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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

Lakeman IMM 1 , van den Broek AJ 2 , Vos JAM 2 , Barnes DR 3 , Adlard J 4 , Andrulis IL 5 Show all authors , Arason A 6 , Arnold N 7 , Arun BK 8 , Balmaña J 9 , Barrowdale D 3 , Benitez J 10 , Borg A 11 , Caldés T 12 , Caligo MA 13 , Chung WK 14 , Claes KBM 15 , GEMO Study Collaborators , EMBRACE Collaborators , Collée JM 16 , Couch FJ 17 , Daly MB 18 , Dennis J 3 , Dhawan M 19 , Domchek SM 20 , Eeles R 21 , Engel C 22 , Evans DG 23 , Feliubadaló L 24 , Foretova L 25 , Friedman E 26 , Frost D 3 , Ganz PA 27 , Garber J 28 , Gayther SA 29 , Gerdes AM 30 , Godwin AK 31 , Goldgar DE 32 , Hahnen E 33 , Hake CR 34 , Hamann U 35 , Hogervorst FBL 36 , Hooning MJ 37 , Hopper JL 38 , Hulick PJ 39 , Imyanitov EN 40 , OCGN Investigators , HEBON Investigators , KconFab Investigators , Isaacs C 41 , Izatt L 42 , Jakubowska A 43 , James PA 44 , Janavicius R 45 , Jensen UB 46 , Jiao Y 47 , John EM 48 , Joseph V 49 , Karlan BY 50 , Kets CM 36 , Konstantopoulou I 51 , Kwong A 52 , Legrand C 53 , Leslie G 3 , Lesueur F 47 , Loud JT 54 , Lubiński J 43 , Manoukian S 55 , McGuffog L 3 , Miller A 56 , Gomes DM 57 , Montagna M 58 , Mouret-Fourme E 59 , Nathanson KL 20 , Neuhausen SL 60 , Nevanlinna H 61 , Yie JNY 62 , Olah E 63 , Olopade OI 64 , Park SK 65 , Parsons MT 66 , Peterlongo P 67 , Piedmonte M 56 , Radice P 68 , Rantala J 69 , Rennert G 70 , Risch HA 71 , Schmutzler RK 33 , Sharma P 72 , Simard J 73 , Singer CF 74 , Stadler Z 75 , Stoppa-Lyonnet D 59 , Sutter C 76 , Tan YY 77 , Teixeira MR 78 , Teo SH 79 , Teulé A 24 , Thomassen M 80 , Thull DL 81 , Tischkowitz M 82 , Toland AE 83 , Tung N 84 , van Rensburg EJ 85 , Vega A 10 , Wappenschmidt B 33 , Devilee P 1 , van Asperen CJ 86 , Bernstein JL 87 , Offit K 49 , Easton DF 3 , Rookus MA 88 , Chenevix-Trench G 66 , Antoniou AC 3 , Robson M 75 , Schmidt MK 89

Affiliations 

  • 1 Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands
  • 2 Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 4 Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
  • 5 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
  • 6 Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland
  • 7 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany
  • 8 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 9 Hereditary cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain
  • 10 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  • 11 Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden
  • 12 Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
  • 13 SOD Genetica Molecolare. University Hospital, Pisa, Italy
  • 14 Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA
  • 15 Centre for Medical Genetics, Ghent University, Ghent, Belgium
  • 16 Department of Clinical Genetics, Erasmus University Medical Center, CA, Rotterdam, The Netherlands
  • 17 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 18 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
  • 19 Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA
  • 20 Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
  • 21 Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK
  • 22 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 23 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, UK
  • 24 Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain
  • 25 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic
  • 26 The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
  • 27 Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA
  • 28 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA
  • 29 Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core. Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 30 Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 31 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
  • 32 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 33 Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • 34 Waukesha Memorial Hospital-Pro Health Care, Waukesha, WI, USA
  • 35 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 36 Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 37 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 38 Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia
  • 39 Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA
  • 40 N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 41 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
  • 42 Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
  • 43 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 44 Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, VIC, Australia
  • 45 Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania
  • 46 Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark
  • 47 Genetic Epidemiology of Cancer team, Paris, France
  • 48 Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
  • 49 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • 50 David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA
  • 51 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
  • 52 Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong
  • 53 Département de Génétique, CHU de Grenoble, Grenoble, France
  • 54 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  • 55 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy
  • 56 NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA
  • 57 Service de Biologie de la reproduction, Cytogénétique et Génétique Médicale, CHI Poissy-Saint Germain, Poissy, France
  • 58 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy
  • 59 Service de Génétique, Institut Curie, Paris, France
  • 60 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
  • 61 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 62 Cancer Genetics Service, National Cancer Centre, Singapore, Singapore
  • 63 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 64 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA
  • 65 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 66 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
  • 67 Genome Diagnostics Program, IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy
  • 68 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 69 Clinical Genetics, Karolinska Institutet, Stockholm, Sweden
  • 70 Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel
  • 71 Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA
  • 72 Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA
  • 73 Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada
  • 74 Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 75 Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • 76 Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
  • 77 Dept of OB/GYN, Medical University of Vienna, Vienna, Austria
  • 78 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 79 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 80 Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark
  • 81 Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 82 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada
  • 83 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
  • 84 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
  • 85 Department of Genetics, University of Pretoria, Arcadia, South Africa
  • 86 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands
  • 87 Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA
  • 88 Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands
  • 89 Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. mk.schmidt@nki.nl
Genet Med, 2021 Sep;23(9):1726-1737.
PMID: 34113011 DOI: 10.1038/s41436-021-01198-7

Abstract

PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS313) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

METHODS: We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS313 and CBC risk.

RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS313 showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS313, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC 

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

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