 , Montagna M 95 , Mouret-Fourme E 34 , Mukherjee S 96 , Mulligan AM 97 , Nathanson KL 43 , Neuhausen SL 42 , Nevanlinna H 98 , Niederacher D 99 , Nielsen FC 100 , Nikitina-Zake L 101 , Noguès C 102 , Olah E 22 , Olopade OI 103 , Ong KR 104 , O'Shaughnessy-Kirwan A 105 , Osorio A 14 , Ott CE 106 , Papi L 107 , Park SK 108 , Parsons MT 109 , Pedersen IS 110 , Peissel B 11 , Peixoto A 111 , Peterlongo P 112 , Pfeiler G 113 , Phillips KA 30 , Prajzendanc K 16 , Pujana MA 114 , Radice P 115 , Ramser J 116 , Ramus SJ 117 , Rantala J 118 , Rennert G 119 , Risch HA 120 , Robson M 96 , Rønlund K 121 , Salani R 122 , Schuster H 123 , Senter L 124 , Shah PD 23 , Sharma P 125 , Side LE 126 , Singer CF 113 , Slavin TP 127 , Soucy P 45 , Southey MC 128 , Spurdle AB 109 , Steinemann D 129 , Steinsnyder Z 96 , Stoppa-Lyonnet D 34 , Sutter C 130 , Tan YY 65 , Teixeira MR 111 , Teo SH 131 , Thull DL 132 , Tischkowitz M 133 , Tognazzo S 95 , Toland AE 134 , Trainer AH 135 , Tung N 136 , van Engelen K 137 , van Rensburg EJ 44 , Vega A 14 , Vierstraete J 33 , Wagner G 113 , Walker L 138 , Wang-Gohrke S 139 , Wappenschmidt B 66 , Weitzel JN 127 , Yadav S 140 , Yang X 3 , Yannoukakos D 52 , Zimbalatti D 11 , Offit K 81 , Thomassen M 85 , Couch FJ 73 , Schmutzler RK 66 , Simard J 45 , Easton DF 3 , Chenevix-Trench G 109 , Antoniou AC 3 , Consortium of Investigators of Modifiers of BRCA and BRCA2

Affiliations 

  • 1 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK. drb54@medschl.cam.ac.uk
  • 2 The Netherlands Cancer Institute, Department of Epidemiology (PSOE), Amsterdam, The Netherlands
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 4 Chapel Allerton Hospital, Yorkshire Regional Genetics Service, Leeds, UK
  • 5 Great Ormond Street Hospital for Children NHS Trust, North East Thames Regional Genetics Service, London, UK
  • 6 University of Helsinki, Department of Clinical Genetics, Helsinki University Hospital, Helsinki, Finland
  • 7 Inserm U900, Genetic Epidemiology of Cancer team, Paris, France
  • 8 Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Fred A. Litwin Center for Cancer Genetics, Toronto, ON, Canada
  • 9 University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Department of Gynaecology and Obstetrics, Kiel, Germany
  • 10 University of Texas MD Anderson Cancer Center, Department of Breast Medical Oncology, Houston, TX, USA
  • 11 Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Unit of Medical Genetics, Department of Medical Oncology and Hematology, Milan, Italy
  • 12 Vall d'Hebron Institute of Oncology, High Risk and Cancer Prevention Group, Barcelona, Spain
  • 13 Landspitali University Hospital, Department of Pathology, Reykjavik, Iceland
  • 14 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  • 15 Centre François Baclesse, Département de Biopathologie, Caen, France
  • 16 Pomeranian Medical University, Department of Genetics and Pathology, Szczecin, Poland
  • 17 University of California San Francisco, Cancer Genetics and Prevention Program, San Francisco, CA, USA
  • 18 Maastricht University Medical Center, Department of Clinical Genetics, Maastricht, The Netherlands
  • 19 IEO, European Institute of Oncology IRCCS, Division of Cancer Prevention and Genetics, Milan, Italy
  • 20 Zealand University Hospital, Clinical Genetic Unit, Department of Paediatrics, Roskilde, Denmark
  • 21 Lund University, Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund, Sweden
  • 22 National Institute of Oncology, Department of Molecular Genetics, Budapest, Hungary
  • 23 Perelman School of Medicine at the University of Pennsylvania, Department of Medicine, Abramson Cancer Center, Philadelphia, PA, USA
  • 24 Institute of Genetic Medicine, International Centre for Life, Northern Genetic Service, Newcastle upon Tyne, UK
  • 25 Royal Devon & Exeter Hospital, Department of Clinical Genetics, Exeter, UK
  • 26 ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONC, Hereditary Cancer Program, Barcelona, Spain
  • 27 Huntsman Cancer Institute, Department of Medicine, Salt Lake City, UT, USA
  • 28 CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Molecular Oncology Laboratory, Madrid, Spain
  • 29 University Hospital, SOD Genetica Molecolare, Pisa, Italy
  • 30 Peter MacCallum Cancer Center, Melbourne, VIC, Australia
  • 31 Aarhus University Hospital, Department of Clinical Medicine,, Aarhus, Denmark
  • 32 Columbia University, Departments of Pediatrics and Medicine, New York, NY, USA
  • 33 Ghent University, Centre for Medical Genetics, Ghent, Belgium
  • 34 Institut Curie, Service de Génétique, Paris, France
  • 35 CHU de Besançon, Service de Génétique, Besançon, France
  • 36 Sheffield Children's Hospital, Sheffield Clinical Genetics Service, Sheffield, UK
  • 37 Fox Chase Cancer Center, Department of Clinical Genetics, Philadelphia, PA, USA
  • 38 Queen Elizabeth University Hospitals, Department of Clinical Genetics, Glasgow, UK
  • 39 CHU Nantes, Laboratoire de genetique moleculaire, Nantes, France
  • 40 Leiden University Medical Center, Department of Pathology, Leiden, The Netherlands
  • 41 Vall dHebron Institute of Oncology (VHIO), Oncogenetics Group, Barcelona, Spain
  • 42 Beckman Research Institute of City of Hope, Department of Population Sciences, Duarte, CA, USA
  • 43 University of Pennsylvania, Basser Center for BRCA, Abramson Cancer Center, Philadelphia, PA, USA
  • 44 University of Pretoria, Department of Genetics, Arcadia, South Africa
  • 45 Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Genomics Center,, Québec City, QC, Canada
  • 46 The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Oncogenetics Team, London, UK
  • 47 Rigshospitalet, Copenhagen University Hospital, Department of Oncology, Copenhagen, Denmark
  • 48 University of Leipzig, Institute for Medical Informatics, Statistics and Epidemiology, Leipzig, Germany
  • 49 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
  • 50 Centre Georges-François Leclerc, Unité d'oncogénétique, Centre de Lutte Contre le Cancer, Dijon, France
  • 51 Masaryk Memorial Cancer Institute, Department of Cancer Epidemiology and Genetics, Brno, Czech Republic
  • 52 National Centre for Scientific Research 'Demokritos', Molecular Diagnostics Laboratory, INRASTES, Athens, Greece
  • 53 NHMRC Clinical Trials, ANZ GOTG Coordinating Centre, Camperdown, NSW, Australia
  • 54 Chaim Sheba Medical Center, The Susanne Levy Gertner Oncogenetics Unit, Ramat Gan, Israel
  • 55 Jonsson Comprehensive Cancer Centre, UCLA, Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Los Angeles, CA, USA
  • 56 Dana-Farber Cancer Institute, Cancer Risk and Prevention Clinic, Boston, MA, USA
  • 57 University Würzburg, Department of Human Genetics, Würzburg, Germany
  • 58 Rigshospitalet, Copenhagen University Hospital, Department of Clinical Genetics, Copenhagen, Denmark
  • 59 CH Niort, Service Régional Oncogénétique Poitou-Charentes, Niort, France
  • 60 Hospices Civils de Lyon, Department of Genetics, Bron, France
  • 61 University of Kansas Medical Center, Department of Pathology and Laboratory Medicine, Kansas City, KS, USA
  • 62 Huntsman Cancer Institute, University of Utah School of Medicine, Department of Dermatology, Salt Lake City, UT, USA
  • 63 Spanish National Cancer Research Centre (CNIO), Human Cancer Genetics Programme, Madrid, Spain
  • 64 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  • 65 Medical University of Vienna, Dept of OB/GYN, Vienna, Austria
  • 66 Faculty of Medicine and University Hospital Cologne, University of Cologne, Center for Familial Breast and Ovarian Cancer, Cologne, Germany
  • 67 German Cancer Research Center (DKFZ), Molecular Genetics of Breast Cancer, Heidelberg, Germany
  • 68 St George's NHS Foundation Trust, Southwest Thames Regional Genetics Service, London, UK
  • 69 University Hospital Leipzig, Institute of Human Genetics, Leipzig, Germany
  • 70 The Netherlands Cancer Institute - Antoni van Leeuwenhoek hospital, Family Cancer Clinic, Amsterdam, The Netherlands
  • 71 Erasmus MC Cancer Institute, Department of Medical Oncology, Family Cancer Clinic, Rotterdam, The Netherlands
  • 72 University of Münster, Institute of Human Genetics, Münster, Germany
  • 73 Mayo Clinic, Department of Laboratory Medicine and Pathology, Rochester, MN, USA
  • 74 NorthShore University HealthSystem, Center for Medical Genetics, Evanston, IL, USA
  • 75 N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 76 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
  • 77 Guy's and St Thomas' NHS Foundation Trust, Clinical Genetics, London, UK
  • 78 The University of Melbourne, Sir Peter MacCallum Department of Oncology, Melbourne, VIC, Australia
  • 79 Vilnius University Hospital Santariskiu Clinics, Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius, Lithuania
  • 80 Stanford Cancer Institute, Stanford University School of Medicine, Department of Medicine, Division of Oncology, Stanford, CA, USA
  • 81 Memorial Sloan-Kettering Cancer Center, Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, New York, NY, USA
  • 82 University of California at Los Angeles, David Geffen School of Medicine, Department of Obstetrics and Gynecology, Los Angeles, CA, USA
  • 83 Department of Gynecology and Obstetrics, Medical Faculty and University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  • 84 University Medical Center Utrecht, Department of Medical Genetics, Utrecht, The Netherlands
  • 85 Odense University Hospital, Department of Clinical Genetics, Odense, Denmark
  • 86 Cancer Genetics Centre, Hong Kong Hereditary Breast Cancer Family Registry, Happy Valley, Hong Kong
  • 87 Centre Léon Bérard, Unité de Prévention et d'Epidémiologie Génétique, Lyon, France
  • 88 Karolinska Institutet, Department of Oncology, Stockholm, Sweden
  • 89 Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 90 Centre Antoine Lacassagne, Département d'Hématologie-Oncologie Médicale, Nice, France
  • 91 Amsterdam UMC, location AMC, Department of Clinical Genetics, Amsterdam, The Netherlands
  • 92 University of Munich, Campus Großhadern, Department of Gynecology and Obstetrics, Munich, Germany
  • 93 Radboud University Medical Center, Department of Human Genetics, Nijmegen, The Netherlands
  • 94 Roswell Park Cancer Institute, NRG Oncology, Statistics and Data Management Center, Buffalo, NY, USA
  • 95 Veneto Institute of Oncology IOV - IRCCS, Immunology and Molecular Oncology Unit, Padua, Italy
  • 96 Memorial Sloan-Kettering Cancer Center, Clinical Genetics Service, Department of Medicine, New York, NY, USA
  • 97 University of Toronto, Department of Laboratory Medicine and Pathobiology, Toronto, ON, Canada
  • 98 University of Helsinki, Department of Obstetrics and Gynecology, Helsinki University Hospital, Helsinki, Finland
  • 99 University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Department of Gynecology and Obstetrics, Düsseldorf, Germany
  • 100 Rigshospitalet, Copenhagen University Hospital, Center for Genomic Medicine, Copenhagen, Denmark
  • 101 Latvian Biomedical Research and Study Centre, Riga, Latvia
  • 102 Oncogénétique Clinique and Aix Marseille Univ, INSERM, IRD, SESSTIM, Institut Paoli-Calmettes, Département d'Anticipation et de Suivi des Cancers, Marseille, France
  • 103 The University of Chicago, Center for Clinical Cancer Genetics, Chicago, IL, USA
  • 104 Birmingham Women's Hospital Healthcare NHS Trust, West Midlands Regional Genetics Service, Birmingham, UK
  • 105 Cambridge University Hospitals NHS Foundation Trust, East Anglian Medical Genetics Service, Cambridge, UK
  • 106 Campus Virchov Klinikum, Charite, Institute of Human Genetics, Berlin, Germany
  • 107 University of Florence, Department of Experimental and Clinical Biomedical Sciences 'Mario Serio', Medical Genetics Unit, Florence, Italy
  • 108 Seoul National University College of Medicine, Department of Preventive Medicine, Seoul, Korea
  • 109 QIMR Berghofer Medical Research Institute, Department of Genetics and Computational Biology, Brisbane, QLD, Australia
  • 110 Aalborg University Hospital, Molecular Diagnostics, Aalborg, Denmark
  • 111 Portuguese Oncology Institute, Department of Genetics, Porto, Portugal
  • 112 IFOM - the FIRC Institute of Molecular Oncology, Genome Diagnostics Program, Milan, Italy
  • 113 Medical University of Vienna, Dept of OB/GYN and Comprehensive Cancer Center, Vienna, Austria
  • 114 IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, ProCURE, Barcelona, Spain
  • 115 Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Milan, Italy
  • 116 Klinikum rechts der Isar der Technischen Universität München, Department of Gynaecology and Obstetrics, Munich, Germany
  • 117 University of NSW Sydney, School of Women's and Children's Health, Faculty of Medicine, Sydney, NSW, Australia
  • 118 Karolinska Institutet, Clinical Genetics, Stockholm, Sweden
  • 119 Carmel Medical Center and Technion Faculty of Medicine, Clalit National Cancer Control Center, Haifa, Israel
  • 120 Yale School of Medicine, Chronic Disease Epidemiology, New Haven, CT, USA
  • 121 Region of Southern Denmark, Vejle Hospital, Department of Clinical Genetics, Vejle, Denmark
  • 122 Wexner Medical Center, The Ohio State University, Department of Gynecology and Obstetrics, Columbus, OH, USA
  • 123 Unité d'Oncogénétique Centre de Lutte contre le Cancer Paul Strauss, Strasbourg, France
  • 124 The Ohio State University, Clinical Cancer Genetics Program, Division of Human Genetics, Department of Internal Medicine, The Comprehensive Cancer Center, Columbus, OH, USA
  • 125 University of Kansas Medical Center, Department of Internal Medicine, Division of Medical Oncology, Westwood, KS, USA
  • 126 Princess Anne Hospital, Southampton, UK
  • 127 City of Hope, Clinical Cancer Genomics, Duarte, CA, USA
  • 128 Monash University, Precision Medicine, School of Clinical Sciences at Monash Health, Clayton, VIC, Australia
  • 129 Hannover Medical School, Institute of Human Genetics, Hannover, Germany
  • 130 University Hospital Heidelberg, Institute of Human Genetics, Heidelberg, Germany
  • 131 Cancer Research Malaysia, Breast Cancer Research Programme, Subang Jaya, Selangor, Malaysia
  • 132 Magee-Womens Hospital, University of Pittsburgh School of Medicine, Department of Medicine, Pittsburgh, PA, USA
  • 133 McGill University, Program in Cancer Genetics, Departments of Human Genetics and Oncology, Montréal, QC, Canada
  • 134 The Ohio State University, Department of Cancer Biology and Genetics, Columbus, OH, USA
  • 135 Peter MacCallum Cancer Center, Parkville Familial Cancer Centre, Melbourne, VIC, Australia
  • 136 Beth Israel Deaconess Medical Center, Department of Medical Oncology, Boston, MA, USA
  • 137 Amsterdam UMC, location VUmc, Department of Clinical Genetics, Amsterdam, The Netherlands
  • 138 Oxford University Hospitals, Oxford Centre for Genomic Medicine, Oxford, UK
  • 139 University Hospital Ulm, Department of Gynaecology and Obstetrics, Ulm, Germany
  • 140 Mayo Clinic, Department of Oncology, Rochester, MN, USA
Genet Med, 2020 10;22(10):1653-1666.
PMID: 32665703 DOI: 10.1038/s41436-020-0862-x

Abstract

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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