Journal article

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

Timothy R Rebbeck, Tara M Friebel, Nandita Mitra, Fei Wan, Stephanie Chen, Irene L Andrulis, Paraskevi Apostolou, Norbert Arnold, Banu K Arun, Daniel Barrowdale, Javier Benitez, Raanan Berger, Pascaline Berthet, Ake Borg, Saundra S Buys, Trinidad Caldes, Jonathan Carter, Jocelyne Chiquette, Kathleen BM Claes, Fergus J Couch Show all

BREAST CANCER RESEARCH | BIOMED CENTRAL LTD | Published : 2016

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 ..

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Awarded by National Cancer Institute


Awarded by Lithuania (BFBOCC-LT): Research Council of Lithuania grant


Awarded by Spanish Association against Cancer


Awarded by Cancer Research UK


Awarded by Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research Technology


Awarded by University of Kansas Cancer Center


Awarded by German Cancer Aid


Awarded by Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant)


Awarded by ISCIII (Spain)


Awarded by Academy of Finland


Awarded by Dutch Cancer Society


Awarded by Netherlands Organization of Scientific Research grant


Awarded by Pink Ribbon grant


Awarded by BBMRI grant


Awarded by Hungarian Research Grants


Awarded by Norwegian EEA Financial Mechanism


Awarded by Catalan Health Institute and Autonomous Government of Catalonia


Awarded by Canadian Breast Cancer Research Alliance-grant


Awarded by Ministry of Economic Development, Innovation and Export Trade - grant


Awarded by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer


Awarded by NIH


Awarded by MH CZ - DRO (MMCI)


Awarded by State Budget of the Czech Republic (RECAMO)


Awarded by Charles University in Prague project


Awarded by Westat, Inc, Rockville, MD


Awarded by Russian Federation for Basic Research


Awarded by NRG Oncology Operations grant


Awarded by NRG SDMC grant


Awarded by GOG Tissue Bank


Awarded by GOG Statistical and Data Center


Awarded by Ministry of Science, Technology and Innovation, Ministry of Higher Education


Awarded by National Institutes of Health (NIH)


Awarded by American Cancer Society Early Detection Professorship


Awarded by National Center for Advancing Translational Sciences (NCATS)


Awarded by European Community


Awarded by National Institutes of Health


Awarded by Post-Cancer GWAS initiative


Awarded by Department of Defence



Awarded by National Breast Cancer Foundation


Awarded by NATIONAL CANCER INSTITUTE


Funding Acknowledgements

This work was supported by grant UM1 CA164920 from the National Cancer Institute. The content of this manuscript does not necessarily reflect the views or policies of the National Cancer Institute or any of the collaborating centers in the Breast Cancer Family Registry (BCFR), nor does mention of trade names, commercial products, or organizations imply endorsement by the US Government or the BCFR.BFBOCC is partly supported by: Lithuania (BFBOCC-LT): Research Council of Lithuania grant SEN-18/2015BIDMC is supported by the Breast Cancer Research FoundationBRCA gene mutations and breast cancer in South African women (BMBSA) was supported by grants from the Cancer Association of South Africa (CANSA) to Elizabeth J. van RensburgSLN was partially supported by the Morris and Horowitz Families Endowed Professorship.This work was partially supported by Spanish Association against Cancer (AECC08), RTICC 06/0020/1060, FISPI08/1120, Mutua Madrilena Foundation (FMMA) and SAF2010-20493City of Hope Clinical Cancer Genetics Community Network and the Hereditary Cancer Research Registry, supported in part by Award Number RC4CA153828 (PI: J. Weitzel) from the National Cancer Institute and the Office of the Director, National Institutes of Health. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of HealthFunds from Italian citizens who allocated the 5x1000 share of their tax payment in support of the Fondazione IRCCS Istituto Nazionale Tumori, according to Italian laws (INT-Institutional strategic projects `5x1000') to SM.The CIMBA data management and data analysis were supported by Cancer Research UK grants C12292/A20861, C12292/A11174. ACA is a Cancer Research UK Senior Cancer Research Fellow. GCT is an NHMRC Senior Principal Research Fellow.This research has been co-financed by the European Union (European Social Fund - ESF) and Greek national funds through the Operational Program "Education and Lifelong Learning" of the National Strategic Reference Framework (NSRF) - Research Funding Program of the General Secretariat for Research & Technology: SYN11_10_19 NBCA. Investing in knowledge society through the European Social Fund.The DKFZ study was supported by the DKFZ.EMBRACE is supported by Cancer Research UK Grants C1287/A10118 and C1287/A11990. D. Gareth Evans and Fiona Lalloo are supported by an NIHR grant to the Biomedical Research Centre, Manchester. The Investigators at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust are supported by an NIHR grant to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust. Ros Eeles and Elizabeth Bancroft are supported by Cancer Research UK Grant C5047/A8385. Ros Eeles is also supported by NIHR support to the Biomedical Research Centre at The Institute of Cancer Research and The Royal Marsden NHS Foundation TrustThe authors acknowledge support from The University of Kansas Cancer Center (P30 CA168524) and the Kansas Bioscience Authority Eminent Scholar Program. A.K.G. was funded by 5U01CA113916, R01CA140323, and by the Chancellors Distinguished Chair in Biomedical Sciences Professorship.The German Consortium of Hereditary Breast and Ovarian Cancer (GC-HBOC) is supported by the German Cancer Aid (grant no 110837), Rita K. Schmutzler) and by the Center for Molecular Medicine Cologne (CMMC)The study was supported by the Ligue Nationale Contre le Cancer; the Association "Le cancer du sein, parlons-en!" Award; the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program and the French National Institute of Cancer (INCa).CI received support from the Non-Therapeutic Subject Registry Shared Resource at Georgetown University (NIH/NCI grant P30-CA051008), the Fisher Center for Familial Cancer Research, and Swing Fore the Cure.Was supported by a grant RD12/0036/0006 and 15/00059 from ISCIII (Spain), partially supported by European Regional Development FEDER fundsThe HEBCS was financially supported by the Helsinki University Hospital Research Fund, Academy of Finland (266528), the Finnish Cancer Society and the Sigrid Juselius Foundation.The HEBON study is supported by the Dutch Cancer Society grants NKI1998-1854, NKI2004-3088, NKI2007-3756, the Netherlands Organization of Scientific Research grant NWO 91109024, the Pink Ribbon grant 110005 and the BBMRI grant NWO 184.021.007/CP46. HEBON thanks the registration teams of the Comprehensive Cancer Centre Netherlands and Comprehensive Centre South (together the Netherlands Cancer Registry) and PALGA (Dutch Pathology Registry) for part of the data collection.HRBCP is supported by The Hong Kong Hereditary Breast Cancer Family Registry and the Dr. Ellen Li Charitable Foundation, Hong KongHungarian Breast and Ovarian Cancer Study was supported by Hungarian Research Grants KTIA-OTKA CK-80745, OTKA K-112228 and the Norwegian EEA Financial Mechanism Hu0115/NA/2008-3/OP-9ICO: Contract grant sponsor: Asociacion Espanola Contra el Cancer, Spanish Health Research Fund; Carlos III Health Institute; Catalan Health Institute and Autonomous Government of Catalonia. Contract grant numbers: ISCIIIRETIC RD06/0020/1051, RD12/0036/008, PI10/01422, PI10/00748, PI13/00285, PIE13/00022, 2009SGR290 and 2014SGR364.The IHCC was supported by Grant PBZ_KBN_122/P05/2004This work was supported by the Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program, the Canadian Breast Cancer Research Alliance-grant #019511 and the Ministry of Economic Development, Innovation and Export Trade - grant # PSR-SIIRI-701.IOCHBOCS is supported by Ministero della Salute and "5x1000" Istituto Oncologico Veneto grant.This study was in part supported by Liga Portuguesa Contra o Cancro.kConFab is supported by a grant from the National Breast Cancer Foundation, and previously by the National Health and Medical Research Council (NHMRC), the Queensland Cancer Fund, the Cancer Councils of New South Wales, Victoria, Tasmania and South Australia, and the Cancer Foundation of Western Australia;MAYO is supported by NIH grants CA116167, CA128978 and CA176785, an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), a grant from the Breast Cancer Research Foundation, and a generous gift from the David F. and Margaret T. Grohne Family Foundation.MODSQUAD was supported by MH CZ - DRO (MMCI, 00209805) and by the European Regional Development Fund and the State Budget of the Czech Republic (RECAMO, CZ.1.05/2.1.00/03.0101) to LF, and by Charles University in Prague project UNCE204024 (MZ).MSKCC is supported by grants from the Breast Cancer Research Foundation, the Robert and Kate Niehaus Clinical Cancer Genetics Initiative, and the Andrew Sabin Research Fund.The research of Drs. MH Greene and PL Mai was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD. For CIMBA PRS paper: The research of Drs. MH Greene and JT Loud was supported by the Intramural Research Program of the US National Cancer Institute, NIH, and by support services contracts NO2-CP-11019-50 and N02-CP-65504 with Westat, Inc, Rockville, MD.This work has been supported by the Russian Federation for Basic Research (grants 14-04-93959 and 15-04-01744).This study was supported by NRG Oncology Operations grant number U10 CA180868 as well as NRG SDMC grant U10 CA180822, Gynecologic Oncology Group (GOG) Administrative Office and the GOG Tissue Bank (CA 27469) and the GOG Statistical and Data Center (CA 37517). Drs. Greene, Mai and Savage were supported by funding from the Intramural Research Program, NCI.OSUCCG is supported by the Ohio State University Comprehensive Cancer Center.This work was supported by the ITT (Istituto Toscano Tumori) grants 2011-2013.Ministry of Science, Technology and Innovation, Ministry of Higher Education (UM.C/HlR/MOHE/06) and Cancer Research Initiatives FoundationThis project was partially funded through a grant by the Israel cancer association and the funding for the Israeli Inherited breast cancer consortiumSWE-BRCA collaborators are supported by the Swedish Cancer SocietyUCHICAGO is supported by NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA125183), R01 CA142996, 1U01CA161032 and by the Ralph and Marion Falk Medical Research Trust, the Entertainment Industry Fund National Women's Cancer Research Alliance and the Breast Cancer research Foundation. OIO is an ACS Clinical Research Professor.Jonsson Comprehensive Cancer Center Foundation; Breast Cancer Research FoundationUCSF Cancer Risk Program and Helen Diller Family Comprehensive Cancer CenterUKFOCR was supported by a project grant from CRUK to Paul Pharoah.National Institutes of Health (NIH) (R01-CA102776 and R01-CA083855; Breast Cancer Research Foundation; Susan G. Komen Foundation for the cure, Basser Research Center for BRCAFrieda G. and Saul F. Shapira BRCA-Associated Cancer Research Program; Hackers for Hope PittsburghVictorian Cancer Agency, Cancer Australia, National Breast Cancer FoundationDr Karlan is funded by the American Cancer Society Early Detection Professorship (SIOP-06-258-01-COUN) and the National Center for Advancing Translational Sciences (NCATS), Grant UL1TR000124Funding for the iCOGS infrastructure came from: the European Community's Seventh Framework Programme under grant agreement no 223175 (HEALTH-F2-2009-223175) (COGS), Cancer Research UK (C1287/A10118, C1287/A 10710, C12292/A11174, C1281/A12014, C5047/A8384, C5047/A15007, C5047/A10692, C8197/A16565), the National Institutes of Health (CA128978) and Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 - the GAME- ON initiative), the Department of Defence (W81XWH-10-1-0341), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, Komen Foundation for the Cure, the Breast Cancer Research Foundation, and the Ovarian Cancer Research Fund