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Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

Hakkaart C 1 , Pearson JF 1 , Marquart L 2 , Dennis J 3 , Wiggins GAR 1 , Barnes DR 3 Show all authors , Robinson BA 4 , Mace PD 5 , Aittomäki K 6 , Andrulis IL 7 , Arun BK 8 , Azzollini J 9 , Balmaña J 10 , Barkardottir RB 11 , Belhadj S 12 , Berger L 13 , Blok MJ 14 , Boonen SE 15 , Borde J 16 , Bradbury AR 17 , Brunet J 18 , Buys SS 19 , Caligo MA 20 , Campbell I 21 , Chung WK 22 , Claes KBM 23 , GEMO Study Collaborators , EMBRACE Collaborators , Collonge-Rame MA 24 , Cook J 25 , Cosgrove C 26 , Couch FJ 27 , Daly MB 28 , Dandiker S 12 , Davidson R 29 , de la Hoya M 30 , de Putter R 23 , Delnatte C 31 , Dhawan M 32 , Diez O 10 , Ding YC 33 , Domchek SM 34 , Donaldson A 35 , Eason J 36 , Easton DF 3 , Ehrencrona H 37 , Engel C 38 , Evans DG 39 , Faust U 40 , Feliubadaló L 18 , Fostira F 41 , Friedman E 42 , Frone M 43 , Frost D 3 , Garber J 44 , Gayther SA 45 , Gehrig A 46 , Gesta P 47 , Godwin AK 48 , Goldgar DE 49 , Greene MH 43 , Hahnen E 16 , Hake CR 50 , Hamann U 51 , Hansen TVO 52 , Hauke J 16 , Hentschel J 53 , Herold N 16 , Honisch E 54 , Hulick PJ 55 , Imyanitov EN 56 , SWE-BRCA Investigators , kConFab Investigators , HEBON Investigators , Isaacs C 57 , Izatt L 58 , Izquierdo A 18 , Jakubowska A 59 , James PA 60 , Janavicius R 61 , John EM 62 , Joseph V 12 , Karlan BY 63 , Kemp Z 64 , Kirk J 65 , Konstantopoulou I 41 , Koudijs M 66 , Kwong A 67 , Laitman Y 42 , Lalloo F 68 , Lasset C 69 , Lautrup C 70 , Lazaro C 18 , Legrand C 71 , Leslie G 3 , Lesueur F 72 , Mai PL 73 , Manoukian S 9 , Mari V 74 , Martens JWM 75 , McGuffog L 3 , Mebirouk N 72 , Meindl A 76 , Miller A 77 , Montagna M 78 , Moserle L 78 , Mouret-Fourme E 79 , Musgrave H 80 , Nambot S 81 , Nathanson KL 34 , Neuhausen SL 33 , Nevanlinna H 82 , Yie JNY 83 , Nguyen-Dumont T 84 , Nikitina-Zake L 85 , Offit K 12 , Olah E 86 , Olopade OI 87 , Osorio A 88 , Ott CE 89 , Park SK 90 , Parsons MT 91 , Pedersen IS 92 , Peixoto A 93 , Perez-Segura P 30 , Peterlongo P 94 , Pocza T 86 , Radice P 95 , Ramser J 96 , Rantala J 97 , Rodriguez GC 98 , Rønlund K 99 , Rosenberg EH 100 , Rossing M 101 , Schmutzler RK 16 , Shah PD 17 , Sharif S 102 , Sharma P 103 , Side LE 104 , Simard J 105 , Singer CF 106 , Snape K 107 , Steinemann D 108 , Stoppa-Lyonnet D 79 , Sutter C 109 , Tan YY 106 , Teixeira MR 93 , Teo SH 110 , Thomassen M 15 , Thull DL 111 , Tischkowitz M 112 , Toland AE 113 , Trainer AH 114 , Tripathi V 115 , Tung N 116 , van Engelen K 117 , van Rensburg EJ 118 , Vega A 119 , Viel A 120 , Walker L 121 , Weitzel JN 122 , Wevers MR 123 , Chenevix-Trench G 91 , Spurdle AB 91 , Antoniou AC 3 , Walker LC 124

Affiliations 

  • 1 Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand
  • 2 QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 3 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
  • 4 Department of Medicine, University of Otago, Christchurch, New Zealand
  • 5 Department of Biochemistry, School of Biomedical Sciences, University of Otago, Dunedin, New Zealand
  • 6 Department of Medical and Clinical Genetics, University of Helsinki, Helsinki, Finland
  • 7 Fred A. Litwin Center for Cancer Genetics, Lunenfeld-Tanenbaum Research Institute of Mount Sinai Hospital, Toronto, ON, Canada
  • 8 Department of Breast Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA
  • 9 Unit of Medical Genetics, Department of Medical Oncology and Hematology, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 10 Hereditary cancer Genetics Group, Vall d'Hebron Institute of Oncology, Vall d'Hebron Hospital Campus, Barcelona, Spain
  • 11 Department of Pathology, Landspitali University Hospital, Reykjavik, Iceland
  • 12 Clinical Genetics Research Lab, Department of Cancer Biology and Genetics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
  • 13 Department of Clinical Genetics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
  • 14 Department of Clinical Genetics, Maastricht University Medical Center, Maastricht, The Netherlands
  • 15 Department of Clinical Genetics, Odense University Hospital, Odence C, Denmark
  • 16 Center for Integrated Oncology (CIO), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • 17 Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  • 18 Hereditary Cancer Program, Catalan Institute of Oncology (ICO), ONCOBELL-IDIBELL-IGTP, CIBERONC, Barcelona, Spain
  • 19 Department of Medicine, Huntsman Cancer Institute, Salt Lake City, UT, USA
  • 20 SOD Genetica Molecolare, University Hospital, Pisa, Italy
  • 21 Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 22 Departments of Pediatrics and Medicine, Columbia University, New York, NY, USA
  • 23 Centre for Medical Genetics, Ghent University Hospital, Gent, Belgium
  • 24 Service de Génétique Biologique, CHRU de Besançon, Besançon, France
  • 25 Sheffield Clinical Genetics Service, Sheffield Children's Hospital, Sheffield, UK
  • 26 Gynecologic Oncology, Translational Therapeutics, Department of Obstetrics and Gynecology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA
  • 27 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA
  • 28 Department of Clinical Genetics, Fox Chase Cancer Center, Philadelphia, PA, USA
  • 29 Department of Clinical Genetics, Queen Elizabeth University Hospital, Glasgow, UK
  • 30 Molecular Oncology Laboratory, CIBERONC, Hospital Clinico San Carlos, IdISSC (Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Madrid, Spain
  • 31 Oncogénétique, Institut de Cancérologie de l'Ouest siteRené Gauducheau, Saint Herblain, France
  • 32 Cancer Genetics and Prevention Program, University of California San Francisco, San Francisco, CA, USA
  • 33 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
  • 34 Basser Center for BRCA, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
  • 35 Clinical Genetics Department, St Michael's Hospital, Bristol, UK
  • 36 Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust, Nottingham, UK
  • 37 Department of Clinical Genetics and Pathology, Laboratory Medicine, Skåne University Hospital, Lund, Sweden
  • 38 Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany
  • 39 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
  • 40 Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany
  • 41 Molecular Diagnostics Laboratory, INRASTES, National Centre for Scientific Research 'Demokritos', Athens, Greece
  • 42 The Susanne Levy Gertner Oncogenetics Unit, Chaim Sheba Medical Center, Ramat Gan, Israel
  • 43 Clinical Genetics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD, USA
  • 44 Cancer Risk and Prevention Clinic, Dana-Farber Cancer Institute, Boston, MA, USA
  • 45 Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, CA, USA
  • 46 Department of Human Genetics, University Würzburg, Würzburg, Germany
  • 47 Service Régional Oncogénétique Poitou-Charentes, CH Niort, Niort, France
  • 48 Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA
  • 49 Department of Dermatology, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA
  • 50 Waukesha Memorial Hospital-Pro Health Care, Waukesha, USA
  • 51 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Heidelberg, Germany
  • 52 Department of Clinical Genetics, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark
  • 53 Institute of Human Genetics, University Hospital Leipzig, Leipzig, Germany
  • 54 Department of Gynecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  • 55 Center for Medical Genetics, NorthShore University HealthSystem, Evanston, IL, USA
  • 56 N.N. Petrov Institute of Oncology, St. Petersburg, Russia
  • 57 Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA
  • 58 Clinical Genetics, Guy's and St Thomas' NHS Foundation Trust, London, UK
  • 59 Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland
  • 60 Sir Peter MacCallum Department of Oncology, The University of Melbourne, Melbourne, Victoria, Australia
  • 61 Faculty of Medicine, Institute of Biomedical Sciences, Dept. Of Human and Medical Genetics, Vilnius University, Vilnius, Lithuania
  • 62 Department of Epidemiology & Population Health, Stanford University School of Medicine, Stanford, CA, USA
  • 63 David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA
  • 64 Breast and Cancer Genetics Units, The Royal Marsden NHS Foundation Trust, London, UK
  • 65 Familial Cancer Service, Weatmead Hospital, Wentworthville, New South Wales, Australia
  • 66 Department of Medical Genetics, University Medical Center, Utrecht, The Netherlands
  • 67 Hong Kong Hereditary Breast Cancer Family Registry, Hong Kong, China
  • 68 Department of Population Health Sciences, Weill Cornell Medicine, New York, NY, USA
  • 69 Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, Lyon, France
  • 70 Department of Clinical Genetics, Aarhus University Hospital, Aarhus N, Denmark
  • 71 Département de Génétique, CHU de Grenoble, Grenoble, France
  • 72 Genetic Epidemiology of Cancer team, Inserm U900, Paris, France
  • 73 Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 74 Département d'Hématologie-Oncologie Médicale, Centre Antoine Lacassagne, Nice, France
  • 75 Department of Medical Oncology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands
  • 76 Department of Gynecology and Obstetrics, University of Munich, Campus Großhadern, Munich, Germany
  • 77 NRG Oncology, Statistics and Data Management Center, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA
  • 78 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOV - IRCCS, Padua, Italy
  • 79 Service de Génétique, Institut Curie, Paris, France
  • 80 Department of Clinical Genetics, Yorkshire Regional Genetics Service, Chapel Allerton Hospital, Leeds, UK
  • 81 Unité d'oncogénétique, Centre de Lutte Contre le Cancer, Centre Georges-François Leclerc, Dijon, France
  • 82 Department of Obstetrics and Gynecology, Helsinki University Hospital, University of Helsinki, Helsinki, Finland
  • 83 Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
  • 84 Precision Medicine, School of Clinical Sciences at Monash Health, Monash University, Clayton, Victoria, Australia
  • 85 Latvian Biomedical Research and Study Centre, Riga, Latvia
  • 86 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 87 Center for Clinical Cancer Genetics, The University of Chicago, Chicago, IL, USA
  • 88 Familial Cancer Clinical Unit, Human Cancer Genetics Programme, Spanish National Cancer Research Centre (CNIO) and Spanish Network on Rare Diseases (CIBERER), Madrid, Spain
  • 89 Institute of Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin and Berlin Institute of Health, Berlin, Germany
  • 90 Department of Preventive Medicine, Seoul National University College of Medicine, Seoul, Korea
  • 91 Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland, Australia
  • 92 Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark
  • 93 Department of Genetics, Portuguese Oncology Institute, Porto, Portugal
  • 94 Genome Diagnostics Program, IFOM ETS - the AIRC Institute of Molecular Oncology, Milan, Italy
  • 95 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Research, Fondazione IRCCS Istituto Nazionale dei Tumori (INT), Milan, Italy
  • 96 Division of Gynaecology and Obstetrics, Klinikum rechts der Isar der Technischen Universität München, Munich, Germany
  • 97 Clinical Genetics, Karolinska Institutet, Stockholm, Sweden
  • 98 Division of Gynecologic Oncology, NorthShore University HealthSystem, University of Chicago, Evanston, IL, USA
  • 99 Department of Clinical Genetics, University Hospital of Southern Denmark, Vejle Hospital, Vejle, Denmark
  • 100 Department of Pathology, The Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands
  • 101 Center for Genomic Medicine, Rigshospitalet, Copenhagen, Denmark
  • 102 West Midlands Regional Genetics Service, Birmingham Women's Hospital Healthcare NHS Trust, Birmingham, UK
  • 103 Department of Internal Medicine, Division of Medical Oncology, University of Kansas Medical Center, Westwood, KS, USA
  • 104 Princess Anne Hospital, Southampton, UK
  • 105 Genomics Center, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Québec City, QC, Canada
  • 106 Dept of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
  • 107 Medical Genetics Unit, St George's, University of London, London, UK
  • 108 Institute of Human Genetics, Hannover Medical School, Hannover, Germany
  • 109 Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
  • 110 Breast Cancer Research Programme, Cancer Research Malaysia, Subang Jaya, Selangor, Malaysia
  • 111 Department of Medicine, Magee-Womens Hospital, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA
  • 112 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montréal, QC, Canada
  • 113 Department of Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA
  • 114 Parkville Familial Cancer Centre, Peter MacCallum Cancer Center, Melbourne, Victoria, Australia
  • 115 South East Thames Regional Genetics Service, Guy's and St Thomas' NHS Foundation Trust, London, UK
  • 116 Department of Medical Oncology, Beth Israel Deaconess Medical Center, Boston, MA, USA
  • 117 Department of Clinical Genetics, VU University Medical Center, Amsterdam, The Netherlands
  • 118 Department of Genetics, University of Pretoria, Arcadia, South Africa
  • 119 Centro de Investigación en Red de Enfermedades Raras (CIBERER), Madrid, Spain
  • 120 Division of Functional onco-genomics and genetics, Centro di Riferimento Oncologico di Aviano (CRO), IRCCS, Aviano, Italy
  • 121 Oxford Regional Genetics Service, Churchill Hospital, Oxford, UK
  • 122 Latin American School of Oncology, Tuxtla Gutiérrez, Chiapas, Mexico
  • 123 Radboud University Medical Center, Nijmegen, Netherlands
  • 124 Department of Pathology and Biomedical Science, University of Otago, Christchurch, New Zealand. [email protected]
Commun Biol, 2022 Oct 06;5(1):1061.
PMID: 36203093 DOI: 10.1038/s42003-022-03978-6

Abstract

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09-1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

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

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