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



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.



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 < 0.001). BC in TH was more likely to be estrogen receptor (ER) positive (p = 0.010) or progesterone receptor (PR) positive (p = 0.013) than in SH1, but less likely to be ER positive (p < 0.001) or PR positive (p = 0.012) than SH2. Among 15 tumors from TH patients, there was no clear pattern of loss of heterozygosity (LOH) for BRCA1 or BRCA2 in either BC or OC.



Our observations suggest that clinical TH phenotypes resemble SH1. However, TH breast tumor marker characteristics are phenotypically intermediate to SH1 and SH2.
Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA, USA. Timothy_Rebbeck@dfci.harvard.edu.
Timothy R
TR
Rebbeck
Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA, USA.
Tara M
TM
Friebel
Department of Biostatistics and Epidemiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Nandita
N
Mitra
Biostatistics Unit, Group Health Research Institute, Seattle, WA, USA.
Fei
F
Wan
Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA.
Stephanie
S
Chen
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.|Departments of Molecular Genetics and Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
Irene L
IL
Andrulis
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.
Paraskevi
P
Apostolou
Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University, Kiel, Germany.
Norbert
N
Arnold
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.
Banu K
BK
Arun
Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
Daniel
D
Barrowdale
Human Genetics Group, Spanish National Cancer Centre (CNIO), Madrid, Spain.|Biomedical Network on Rare Diseases (CIBERER), Madrid, Spain.|Human Genotyping (CEGEN) Unit, Human Cancer Genetics Program, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
Javier
J
Benitez
The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel.
Raanan
R
Berger
Centre François Baclesse, 3 avenue Général Harris, Caen, France.
Pascaline
P
Berthet
Department of Oncology, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
Ake
A
Borg
Department of Medicine, Huntsman Cancer Institute, 2000 Circle of Hope, Salt Lake City, UT, 84112, USA.
Saundra S
SS
Buys
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
Trinidad
T
Caldes
Gynaecological Oncology, The University of Sydney Cancer Centre, Royal Prince Alfred Hospital, Sydney, Australia.
Jonathan
J
Carter
Unité de recherche en santé des populations, Centre des maladies du sein Deschênes-Fabia, Hôpital du Saint-Sacrement, 1050, chemin Sainte-Foy, Québec, Canada.
Jocelyne
J
Chiquette
Center for Medical Genetics, Ghent University, De Pintelaan 185, 9000, Gent, Belgium.
Kathleen B M
KB
Claes
Department of Laboratory Medicine and Pathology, and Health Sciences Research, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, USA.
Fergus J
FJ
Couch
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Cezary
C
Cybulski
Division of Population Science, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA, 19111, USA.
Mary B
MB
Daly
Molecular Oncology Laboratory, Hospital Clinico San Carlos, IdISSC (El Instituto de Investigación Sanitaria del Hospital Clínico San Carlos), Martin Lagos s/n, Madrid, Spain.
Miguel
M
de la Hoya
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.
Orland
O
Diez
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Susan M
SM
Domchek
Department of Medicine, Abramson Cancer Center, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
Katherine L
KL
Nathanson
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Katarzyna
K
Durda
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
Steve
S
Ellis
Genomic Medicine, Manchester Academic Health Sciences Centre, Institute of Human Development, Manchester University, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK.
D Gareth
DG
Evans
Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Zluty kopec 7, Brno, 65653, Czech Republic.
Lenka
L
Foretova
The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel.
Eitan
E
Friedman
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Strangeways Research Laboratory, Worts Causeway, Cambridge, UK.
Debra
D
Frost
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.
Patricia A
PA
Ganz
Department Epidemiology, Dana Farber Cancer Institute and Harvard T.H. Chan School of Public Health, 1101 Dana Building, 450 Brookline Avenue, Boston, MA, USA.
Judy
J
Garber
Ontario Cancer Genetics Network: Samuel Lunenfeld Research Institute, Mount Sinai Hospital, Toronto, Ontario, M5G 1X5, Canada.
Gord
G
Glendon
Department of Pathology and Laboratory Medicine, 3901 Rainbow Boulevard, 4019 Wahl Hall East, MS, 3040, Kansas, USA.|University of Kansas Medical Center, Kansas City, Kansas, USA.
Andrew K
AK
Godwin
Clinical Genetics Branch, DCEG, NCI, NIH, 9609 Medical Center Drive, Room 6E-454, Bethesda, MD, USA.
Mark H
MH
Greene
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Jacek
J
Gronwald
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.
Eric
E
Hahnen
Department of Health Sciences Research, Mayo Clinic, 13400 E. Scottsdale Blvd., Scottsdale, AZ, USA.
Emily
E
Hallberg
Molecular Genetics of Breast Cancer, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120, Heidelberg, Germany.
Ute
U
Hamann
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital, Blegdamsvej 9, DK-2100, Copenhagen, Denmark.
Thomas V O
TV
Hansen
N.N. Petrov Institute of Oncology, St.-Petersburg, 197758, Russia.
Evgeny N
EN
Imyanitov
Lombardi Comprehensive Cancer Center, Georgetown University, 3800 Reservoir Road NW, Washington, DC, USA.
Claudine
C
Isaacs
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Anna
A
Jakubowska
Department of Molecular and Regenerative Medicine, Vilnius University Hospital Santariskiu Clinics, Hematology, oncology and transfusion medicine center, Santariskiu st, Vilnius, Lithuania.|State Research Institute Centre for Innovative medicine, Zygymantu st. 9, Vilnius, Lithuania.
Ramunas
R
Janavicius
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Katarzyna
K
Jaworska-Bieniek
Department of Epidemiology, Cancer Prevention Institute of California, 2201 Walnut Avenue, Suite 300, Fremont, CA, 94538, USA.
Esther M
EM
John
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA.
Beth Y
BY
Karlan
The Institute of Oncology, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel.
Bella
B
Kaufman
Kathleen Cuningham Consortium for Research into Familial Breast Cancer, Peter MacCallum Cancer Center, Melbourne, Australia.
KConFab
K
Investigators
The Hong Kong Hereditary Breast Cancer Family Registry; Cancer Genetics Center, Hong Kong Sanatorium and Hospital, Hong Kong, Hong Kong.|Department of Surgery, The University of Hong Kong, Hong Kong, Hong Kong.
Ava
A
Kwong
The Susanne Levy Gertner Oncogenetics Unit, Institute of Human Genetics, Chaim Sheba Medical Center, Ramat Gan, 52621, Israel.|Sackler Faculty of Medicine, Tel Aviv University, Ramat Aviv, 69978, Israel.
Yael
Y
Laitman
Unité de Prévention et d'Epidémiologie Génétique, Centre Léon Bérard, 28 rue Laënnec, Lyon, France.
Christine
C
Lasset
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.
Conxi
C
Lazaro
Women's Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, 8700 Beverly Boulevard, Suite 290W, Los Angeles, CA, USA.
Jenny
J
Lester
Department of Oncology, Lund University Hospital, Lund, Sweden.
Niklas
N
Loman
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Jan
J
Lubinski
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.
Siranoush
S
Manoukian
Familial Cancer Centre, Peter MacCallum Cancer Centre, Locked Bag 1, A'Beckett Street, Melbourne, VIC, 8006, Australia.|Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, VIC, 3052, Australia.
Gillian
G
Mitchell
Immunology and Molecular Oncology Unit, Veneto Institute of Oncology IOC - IRCCS, Via Gattamelata 64, Padua, Italy.
Marco
M
Montagna
Department of Population Sciences, Beckman Research Institute of City of Hope, Duarte, CA, USA.
Susan L
SL
Neuhausen
Department of Obstetrics and Gynecology, University of Helsinki and Helsinki University Hospital, Biomedicum Helsinki, P.O. BOX 700, (Haartmaninkatu 8), 00029, HUS, Helsinki, Finland.
Heli
H
Nevanlinna
Department of Gynaecology and Obstetrics, University Hospital Düsseldorf, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany.
Dieter
D
Niederacher
, 513 Parnassus Ave., HSE 901E, San Francisco, CA, 94143-0794, USA.
Robert L
RL
Nussbaum
Clinical Genetics Research Laboratory, Department of Medicine, Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY, 10044, USA.
Kenneth
K
Offit
Department of Molecular Genetics, National Institute of Oncology, Budapest, Hungary.
Edith
E
Olah
, 5841 South Maryland Avenue, MC 2115, Chicago, IL, USA.
Olufunmilayo I
OI
Olopade
Department of Preventive Medicine, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul, 110-799, Korea.
Sue Kyung
SK
Park
NRG Oncology, Statistics and Data Management Center, Roswell Park Cancer Institute, Elm St & Carlton St, Buffalo, NY, 14263, USA.
Marion
M
Piedmonte
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.
Paolo
P
Radice
Department of OB/GYN, Medical University of Vienna, Waehringer Guertel 18-20, A 1090, Vienna, Austria.
Christine
C
Rappaport-Fuerhauser
Department of Epidemiology, Netherlands Cancer Institute, P.O. Box 90203, 1000, BE, Amsterdam, The Netherlands.
Matti A
MA
Rookus
Department of Medical Oncology, Family Cancer Clinic Erasmus University Medical Center Cancer institute, P.O. Box 5201, 3008, AE, Rotterdam, The Netherlands.
Caroline
C
Seynaeve
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec, Canada.
Jacques
J
Simard
Department of OB/GYN and Comprehensive Cancer Center, Medical University of Vienna, Waehringer Guertel 18-20, A 1090, Vienna, Austria.
Christian F
CF
Singer
Genomics Center, Centre Hospitalier Universitaire de Québec Research Center and Laval University, 2705 Laurier Boulevard, Quebec City, Quebec, Canada.
Penny
P
Soucy
Genetic Epidemiology Laboratory, Department of Pathology, University of Melbourne, Parkville, Victoria, Australia.
Melissa
M
Southey
Service de Génétique Oncologique, Institut Curie, 26, rue d'Ulm, Paris, Cedex 05, France.
Dominique
D
Stoppa-Lyonnet
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Grzegorz
G
Sukiennicki
National Human Genome Research Institute, National Institutes of Health Building 50, Room 5312, 50 South Drive, MSC 004, Bethesda, MD, 20892-8004, USA.
Csilla I
CI
Szabo
Section of Genetic Oncology, Department of Laboratory Medicine, University and University Hospital of Pisa, Pisa, Italy.
Mariella
M
Tancredi
Department of Genetics, Portuguese Oncology Institute, Rua Dr. António Bernardino de Almeida, 4200-072, Porto, Portugal.
Manuel R
MR
Teixeira
Cancer Research Initiatives Foundation, Sime Darby Medical Centre, 1 Jalan SS12/1A, Subang Jaya, 47500, Malaysia.|University Malaya Cancer Research Institute, University Malaya, 50603, Kuala Lumpur, Malaysia.
Soo-Hwang
SH
Teo
Department of Epidemiology, Columbia University, New York, NY, USA.
Mary Beth
MB
Terry
Department of Clinical Genetics, Odense University Hospital, Sonder Boulevard 29, Odense C, Denmark.
Mads
M
Thomassen
Latvian Biomedical Research and Study Centre, Ratsupites str 1, Riga, Latvia.
Laima
L
Tihomirova
Program in Cancer Genetics, Departments of Human Genetics and Oncology, McGill University, Montreal, Quebec, Canada.
Marc
M
Tischkowitz
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.
Amanda Ewart
AE
Toland
Department of Genetics and Pathology, Pomeranian Medical University, Polabska 4, Szczecin, Poland.
Aleksandra
A
Toloczko-Grabarek
Department of Medical Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, Boston, MA, 02215, USA.
Nadine
N
Tung
Cancer Genetics Laboratory, Department of Genetics, University of Pretoria, Private Bag X323, Arcadia, 0007, South Africa.
Elizabeth J
EJ
van Rensburg
Clinical Cancer Genetics Laboratory, Memorial Sloane Kettering Cancer Center, New York, NY, USA.
Danylo
D
Villano
Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
Shan
S
Wang-Gohrke
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.
Barbara
B
Wappenschmidt
Clinical Cancer Genetics, City of Hope, 1500 East Duarte Road, Duarte, California, 91010, USA.
Jeffrey N
JN
Weitzel
Institute of Oncology, Rivka Ziv Medical Center, 13000, Zefat, Israel.|The Faculty of Medicine, Bar-Ilan University, Zefat, Israel.
Jamal
J
Zidan
, 4301 West Markham Street, Slot 793, Little Rock, AR, 72205, USA.
Kristin K
KK
Zorn
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Lesley
L
McGuffog
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Douglas
D
Easton
Department of Genetics and Computational Biology, QIMR Berghofer Institute of Medical Research, Brisbane, Australia.
Georgia
G
Chenevix-Trench
Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK.
Antonis C
AC
Antoniou
Department of Preventive Medicine, Keck School of Medicine, USC/Norris Comprehensive Cancer Center, University of Southern California, California, USA.|Present Address: School of Women's and Children's Health, University of New South Wales and The Kinghorn Cancer Centre, Garvan Institute of Medical Research, 384 Victoria Street, Darlinghurst, NSW, 2010, Australia.
Susan J
SJ
Ramus
D000483:Alleles; D001943:Breast Neoplasms / Q000235:genetics / Q000473:pathology; D005091:Exons; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D019656:Loss of Heterozygosity; D010641:Phenotype; D011159:Population Surveillance; D011401:Promoter Regions, Genetic
BRCA1; BRCA2; Hereditary breast and ovarian cancer; Transheterozygosity