Inheritance of deleterious mutations at both BRCA1 and BRCA2 in an international sample of 32,295 women

Rebbeck TR 1 , Friebel TM 2 , Mitra N 3 , Wan F 4 , Chen S 5 , Andrulis IL 6 Show all authors , Apostolou P 7 , Arnold N 8 , Arun BK 9 , Barrowdale D 10 , Benitez J 11 , Berger R 12 , Berthet P 13 , Borg A 14 , Buys SS 15 , Caldes T 16 , Carter J 17 , Chiquette J 18 , Claes KB 19 , Couch FJ 20 , Cybulski C 21 , Daly MB 22 , de la Hoya M 16 , Diez O 23 , Domchek SM 24 , Nathanson KL 24 , Durda K 21 , Ellis S 25 , EMBRACE , Evans DG 26 , Foretova L 27 , Friedman E 28 , Frost D 25 , Ganz PA 29 , Garber J 2 , Glendon G 30 , Godwin AK 31 , Greene MH 32 , Gronwald J 21 , Hahnen E 33 , Hallberg E 34 , Hamann U 35 , Hansen TV 36 , HEBON , Imyanitov EN 37 , Isaacs C 38 , Jakubowska A 21 , Janavicius R 39 , Jaworska-Bieniek K 21 , John EM 40 , Karlan BY 41 , Kaufman B 12 , Investigators K 42 , Kwong A 43 , Laitman Y 28 , Lasset C 44 , Lazaro C 45 , Lester J 41 , Loman N 46 , Lubinski J 21 , Manoukian S 47 , Mitchell G 48 , Montagna M 49 , Neuhausen SL 50 , Nevanlinna H 51 , Niederacher D 52 , Nussbaum RL 53 , Offit K 54 , Olah E 55 , Olopade OI 56 , Park SK 57 , Piedmonte M 58 , Radice P 59 , Rappaport-Fuerhauser C 60 , Rookus MA 61 , Seynaeve C 62 , Simard J 63 , Singer CF 64 , Soucy P 63 , Southey M 65 , Stoppa-Lyonnet D 66 , Sukiennicki G 21 , Szabo CI 67 , Tancredi M 68 , Teixeira MR 69 , Teo SH 70 , Terry MB 71 , Thomassen M 72 , Tihomirova L 73 , Tischkowitz M 74 , Toland AE 75 , Toloczko-Grabarek A 21 , Tung N 76 , van Rensburg EJ 77 , Villano D 78 , Wang-Gohrke S 79 , Wappenschmidt B 33 , Weitzel JN 80 , Zidan J 81 , Zorn KK 82 , McGuffog L 83 , Easton D 83 , Chenevix-Trench G 10 , Antoniou AC 83 , Ramus SJ 5

Affiliations 

  • 1 Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA, USA. [email protected]
  • 2 Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA, USA
  • 3 Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  • 4 Biostatistics Unit, Group Health Research Institute, Seattle, WA, USA
  • 5 Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA
  • 6 Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
  • 7 Molecular Diagnostics Laboratory, (INRASTES) Institute of Nuclear and Radiological Sciences and Technology, National Centre for Scientific Research "Demokritos", Patriarchou Gregoriou & Neapoleos str. Aghia Paraskevi Attikis, Athens, Greece
  • 8 Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University, Kiel, Germany
  • 9 Department of Breast Medical Oncology and Clinical Cancer Genetics Program, University Of Texas MD Anderson Cancer Center, 1515 Pressler Street, CBP 5, Houston, TX, USA
  • 10 Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia
  • 11 Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain
  • 12 The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel
  • 13 Centre François Baclesse, 3 avenue Général Harris, Caen, France
  • 14 Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden
  • 15 Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA
  • 16 Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain
  • 17 Gynaecological Oncology, The University of Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia
  • 18 Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050, chemin Sainte-Foy, Québec, Canada
  • 19 Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Gent, Belgium
  • 20 Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, USA
  • 21 Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland
  • 22 Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA
  • 23 Oncogenetics Group, Vall d'Hebron Institute of Oncology (VHIO), Clinical and Molecular Genetics Area, Vall d'Hebron University Hospital, Passeig Vall d'Hebron 119-129, Barcelona, Spain
  • 24 Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
  • 25 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK
  • 26 Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK
  • 27 Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic
  • 28 The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel
  • 29 UCLA Schools of Medicine and Public Health, Division of Cancer Prevention & Control Research Jonsson Comprehensive Cancer Center, 650 Charles Young Drive South, Room A2-125 HS, Los Angeles, CA, 90095-6900, USA
  • 30 Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada
  • 31 Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS, 3040, Kansas, USA
  • 32 Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, USA
  • 33 Center for Hereditary Breast and Ovarian Cancer, Center for Integrated Oncology (CIO) and Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany
  • 34 Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ, USA
  • 35 Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany
  • 36 Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark
  • 37 N.N. Petrov Institute of Oncology, St.-Petersburg, 197758, Russia
  • 38 Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, USA
  • 39 Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Santariskiu st, Vilnius, Lithuania
  • 40 Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA, 94538, USA
  • 41 Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA
  • 42 Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia
  • 43 The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong
  • 44 Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France
  • 45 Molecular Diagnostic Unit, Hereditary Cancer Program, IDIBELL (Bellvitge Biomedical Research Institute) Catalan Institute of Oncology, Gran Via de l'Hospitalet, 199-203, 08908, L'Hospitalet Barcelona, Barcelona, Spain
  • 46 Department of Oncology, Lund University Hospital, Lund, Sweden
  • 47 Unit of Medical Genetics, Department of Preventive and Predictive Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), Via Giacomo Venezian 1, 20133, Milan, Italy
  • 48 Familial Cancer Centre, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, VIC, 8006, Australia
  • 49 Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOC - IRCCS, Via Gattamelata 64, Padua, Italy
  • 50 Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA
  • 51 Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700, (Haartmaninkatu 8), 00029, HUS, Helsinki, Finland
  • 52 Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
  • 53 , 513 Parnassus Ave., HSE 901E, San Francisco, CA, 94143-0794, USA
  • 54 Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA
  • 55 Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary
  • 56 , 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA
  • 57 Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea
  • 58 NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY, 14263, USA
  • 59 Unit of Molecular Bases of Genetic Risk and Genetic Testing, Department of Preventive and Predicted Medicine, Fondazione IRCCS (Istituto Di Ricovero e Cura a Carattere Scientifico) Istituto Nazionale Tumori (INT), c/o Amaedeolab, via GA Amadeo 42, 20133, Milan, Italy
  • 60 Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A 1090, Vienna, Austria
  • 61 Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000, BE, Amsterdam, The Netherlands
  • 62 Department of Medical Oncology, Family Cancer Clinic Erasmus University Medical Center Cancer institute, P.O. Box 5201, 3008, AE, Rotterdam, The Netherlands
  • 63 Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec, Canada
  • 64 Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A 1090, Vienna, Austria
  • 65 Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia
  • 66 Service de Génétique Oncologique, Institut Curie, 26, rue d'Ulm, Paris, Cedex 05, France
  • 67 National Human Genome Research Institute, National Institutes of Health Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD, 20892-8004, USA
  • 68 Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy
  • 69 Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal
  • 70 Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500, Malaysia
  • 71 Department of Epidemiology, Columbia University, New York, NY, USA
  • 72 Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark
  • 73 Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia
  • 74 Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada
  • 75 Divison of Human Cancer Genetics, Departments of Internal Medicine and Molecular Virology, Immunology and Medical Genetics, Comprehensive Cancer Center, The Ohio State University, 998 Biomedical Research Tower, Columbus, OH, USA
  • 76 Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA
  • 77 Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007, South Africa
  • 78 Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY, USA
  • 79 Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany
  • 80 Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA
  • 81 Institute of Oncology, Rivka Ziv Medical Center, 13000, Zefat, Israel
  • 82 , 4301 West Markham Street, Slot 793, Little Rock, AR, 72205, USA
  • 83 Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK
Breast Cancer Res, 2016 11 11;18(1):112.
PMID: 27836010

Abstract

BACKGROUND: Most BRCA1 or BRCA2 mutation carriers have inherited a single (heterozygous) mutation. Transheterozygotes (TH) who have inherited deleterious mutations in both BRCA1 and BRCA2 are rare, and the consequences of transheterozygosity are poorly understood.

METHODS: From 32,295 female BRCA1/2 mutation carriers, we identified 93 TH (0.3 %). "Cases" were defined as TH, and "controls" were single mutations at BRCA1 (SH1) or BRCA2 (SH2). Matched SH1 "controls" carried a BRCA1 mutation found in the TH "case". Matched SH2 "controls" carried a BRCA2 mutation found in the TH "case". After matching the TH carriers with SH1 or SH2, 91 TH were matched to 9316 SH1, and 89 TH were matched to 3370 SH2.

RESULTS: The majority of TH (45.2 %) involved the three common Jewish mutations. TH were more likely than SH1 and SH2 women to have been ever diagnosed with breast cancer (BC; p = 0.002). TH were more likely to be diagnosed with ovarian cancer (OC) than SH2 (p = 0.017), but not SH1. Age at BC diagnosis was the same in TH vs. SH1 (p = 0.231), but was on average 4.5 years younger in TH than in SH2 (p 

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

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