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    Journal of the National Cancer Institute. 2021 Jul 28. pii: 6329642. doi: 10.1093/jnci/djab147
    Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores.
    Barnes DR1,  Silvestri V2,  Leslie G3,  McGuffog L4,  Dennis J5,  Yang X6,  Adlard J7,  Agnarsson BA8,  Ahmed M9,  Aittomäki K10,  Andrulis IL11,  Arason A12,  Arnold N13,  Auber B14,  Azzollini J15,  Balmaña J16,  Barkardottir RB17,  Barrowdale D18,  Barwell J19,  Belotti M20,  Benitez J21,  Berthet P22,  Boonen SE23,  Borg Å24,  Bozsik A25,  Brady A26,  Brennan P27,  Brewer C28,  Brunet J29,  Bucalo A30,  Buys SS31,  Caldés T32,  Caligo MA33,  Campbell I34,  Cassingham H35,  Lotte Christensen L36,  Cini G37,  Claes KBM38,  Cook J39,  Coppa A40,  Cortesi L41,  Damante G42,  Darder E43,  Davidson R44,  de la Hoya M45,  De Leeneer K46,  de Putter R47,  Del Valle J48,  Diez O49,  Chun Ding Y50,  Domchek SM51,  Donaldson A52,  Eason J53,  Eeles R54,  Engel C55,  Gareth Evans D56,  Feliubadaló L57,  Fostira F58,  Frone M59,  Frost D60,  Gallagher D61,  Gehrig A62,  Giraud S63,  Glendon G64,  Godwin AK65,  Goldgar DE66,  Greene MH67,  Gregory H68,  Gross E69,  Hahnen E70,  Hamann U71,  Hansen TVO72,  Hanson H73,  Hentschel J74,  Horvath J75,  Izatt L76,  Izquierdo A77,  James PA78,  Janavicius R79,  Birk Jensen U80,  Johannsson OT81,  John EM82,  Kramer G83,  Kroeldrup L84,  Kruse TA85,  Lautrup C86,  Lazaro C87,  Lesueur F88,  Lopez-Fernández A89,  Mai PL90,  Manoukian S91,  Matrai Z92,  Matricardi L93,  Maxwell KN94,  Mebirouk N95,  Meindl A96,  Montagna M97,  Monteiro AN98,  Morrison PJ99,  Muranen TA100,  Murray A101,  Nathanson KL102,  Neuhausen SL103,  Nevanlinna H104,  Nguyen-Dumont T105,  Niederacher D106,  Olah E107,  Olopade OI108,  Palli D109,  Parsons MT110,  Sokilde Pedersen I111,  Peissel B112,  Perez-Segura P113,  Peterlongo P114,  Petersen AH115,  Pinto P116,  Porteous ME117,  Pottinger C118,  Angel Pujana M119,  Radice P120,  Ramser J121,  Rantala J122,  Robson M123,  Rogers MT124,  Rønlund K125,  Rump A126,  María Sánchez de Abajo A127,  Shah PD128,  Sharif S129,  Side LE130,  Singer CF131,  Stadler Z132,  Steele L133,  Stoppa-Lyonnet D134,  Sutter C135,  Yen Tan Y136,  Teixeira MR137,  Teulé A138,  Thull DL139,  Tischkowitz M140,  Toland AE141,  Tommasi S142,  Toss A143,  Trainer AH144,  Tripathi V145,  Valentini V146,  van Asperen CJ147,  Venturelli M148,  Viel A149,  Vijai J150,  Walker L151,  Wang-Gohrke S152,  Wappenschmidt B153,  Whaite A154,  Zanna I155,  Offit K156,  Thomassen M157,  Couch FJ158,  Schmutzler RK159,  Simard J160,  Easton DF161,  Chenevix-Trench G162,  Antoniou AC163,  Ottini L164
    Author information
    1Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    2Department of Molecular Medicine, University La Sapienza, Rome, Italy.
    3Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    4Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    5Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    6Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    7Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
    8Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
    9North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
    10Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    11Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
    12Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
    13Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
    14Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
    15Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
    16Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain.
    17Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
    18Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    19Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK.
    20Service de Génétique, Institut Curie, Paris, France.
    21Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
    22Département de Biopathologie, Centre François Baclesse, Caen, France.
    23Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
    24Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
    25Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    26North West Thames Regional Genetics Service, Kennedy Galton Centre, The North West London Hospitals NHS Trust, Middlesex, UK.
    27Northern Genetics Service, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK.
    28Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
    29Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    30Department of Molecular Medicine, University La Sapienza, Rome, Italy.
    31Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA.
    32Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
    33SOD Genetica Molecolare, University Hospital, Pisa, Italy.
    34Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
    35Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
    36Division of Surgical Oncology, National Cancer Centre, Singapore, Singapore.
    37Division of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
    38Centre for Medical Genetics, Ghent University, Gent, Belgium.
    39Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
    40Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
    41Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
    42Department of Medicine, University of Udine, Udine, Italy.
    43Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    44Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK.
    45Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
    46Centre for Medical Genetics, Ghent University, Gent, Belgium.
    47Centre for Medical Genetics, Ghent University, Gent, Belgium.
    48Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    49Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain.
    50Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    51Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
    52Clinical Genetics Department, St Michael's Hospital, Bristol, UK.
    53Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
    54Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
    55Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
    56Division 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.
    57Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    58Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
    59Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    60Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    61Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.
    62Department of Human Genetics, University Würzburg, Würzburg, Germany.
    63Service de Génétique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
    64Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
    65Department of Pathology and Laboratory Medicine, University of Kansas, Medical Center, Kansas City, KS, USA.
    66Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
    67Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
    68North of Scotland Regional Genetics Service, NHS Grampian & University of Aberdeen, Foresterhill, Aberdeen, UK.
    69Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
    70Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    71Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
    72Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
    73Southwest Thames Regional Genetics Service, St George's Hospital, London, UK.
    74Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
    75Institute of Human Genetics, University of Münster, Münster, Germany.
    76Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
    77Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    78Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
    79Faculty of Medicine, Institute of Biomedical Sciences, Dept. Of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania.
    80Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
    81Department of Oncology, Landspitali University Hospital, Reykjavik, Iceland.
    82Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
    83Department of Urology, Medical University of Vienna, Vienna, Austria.
    84Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
    85Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
    86Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
    87Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    88Institut Curie, Paris, France.
    89Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain.
    90Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    91Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
    92Department of Surgery, National Institute of Oncology, Budapest, Hungary.
    93Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
    94Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
    95Institut Curie, Paris, France.
    96Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany.
    97Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
    98Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
    99Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
    100Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    101All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
    102Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
    103Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    104Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
    105Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
    106Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
    107Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
    108Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
    109Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
    110Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
    111Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
    112Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
    113Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
    114Genome Diagnostics Program, IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy.
    115Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
    116Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    117South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK.
    118All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
    119Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    120Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
    121Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
    122Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
    123Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    124All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
    125Department of General Surgery, Singapore General Hospital, Singapore, Singapore.
    126Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, TU, Dresden, Dresden, Germany.
    127Servicio de Análisis Clínicos y Bioquímica Clínica, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran canaria, Las Palmas de Gran Canaría, Spain.
    128Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
    129West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK.
    130Princess Anne Hospital, Southampton, UK.
    131Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
    132Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    133Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
    134Service de Génétique, Institut Curie, Paris, France.
    135Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
    136Dept of OB/GYN, Medical University of Vienna, Vienna, Austria.
    137Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
    138Hereditary Cancer Program, ONCOBELL-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
    139Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
    140Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
    141Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
    142Istituto Tumori 'Giovanni Paolo II', Bari, Italy.
    143Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
    144Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
    145Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
    146Department of Molecular Medicine, University La Sapienza, Rome, Italy.
    147Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
    148Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
    149Division of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
    150Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    151Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK.
    152Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
    153Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    154Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
    155Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
    156Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
    157Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark.
    158Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
    159Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
    160Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada.
    161Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    162Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
    163Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
    164Department of Molecular Medicine, University La Sapienza, Rome, Italy.
    Abstract

    BACKGROUND: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers.

    METHODS: 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk.

    RESULTS: PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions.

    CONCLUSIONS: Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.


    © The Author(s) 2021. Published by Oxford University Press.

    KEYWORDS: BRCA1, BRCA2, PRS, genetics, male breast cancer, polygenic, prostate cancer

    Publikations ID: 34320204
    Quelle: öffnen
     
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