Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Daniel R Barnes¹, Valentina Silvestri², Goska Leslie¹, Lesley McGuffog¹, Joe Dennis¹, Xin Yang¹, Julian Adlard³, Bjarni A Agnarsson^{4

5}, Munaza Ahmed⁶, Kristiina Aittomäki⁷, Irene L Andrulis^{8

9}, Adalgeir Arason^{4

10}, Norbert Arnold^{11

12}, Bernd Auber¹³, Jacopo Azzollini¹⁴, Judith Balmaña^{15

16}, Rosa B Barkardottir^{4

10}, Daniel Barrowdale¹, Julian Barwell¹⁷, Muriel Belotti¹⁸, Javier Benitez^{19

20}, Pascaline Berthet²¹, Susanne E Boonen²², Åke Borg²³, Aniko Bozsik²⁴, Angela F Brady²⁵, Paul Brennan²⁶, Carole Brewer²⁷, Joan Brunet²⁸, Agostino Bucalo², Saundra S Buys²⁹, Trinidad Caldés³⁰, Maria A Caligo³¹, Ian Campbell^{32

33}, Hayley Cassingham³⁴, Lise Lotte Christensen³⁵, Giulia Cini³⁶, Kathleen B M Claes³⁷; GEMO Study Collaborators; EMBRACE Collaborators; Jackie Cook³⁸, Anna Coppa^{39

40}, Laura Cortesi⁴⁰, Giuseppe Damante⁴¹, Esther Darder²⁸, Rosemarie Davidson⁴², Miguel de la Hoya³⁰, Kim De Leeneer³⁷, Robin de Putter³⁷, Jesús Del Valle²⁸, Orland Diez^{15

43}, Yuan Chun Ding⁴⁴, Susan M Domchek⁴⁵, Alan Donaldson⁴⁶, Jacqueline Eason⁴⁷, Ros Eeles⁴⁸, Christoph Engel^{49

50}, D Gareth Evans^{51

52}, Lidia Feliubadaló²⁸, Florentia Fostira⁵³, Megan Frone⁵⁴, Debra Frost¹, David Gallagher⁵⁵, Andrea Gehrig⁵⁶, Sophie Giraud⁵⁷, Gord Glendon⁸, Andrew K Godwin⁵⁸, David E Goldgar⁵⁹, Mark H Greene⁵⁴, Helen Gregory⁶⁰, Eva Gross⁶¹, Eric Hahnen^{62

63}, Ute Hamann⁶⁴, Thomas V O Hansen⁶⁵, Helen Hanson⁶⁶, Julia Hentschel⁶⁷, Judit Horvath⁶⁸; KConFab Investigators; HEBON Investigators; Louise Izatt⁶⁹, Angel Izquierdo²⁸, Paul A James^{33

70}, Ramunas Janavicius^{71

72}, Uffe Birk Jensen⁷³, Oskar Th Johannsson⁷⁴, Esther M John^{75

76}, Gero Kramer⁷⁷, Lone Kroeldrup²², Torben A Kruse²², Charlotte Lautrup^{78

79}, Conxi Lazaro²⁸, Fabienne Lesueur^{80

81

82}, Adria Lopez-Fernández¹⁵, Phuong L Mai⁸³, Siranoush Manoukian¹⁴, Zoltan Matrai⁸⁴, Laura Matricardi⁸⁵, Kara N Maxwell⁸⁶, Noura Mebirouk^{80

81

82}, Alfons Meindl⁶¹, Marco Montagna⁸⁵, Alvaro N Monteiro⁸⁷, Patrick J Morrison⁸⁸, Taru A Muranen⁸⁹, Alex Murray⁹⁰, Katherine L Nathanson⁴⁵, Susan L Neuhausen⁴⁴, Heli Nevanlinna⁸⁹, Tu Nguyen-Dumont^{91

92}, Dieter Niederacher⁹³, Edith Olah²⁴, Olufunmilayo I Olopade⁹⁴, Domenico Palli⁹⁵, Michael T Parsons⁹⁶, Inge Sokilde Pedersen^{79

97

98}, Bernard Peissel¹⁴, Pedro Perez-Segura³⁰, Paolo Peterlongo⁹⁹, Annabeth H Petersen¹⁰⁰, Pedro Pinto¹⁰¹, Mary E Porteous¹⁰², Caroline Pottinger⁹⁰, Miquel Angel Pujana¹⁰³, Paolo Radice¹⁰⁴, Juliane Ramser¹⁰⁵, Johanna Rantala¹⁰⁶, Mark Robson¹⁰⁷, Mark T Rogers⁹⁰, Karina Rønlund¹⁰⁰, Andreas Rump¹⁰⁸, Ana María Sánchez de Abajo¹⁰⁹, Payal D Shah⁸⁶, Saba Sharif¹¹⁰, Lucy E Side¹¹¹, Christian F Singer¹¹², Zsofia Stadler¹⁰⁷, Linda Steele⁴⁴, Dominique Stoppa-Lyonnet^{18

113

114}, Christian Sutter¹¹⁵, Yen Yen Tan¹¹⁶, Manuel R Teixeira^{101

117}, Alex Teulé²⁸, Darcy L Thull¹¹⁸, Marc Tischkowitz^{119

120}, Amanda E Toland¹²¹, Stefania Tommasi¹²², Angela Toss⁴⁰, Alison H Trainer^{70

123}, Vishakha Tripathi⁶⁹, Virginia Valentini², Christi J van Asperen¹²⁴, Marta Venturelli⁴⁰, Alessandra Viel³⁶, Joseph Vijai^{107

125}, Lisa Walker¹²⁶, Shan Wang-Gohrke¹²⁷, Barbara Wappenschmidt^{62

63}, Anna Whaite¹²⁸, Ines Zanna⁹⁵, Kenneth Offit^{107

125}, Mads Thomassen²², Fergus J Couch¹²⁹, Rita K Schmutzler^{62

63

130}, Jacques Simard¹³¹, Douglas F Easton^{1

132}, Georgia Chenevix-Trench⁹⁶, Antonis C Antoniou¹, Laura Ottini²; Consortium of Investigators of Modifiers of BRCA1 and BRCA2

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
³ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
⁴ Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
⁵ School of Medicine, University of Iceland, Reykjavik, Iceland.
⁶ North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
⁷ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹¹ Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹² Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹³ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
¹⁴ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹⁵ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain.
¹⁶ Department of Medical Oncology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
¹⁷ Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK.
¹⁸ Service de Génétique, Institut Curie, Paris, France.
¹⁹ Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
²⁰ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
²¹ Département de Biopathologie, Centre François Baclesse, Caen, France.
²² Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
²³ Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
²⁴ Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
²⁵ North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
²⁶ Northern Genetics Service, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK.
²⁷ Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
²⁸ Hereditary Cancer Program, Oncobell-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
²⁹ Department of Internal Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA.
³⁰ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
³¹ SOD Genetica Molecolare, University Hospital, Pisa, Italy.
³² Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
³³ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
³⁴ Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
³⁵ Division of Surgical Oncology, National Cancer Centre, Singapore, Singapore.
³⁶ Division of Functional Onco-Genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
³⁷ Centre for Medical Genetics, Ghent University, Gent, Belgium.
³⁸ Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
³⁹ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
⁴⁰ Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
⁴¹ Department of Medicine, University of Udine, Udine, Italy.
⁴² Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK.
⁴³ Area of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴⁴ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁴⁵ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁶ Clinical Genetics Department, St Michael's Hospital, Bristol, UK.
⁴⁷ Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁴⁸ Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
⁴⁹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁰ LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
⁵¹ 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.
⁵² North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁵³ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
⁵⁴ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁵⁵ Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.
⁵⁶ Department of Human Genetics, University Würzburg, Würzburg, Germany.
⁵⁷ Service de Génétique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
⁵⁸ Department of Pathology and Laboratory Medicine, University of Kansas, Medical Center, Kansas City, KS, USA.
⁵⁹ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶⁰ North of Scotland Regional Genetics Service, NHS Grampian & University of Aberdeen, Foresterhill, Aberdeen, UK.
⁶¹ Department of Gynecology and Obstetrics, University of Munich, Munich, Germany.
⁶² Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶³ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶⁴ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁵ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁶⁶ Southwest Thames Regional Genetics Service, St George's Hospital, London, UK.
⁶⁷ Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
⁶⁸ Institute of Human Genetics, University of Münster, Münster, Germany.
⁶⁹ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁷⁰ Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
⁷¹ Faculty of Medicine, Institute of Biomedical Sciences, Department of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania.
⁷² State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
⁷³ Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
⁷⁴ Department of Oncology, Landspitali University Hospital, Reykjavik, Iceland.
⁷⁵ Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁶ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁷ Department of Urology, Medical University of Vienna, Vienna, Austria.
⁷⁸ Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
⁷⁹ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
⁸⁰ Institut Curie, Paris, France.
⁸¹ Mines ParisTech, Fontainebleau, France.
⁸² Genetic Epidemiology of Cancer Team, Inserm U900, Paris, France.
⁸³ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸⁴ Department of Surgery, National Institute of Oncology, Budapest, Hungary.
⁸⁵ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
⁸⁶ Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁸⁷ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁸⁸ Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
⁸⁹ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁹⁰ All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
⁹¹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁹² Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁹³ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
⁹⁴ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
⁹⁵ Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
⁹⁶ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁹⁷ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
⁹⁸ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁹⁹ Genome Diagnostics Program, IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy.
¹⁰⁰ Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
¹⁰¹ Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
¹⁰² South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK.
¹⁰³ Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
¹⁰⁴ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹⁰⁵ Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
¹⁰⁶ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁸ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁰⁹ Servicio de Análisis Clínicos y Bioquímica Clínica, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria , Las Palmas de Gran Canaría, Spain.
¹¹⁰ West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK.
¹¹¹ Princess Anne Hospital, Southampton, UK.
¹¹² Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹¹³ Department of Tumour Biology, INSERM U830, Paris, France.
¹¹⁴ Université Paris Descartes, Paris, France.
¹¹⁵ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
¹¹⁶ Dept of OB/GYN, Medical University of Vienna, Vienna, Austria.
¹¹⁷ Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
¹¹⁸ Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁹ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
¹²⁰ Department of Medical Genetics, University of Cambridge, Cambridge, UK.
¹²¹ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
¹²² IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy.
¹²³ Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
¹²⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹²⁵ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹²⁶ Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK.
¹²⁷ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹²⁸ Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
¹²⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹³⁰ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³¹ Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada.
¹³² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

PMID: 34320204
PMCID: PMC8755508
DOI: 10.1093/jnci/djab147

Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

Daniel R Barnes et al. J Natl Cancer Inst. 2022.

. 2022 Jan 11;114(1):109-122.

doi: 10.1093/jnci/djab147.

Authors

Affiliations

¹ Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
² Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
³ Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK.
⁴ Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland.
⁵ School of Medicine, University of Iceland, Reykjavik, Iceland.
⁶ North East Thames Regional Genetics Service, Great Ormond Street Hospital for Children NHS Trust, London, UK.
⁷ Department of Clinical Genetics, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁸ Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada.
⁹ Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada.
¹⁰ BMC (Biomedical Centre), Faculty of Medicine, University of Iceland, Reykjavik, Iceland.
¹¹ Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹² Institute of Clinical Molecular Biology, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
¹³ Department of Human Genetics, Hannover Medical School, Hannover, Germany.
¹⁴ Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
¹⁵ Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain.
¹⁶ Department of Medical Oncology, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
¹⁷ Leicestershire Clinical Genetics Service, University Hospitals of Leicester NHS Trust, Leicester, UK.
¹⁸ Service de Génétique, Institut Curie, Paris, France.
¹⁹ Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.
²⁰ Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
²¹ Département de Biopathologie, Centre François Baclesse, Caen, France.
²² Department of Clinical Genetics, Odense University Hospital, Odense, Denmark.
²³ Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
²⁴ Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
²⁵ North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
²⁶ Northern Genetics Service, Newcastle Hospitals NHS Foundation Trust, Newcastle, UK.
²⁷ Department of Clinical Genetics, Royal Devon & Exeter Hospital, Exeter, UK.
²⁸ Hereditary Cancer Program, Oncobell-IDIBELL-IGTP, Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
²⁹ Department of Internal Medicine, Huntsman Cancer Institute at the University of Utah, Salt Lake City, UT, USA.
³⁰ Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain.
³¹ SOD Genetica Molecolare, University Hospital, Pisa, Italy.
³² Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
³³ Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia.
³⁴ Department of Internal Medicine, Division of Human Genetics, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
³⁵ Division of Surgical Oncology, National Cancer Centre, Singapore, Singapore.
³⁶ Division of Functional Onco-Genomics and Genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy.
³⁷ Centre for Medical Genetics, Ghent University, Gent, Belgium.
³⁸ Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK.
³⁹ Department of Experimental Medicine, Sapienza University of Rome, Rome, Italy.
⁴⁰ Department of Oncology and Haematology, University of Modena and Reggio Emilia, Modena, Italy.
⁴¹ Department of Medicine, University of Udine, Udine, Italy.
⁴² Department of Clinical Genetics, South Glasgow University Hospitals, Glasgow, UK.
⁴³ Area of Clinical and Molecular Genetics, Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.
⁴⁴ Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
⁴⁵ Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA.
⁴⁶ Clinical Genetics Department, St Michael's Hospital, Bristol, UK.
⁴⁷ Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK.
⁴⁸ Oncogenetics Team, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK.
⁴⁹ Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
⁵⁰ LIFE-Leipzig Research Centre for Civilization Diseases, University of Leipzig, Leipzig, Germany.
⁵¹ 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.
⁵² North West Genomics Laboratory Hub, Manchester Centre for Genomic Medicine, St Mary's Hospital, Manchester University NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester, UK.
⁵³ Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece.
⁵⁴ Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA.
⁵⁵ Academic Unit of Clinical and Molecular Oncology, Trinity College Dublin and St James's Hospital, Dublin, Eire.
⁵⁶ Department of Human Genetics, University Würzburg, Würzburg, Germany.
⁵⁷ Service de Génétique, Groupement Hospitalier Est, Hospices Civils de Lyon, Bron, France.
⁵⁸ Department of Pathology and Laboratory Medicine, University of Kansas, Medical Center, Kansas City, KS, USA.
⁵⁹ Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.
⁶⁰ North of Scotland Regional Genetics Service, NHS Grampian & University of Aberdeen, Foresterhill, Aberdeen, UK.
⁶¹ Department of Gynecology and Obstetrics, University of Munich, Munich, Germany.
⁶² Center for Familial Breast and Ovarian Cancer, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶³ Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
⁶⁴ Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany.
⁶⁵ Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
⁶⁶ Southwest Thames Regional Genetics Service, St George's Hospital, London, UK.
⁶⁷ Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany.
⁶⁸ Institute of Human Genetics, University of Münster, Münster, Germany.
⁶⁹ Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK.
⁷⁰ Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia.
⁷¹ Faculty of Medicine, Institute of Biomedical Sciences, Department of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania.
⁷² State Research Institute Centre for Innovative Medicine, Vilnius, Lithuania.
⁷³ Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark.
⁷⁴ Department of Oncology, Landspitali University Hospital, Reykjavik, Iceland.
⁷⁵ Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁶ Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
⁷⁷ Department of Urology, Medical University of Vienna, Vienna, Austria.
⁷⁸ Department of Clinical Genetics, Aalborg University Hospital, Aalborg, Denmark.
⁷⁹ Clinical Cancer Research Center, Aalborg University Hospital, Aalborg, Denmark.
⁸⁰ Institut Curie, Paris, France.
⁸¹ Mines ParisTech, Fontainebleau, France.
⁸² Genetic Epidemiology of Cancer Team, Inserm U900, Paris, France.
⁸³ Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
⁸⁴ Department of Surgery, National Institute of Oncology, Budapest, Hungary.
⁸⁵ Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
⁸⁶ Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
⁸⁷ Department of Cancer Epidemiology, Moffitt Cancer Center, Tampa, FL, USA.
⁸⁸ Northern Ireland Regional Genetics Centre, Belfast City Hospital, Belfast, UK.
⁸⁹ Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland.
⁹⁰ All Wales Medical Genetics Services, University Hospital of Wales, Cardiff, UK.
⁹¹ Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia.
⁹² Department of Clinical Pathology, The University of Melbourne, Melbourne, Victoria, Australia.
⁹³ Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
⁹⁴ Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA.
⁹⁵ Cancer Risk Factors and Life-Style Epidemiology Unit, Institute for Cancer Research, Prevention and Clinical Network (ISPRO), Florence, Italy.
⁹⁶ Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia.
⁹⁷ Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark.
⁹⁸ Department of Clinical Medicine, Aalborg University, Aalborg, Denmark.
⁹⁹ Genome Diagnostics Program, IFOM-the FIRC Institute of Molecular Oncology, Milan, Italy.
¹⁰⁰ Department of Clinical Genetics, Vejle Hospital, Vejle, Denmark.
¹⁰¹ Department of Genetics, Portuguese Oncology Institute, Porto, Portugal.
¹⁰² South East of Scotland Regional Genetics Service, Western General Hospital, Edinburgh, UK.
¹⁰³ Translational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute), Catalan Institute of Oncology, CIBERONC, Barcelona, Spain.
¹⁰⁴ Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy.
¹⁰⁵ Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany.
¹⁰⁶ Clinical Genetics, Karolinska Institutet, Stockholm, Sweden.
¹⁰⁷ Clinical Genetics Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹⁰⁸ Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
¹⁰⁹ Servicio de Análisis Clínicos y Bioquímica Clínica, Complejo Hospitalario Universitario Insular Materno-Infantil de Gran Canaria , Las Palmas de Gran Canaría, Spain.
¹¹⁰ West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK.
¹¹¹ Princess Anne Hospital, Southampton, UK.
¹¹² Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria.
¹¹³ Department of Tumour Biology, INSERM U830, Paris, France.
¹¹⁴ Université Paris Descartes, Paris, France.
¹¹⁵ Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany.
¹¹⁶ Dept of OB/GYN, Medical University of Vienna, Vienna, Austria.
¹¹⁷ Biomedical Sciences Institute (ICBAS), University of Porto, Porto, Portugal.
¹¹⁸ Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
¹¹⁹ Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada.
¹²⁰ Department of Medical Genetics, University of Cambridge, Cambridge, UK.
¹²¹ Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA.
¹²² IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy.
¹²³ Department of Medicine, University of Melbourne, Melbourne, Victoria, Australia.
¹²⁴ Department of Clinical Genetics, Leiden University Medical Center, Leiden, The Netherlands.
¹²⁵ Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
¹²⁶ Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK.
¹²⁷ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹²⁸ Liverpool Centre for Genomic Medicine, Liverpool Women's NHS Foundation Trust, Liverpool, UK.
¹²⁹ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
¹³⁰ Center for Molecular Medicine Cologne (CMMC), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
¹³¹ Genomics Center, Centre Hospitalier Universitaire de Québec-Université Laval Research Center, Québec City, QC, Canada.
¹³² Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.

PMID: 34320204
PMCID: PMC8755508
DOI: 10.1093/jnci/djab147

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 1318 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 3 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 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios 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 informing clinical management.

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Figures

**Figure 1.**
The predicted absolute risks of developing breast cancer and prostate cancer by PRS percentile. Risks were calculated assuming the per standard deviation ratio estimates in the combined sample of *BRCA1 and BRCA2* carriers (Supplementary Tables 6 and 7). **(A)** The absolute risks of developing breast cancer for *BRCA2* carriers by PRS_ER+ percentiles. **(B)** The absolute risks of developing prostate cancer for *BRCA1* carriers by PRS_PC percentiles. **(C)** The absolute risks of developing prostate cancer for *BRCA2* carriers by PRS_PC percentiles. PRS = polygenic risk scores; PRS_ER+ = ER-positive breast cancer PRS.

**Figure 2.**
The predicted 10-year risks of developing breast cancer and prostate cancer by PRS percentile. Ten-year risks were calculated from the absolute risks of developing breast cancer or prostate cancer (Figure 1). **(A)** The 10-year risks of developing breast cancer for *BRCA2* carriers by PRS_ER+ percentiles. **(B)** The 10-year risks of developing prostate cancer for *BRCA1* pathogenic variant carriers by PRS_PC percentiles. **(C)** The 10-year risks of developing prostate cancer for *BRCA2* pathogenic variant carriers by PRS_PC percentiles. PRS = polygenic risk scores PRS_ER+ = ER-positive breast cancer PRS.

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Comment in

Urological Oncology: Prostate Cancer.
Taneja SS. Taneja SS. J Urol. 2022 Mar;207(3):735-738. doi: 10.1097/JU.0000000000002377. Epub 2021 Dec 17. J Urol. 2022. PMID: 34915718 No abstract available.

References

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Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

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Breast and Prostate Cancer Risks for Male BRCA1 and BRCA2 Pathogenic Variant Carriers Using Polygenic Risk Scores

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