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    Genetics in medicine : official journal of the American College of Medical Genetics. 2021 Jun 10. doi: 10.1038/s41436-021-01198-7. pii: 10.1038/s41436-021-01198-7
    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 IMM1,  van den Broek AJ2,  Vos JAM3,  Barnes DR4,  Adlard J5,  Andrulis IL6,  Arason A7,  Arnold N8,  Arun BK9,  Balmaña J10,  Barrowdale D11,  Benitez J12,  Borg A13,  Caldés T14,  Caligo MA15,  Chung WK16,  Claes KBM17,  Collée JM18,  Couch FJ19,  Daly MB20,  Dennis J21,  Dhawan M22,  Domchek SM23,  Eeles R24,  Engel C25,  Evans DG26,  Feliubadaló L27,  Foretova L28,  Friedman E29,  Frost D30,  Ganz PA31,  Garber J32,  Gayther SA33,  Gerdes AM34,  Godwin AK35,  Goldgar DE36,  Hahnen E37,  Hake CR38,  Hamann U39,  Hogervorst FBL40,  Hooning MJ41,  Hopper JL42,  Hulick PJ43,  Imyanitov EN44,  Isaacs C45,  Izatt L46,  Jakubowska A47,  James PA48,  Janavicius R49,  Jensen UB50,  Jiao Y51,  John EM52,  Joseph V53,  Karlan BY54,  Kets CM55,  Konstantopoulou I56,  Kwong A57,  Legrand C58,  Leslie G59,  Lesueur F60,  Loud JT61,  Lubiński J62,  Manoukian S63,  McGuffog L64,  Miller A65,  Gomes DM66,  Montagna M67,  Mouret-Fourme E68,  Nathanson KL69,  Neuhausen SL70,  Nevanlinna H71,  Yie JNY72,  Olah E73,  Olopade OI74,  Park SK75,  Parsons MT76,  Peterlongo P77,  Piedmonte M78,  Radice P79,  Rantala J80,  Rennert G81,  Risch HA82,  Schmutzler RK83,  Sharma P84,  Simard J85,  Singer CF86,  Stadler Z87,  Stoppa-Lyonnet D88,  Sutter C89,  Tan YY90,  Teixeira MR91,  Teo SH92,  Teulé A93,  Thomassen M94,  Thull DL95,  Tischkowitz M96,  Toland AE97,  Tung N98,  van Rensburg EJ99,  Vega A100,  Wappenschmidt B101,  Devilee P102,  van Asperen CJ103,  Bernstein JL104,  Offit K105,  Easton DF106,  Rookus MA107,  Chenevix-Trench G108,  Antoniou AC109,  Robson M110,  Schmidt MK111
    Collaborators
    Barouk-Simonet E Belotti M Berthet P Bignon YJ Bonadona V Bressac-de Paillerets B Buecher B Caputo S Caron O Castera L Caux-Moncoutier V Colas C Collonge-Rame MA Coupier I de Pauw A Delnatte C Elan C Faivre L Ferrer SF Gauthier-Villars M Gesta P Giraud S Golmard L Houdayer C Lasset C Laurent M Leroux D Longy M Mari V Mazoyer S Mebirouk N Mortemousque I Prieur F Pujol P Saule C Schuster H Sevenet N Sobol H Sokolowska J Venat-Bouvet L Ahmed M Barwell J Brady A Brennan P Brewer C Cook J Davidson R Donaldson A Dunning AM Eason J Eccles DM Gregory H Hanson H Harrington PA Henderson A Hodgson S Kennedy MJ Lalloo F Miller C Morrison PJ Ong KR O'Shaughnessy-Kirwan A Perkins J Porteous ME Rogers MT Side LE Snape K Walker L Glendon G Mulligan AM van Asperen CJ Aalfs CM Adank MA Ausems MGEM Blok MJ Gómez Garcia EB Heemskerk-Gerritsen BAM Hollestelle A Jager A Koppert LB Koudijs M Kriege M Meijers-Heijboer HEJ Mensenkamp AR Mooij TM Oosterwijk JC van den Ouweland AMW van der Baan FH van der Hout AH van der Kolk LE van der Luijt RB van Deurzen CHM van Doorn HC van Engelen K van Hest LP van Os TAM Verhoef S Vogel MJ Wijnen JT Beesley J Fox S Holland H Phillips KA Spurdle AB
    Author information
    1Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    2Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
    3Division of Molecular Pathology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
    4Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    5Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
    6Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
    7Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
    8Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
    9Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.
    10Hereditary cancer Genetics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.
    11Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    12Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
    13Department of Oncology, Lund University and Skåne University Hospital, Lund, Sweden.
    14Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
    15SOD Genetica Molecolare. University Hospital, Pisa, Italy.
    16Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA.
    17Centre for Medical Genetics, Ghent University, Ghent, Belgium.
    18Department of Clinical Genetics, Erasmus University Medical Center, CA, Rotterdam, The Netherlands.
    19Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
    20Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA.
    21Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    22Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA.
    23Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
    24Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
    25Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
    26Division 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.
    27Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    28Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic.
    29The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel.
    30Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    31Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research, Jonsson Comprehensive Cancer Centre, UCLA, Los Angeles, CA, USA.
    32Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA.
    33Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core. Cedars-Sinai Medical Center, Los Angeles, CA, USA.
    34Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    35Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
    36Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
    37Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    38Waukesha Memorial Hospital-Pro Health Care, Waukesha, WI, USA.
    39Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    40Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
    41Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
    42Centre for Epidemiology and Biostatistics, Melbourne School of Population and Global Health, The University of Melbourne, Melbourne, VIC, Australia.
    43Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA.
    44N.N. Petrov Institute of Oncology, St. Petersburg, Russia.
    45Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA.
    46Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
    47Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    48Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, VIC, Australia.
    49Hematology, Oncology and Transfusion Medicine Center, Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Vilnius, Lithuania.
    50Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark.
    51Genetic Epidemiology of Cancer team, Paris, France.
    52Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
    53Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    54David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA.
    55Family Cancer Clinic, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands.
    56Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
    57Hong Kong Hereditary Breast Cancer Family Registry, Cancer Genetics Centre, Happy Valley, Hong Kong.
    58Département de Génétique, CHU de Grenoble, Grenoble, France.
    59Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    60Genetic Epidemiology of Cancer team, Paris, France.
    61Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    62Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland.
    63Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
    64Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    65NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
    66Service de Biologie de la reproduction, Cytogénétique et Génétique Médicale, CHI Poissy-Saint Germain, Poissy, France.
    67Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
    68Service de Génétique, Institut Curie, Paris, France.
    69Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
    70Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    71Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    72Cancer Genetics Service, National Cancer Centre, Singapore, Singapore.
    73Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    74Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
    75Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea.
    76Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
    77Genome Diagnostics Program, IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy.
    78NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Buffalo, NY, USA.
    79Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    80Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
    81Clalit National Cancer Control Center, Carmel Medical Center and Technion Faculty of Medicine, Haifa, Israel.
    82Chronic Disease Epidemiology, Yale School of Public Health, New Haven, CT, USA.
    83Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    84Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA.
    85Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada.
    86Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    87Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    88Service de Génétique, Institut Curie, Paris, France.
    89Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    90Dept of OB/GYN, Medical University of Vienna, Vienna, Austria.
    91Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    92Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia.
    93Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    94Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
    95Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    96Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
    97Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
    98Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA.
    99Department of Genetics, University of Pretoria, Arcadia, South Africa.
    100Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain.
    101Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    102Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    103Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    104Department of Epidemiology and Biostatistics, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
    105Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    106Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    107Division of Psychosocial Research and Epidemiology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek hospital, Amsterdam, The Netherlands.
    108Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia.
    109Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    110Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    111Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands. mk.schmidt@nki.nl.
    Abstract

    PURPOSE: To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS) 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 PRS and CBC risk.

    RESULTS: For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS 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 PRS, 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 < age 40 years, the cumulative PRS 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

    CONCLUSION: The PRS can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.


    Publikations ID: 34113011
    Quelle: öffnen
     
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