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Genome-Wide Association Study in BRCA1 Mutation Carriers Identifies Novel Loci Associated with Breast and Ovarian Cancer Risk

Lookup NU author(s): Dr Fiona Douglas

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Abstract

BRCA1-associated breast and ovarian cancer risks can be modified by common genetic variants. To identify further cancer risk-modifying loci, we performed a multi-stage GWAS of 11,705 BRCA1 carriers (of whom 5,920 were diagnosed with breast and 1,839 were diagnosed with ovarian cancer), with a further replication in an additional sample of 2,646 BRCA1 carriers. We identified a novel breast cancer risk modifier locus at 1q32 for BRCA1 carriers (rs2290854, P = 2.7 x 10(-8), HR = 1.14, 95% CI: 1.09-1.20). In addition, we identified two novel ovarian cancer risk modifier loci: 17q21.31 (rs17631303, P = 1.4 x 10(-8), HR = 1.27, 95% CI: 1.17-1.38) and 4q32.3 (rs4691139, P = 3.4 x 10(-8), HR = 1.20, 95% CI: 1.17-1.38). The 4q32.3 locus was not associated with ovarian cancer risk in the general population or BRCA2 carriers, suggesting a BRCA1-specific association. The 17q21.31 locus was also associated with ovarian cancer risk in 8,211 BRCA2 carriers (P = 2 x 10(-4)). These loci may lead to an improved understanding of the etiology of breast and ovarian tumors in BRCA1 carriers. Based on the joint distribution of the known BRCA1 breast cancer risk-modifying loci, we estimated that the breast cancer lifetime risks for the 5% of BRCA1 carriers at lowest risk are 28%-50% compared to 81%-100% for the 5% at highest risk. Similarly, based on the known ovarian cancer risk-modifying loci, the 5% of BRCA1 carriers at lowest risk have an estimated lifetime risk of developing ovarian cancer of 28% or lower, whereas the 5% at highest risk will have a risk of 63% or higher. Such differences in risk may have important implications for risk prediction and clinical management for BRCA1 carriers.


Publication metadata

Author(s): Couch FJ, Wang XS, McGuffog L, Lee A, Olswold C, Kuchenbaecker KB, Soucy P, Fredericksen Z, Barrowdale D, Dennis J, Gaudet MM, Dicks E, Kosel M, Healey S, Sinilnikova OM, Lee A, Bacot F, Vincent D, Hogervorst FBL, Peock S, Stoppa-Lyonnet D, Jakubowska A, Radice P, Schmutzler RK, Domchek SM, Piedmonte M, Singer CF, Friedman E, Thomassen M, Hansen TVO, Neuhausen SL, Szabo CI, Blanco I, Greene MH, Karlan BY, Garber J, Phelan CM, Weitzel JN, Montagna M, Olah E, Andrulis IL, Godwin AK, Yannoukakos D, Goldgar DE, Caldes T, Nevanlinna H, Osorio A, Terry MB, Daly MB, van Rensburg EJ, Hamann U, Ramus SJ, Toland AE, Caligo MA, Olopade OI, Tung N, Claes K, Beattie MS, Southey MC, Imyanitov EN, Tischkowitz M, Janavicius R, John EM, Kwong A, Diez O, Balmana J, Barkardottir RB, Arun BK, Rennert G, Teo SH, Ganz PA, Campbell I, van der Hout AH, van Deurzen CHM, Seynaeve C, Garcia EBG, van Leeuwen FE, Meijers-Heijboer HEJ, Gille JJP, Ausems MGEM, Blok MJ, Ligtenberg MJL, Rookus MA, Devilee P, Verhoef S, van Os TAM, Wijnen JT, Frost D, Ellis S, Fineberg E, Platte R, Evans DG, Izatt L, Eeles RA, Adlard J, Eccles DM, Cook J, Brewer C, Douglas F, Hodgson S, Morrison PJ, Side LE, Donaldson A, Houghton C, Rogers MT, Dorkins H, Eason J, Gregory H, McCann E, Murray A, Calender A, Hardouin A, Berthet P, Delnatte C, Nogues C, Lasset C, Houdayer C, Leroux D, Rouleau E, Prieur F, Damiola F, Sobol H, Coupier I, Venat-Bouvet L, Castera L, Gauthier-Villars M, Leone M, Pujol P, Mazoyer S, Bignon YJ, Zlowocka-Perlowska E, Gronwald J, Lubinski J, Durda K, Jaworska K, Huzarski T, Spurdle AB, Viel A, Peissel B, Bonanni B, Melloni G, Ottini L, Papi L, Varesco L, Tibiletti MG, Peterlongo P, Volorio S, Manoukian S, Pensotti V, Arnold N, Engel C, Deissler H, Gadzicki D, Gehrig A, Kast K, Rhiem K, Meindl A, Niederacher D, Ditsch N, Plendl H, Preisler-Adams S, Engert S, Sutter C, Varon-Mateeva R, Wappenschmidt B, Weber BHF, Arver B, Stenmark-Askmalm M, Loman N, Rosenquist R, Einbeigi Z, Nathanson KL, Rebbeck TR, Blank SV, Cohn DE, Rodriguez GC, Small L, Friedlander M, Bae-Jump VL, Fink-Retter A, Rappaport C, Gschwantler-Kaulich D, Pfeiler G, Tea MK, Lindor NM, Kaufman B, Paluch SS, Laitman Y, Skytte AB, Gerdes AM, Pedersen IS, Moeller ST, Kruse TA, Jensen UB, Vijai J, Sarrel K, Robson M, Kauff N, Mulligan AM, Glendon G, Ozcelik H, Ejlertsen B, Nielsen FC, Jonson L, Andersen MK, Ding YC, Steele L, Foretova L, Teule A, Lazaro C, Brunet J, Pujana MA, Mai PL, Loud JT, Walsh C, Lester J, Orsulic S, Narod SA, Herzog J, Sand SR, Tognazzo S, Agata S, Vaszko T, Weaver J, Stavropoulou AV, Buys SS, Romero A, de la Hoya M, Aittomaki K, Muranen TA, Duran M, Chung WK, Lasa A, Dorfling CM, Miron A, Benitez J, Senter L, Huo DZ, Chan SB, Sokolenko AP, Chiquette J, Tihomirova L, Friebel TM, Agnarsson BA, Lu KH, Lejbkowicz F, James PA, Hall P, Dunning AM, Tessier D, Cunningham J, Slager SL, Wang C, Hart S, Stevens K, Simard J, Pastinen T, Pankratz VS, Offit K, Easton DF, Chenevix-Trench G, Antoniou AC, KConFab Investigators, SWE-BRCA, Ontario Canc Genetics Network, HEBON, EMBRACE, GEMO Study Collaborators, BCFR, CIMBA

Publication type: Article

Publication status: Published

Journal: PLoS Genetics

Year: 2013

Volume: 9

Issue: 3

Online publication date: 27/03/2013

Acceptance date: 14/11/2012

Date deposited: 22/10/2015

ISSN (print): 1553-7390

ISSN (electronic): 1553-7404

Publisher: Public Library of Science

URL: http://dx.doi.org/10.1371/journal.pgen.1003212

DOI: 10.1371/journal.pgen.1003212

PubMed id: 23544013


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Funding

Funder referenceFunder name
Asociacion Espanola Contra el Cancer
Association "Le cancer du sein, parlons-en!"
Breast Cancer Family Registry (BCFR)
Breast Cancer Research Foundation (BCRF), NY
Canadian Institutes of Health Research
Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program
Cancer Councils of New South Wales, South Australia
Center for Molecular Medicine Cologne (CMMC)
CRUK
DKFZ
Dr. Ellen Li Charitable Foundation, Hong Kong
European Regional Development Fund
Finnish Cancer Society
Helen Diller Family Comprehensive Cancer Center
Helsinki University Central Hospital Research Fund
Hereditary Cancer Association (Paveldimo vezio asociacija)
Hong Kong Hereditary Breast Cancer Family Registry
Instituto de Salud Carlos III
Israel Cancer Association
Italian Ministry of Education, University and Research, Centro di Ascolto Donne Operate al Seno (CAOS) association
Italian Minitry of Health
Jewish General Hospital
Kansas Bioscience Authority Eminent Scholar Program
Komen Foundation for the Cure
Macdonald Family Foundation
NHMRC
NIHR
Office of the Director, National Institutes of Health
Ohio State University Comprehensive Cancer Center
Polish Foundation of Science
Queensland Cancer Fund
Ramon Areces Foundation
Royal Marsden NHS Foundation Trust
Spanish Ministry of Economy and Competitivity
Swedish Cancer Society
Victorian Breast Cancer Research Consortium
Victorian Cancer Agency
Andrew Sabin Family Foundation
Breast Cancer Research Foundation
Cancer Association of South Africa (CANSA)
Cancer Australia
Cancer Councils of New South Wales, Tasmania
Cancer Councils of New South Wales, Victoria
Cancer Foundation of Western Australia
Carlos III Health Institute
Catalan Health Institute
Chancellors Distinguished Chair in Biomedical Sciences Professorship
Clalit Health Services in Israel
Entertainment Industry Fund National Women's Cancer Research Alliance,
European Regional Development Fund (ERDF)
Fondazione Italiana per la Ricerca sul Cancro (Special Project "Hereditary tumors")
Icelandic Association "Walking for Breast Cancer Research"
Intramural Research Program of the US National Cancer Institute, NIH
Intramural Research Program, NCI, NIH
Jonsson Comprehensive Cancer Center Foundation
Landspitali University Hospital Research Fund
Ligue National Contre le Cancer
Lithuania (BFBOCC-LT)
Lymphoma Foundation
Ministero dell'Istruzione, dell'Universitae della Ricerca
Morris and Horowitz Families Endowed Professorship
Mutua Madrilena Foundation (FMMA)
National Breast Cancer Foundation
National Center for Research Resources
National Health and Medical Research Council (NHMRC)
National Health and Medical Research Council of Australia
New South Wales Cancer Council
NEYE Foundation
Niehaus Clinical Cancer Genetics Initiative
Nordic Cancer Union
Quebec Ministry of Economic Development, Innovation, and Export Trade
Ralph and Marion Falk Medical Research Trust
Rooney Family Foundation
Sigrid Juselius Foundation
Spanish Health Research Foundation
Susan G. Komen Foundation for the Cure
UCSF Cancer Risk Program
University of Kansas Cancer Center
US National Cancer Institute (NIH/NCI)
Victorian Health Promotion Foundation (Australia)
019511Canadian Breast Cancer Research Alliance
02.740.11.0780Federal Agency for Science and Innovations, Russia
06/0020/0021RETICC
09/00859FIS
10.0010.08LSC
109076German Cancer Aid
11-04-00227Russian Foundation for Basic Research
12-04-00928Russian Foundation for Basic Research
12-04-01490Russian Foundation for Basic Research
1R01 CA149429-01NIH
2009/0220/1DP/1.1.1.2.0/09/APIA/VIAA/016ESF
2009SGR283Autonomous Government of Catalonia
110005Pink Ribbon grant
132473Academy of Finland
2009SGR290Autonomous Government of Catalonia
5U01CA113916
223175 (HEALTH-F2-2009-223175)European Commission
91109024NWO
ACC2/R6.9Ministero della Salute
628333Cancer Australia
CA 101165National Cancer Institute
CA-06-503National Cancer Institute, National Institutes of Health under RFA
AECC08Spanish Association against Cancer
CA128978NIH
CP46/NWOBBMRI
CZ.1.05/2.1.00/03.0101State Budget of the Czech Republic (RECAMO)
C12292/A11174Cancer Research UK
C1287/A10118Cancer Research UK
C1287/A11990Cancer Research UK
C5047/A8385Cancer Research UK
CA 27469National Cancer Institute
CA 37517National Cancer Institute
CA116201NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer
FISPI08/1120Spanish Association against Cancer
HU0115/NA/2008-3/OP-9Hungarian Research
IG 8713Italian Association for Cancer Research (AIRC)
JP090615Royal Society
LIG-19/2010Research Council of Lithuania
ISCIIIRETIC RD06/0020/1051Autonomous Government of Catalonia
N02-CP-65504Westat, Rockville, MD
NKI1998-1854Dutch Cancer Society
NKI2004-3088Dutch Cancer Society
P01 CA16094National Institutes of Health
P30 CA033752NIH
P30 CA042014National Cancer Institute
PI10/01422Autonomous Government of Catalonia
PSR-SIIRI-701Ministry of Economic Development, Innovation and Export Trade
R01 CA22435National Institutes of Health
R01-CA083855National Institutes of Health (NIH)
R01-CA102776National Institutes of Health (NIH)
R01CA140323
R01CA74415NIH
NKI2007-3756Dutch Cancer Society
NO2-CP-11019-50Westat, Rockville, MD
RC4A153828National Cancer Institute
RFPS 2006-5-341353Ministero della Salute
PI09/02483Autonomous Government of Catalonia
SIOP-06-258-01-COUNAmerican Cancer Society Early Detection Professorship
PI10/00748Autonomous Government of Catalonia
U01 CA69398Columbia University
U01 CA69417Cancer Prevention Institute of California
U01 CA69446Huntsman Cancer Institute
U01 CA69631Fox Chase Cancer Center
UL1 RR025764National Center for Advancing Translational Sciences, NIH
W81XWH-10-1-0341U.S. Department of Defense Ovarian Cancer Idea award
RTICC 06/0020/1060Spanish Association against Cancer
SAF2010-20493
U01 CA69467Cancer Care Ontario
U01 CA69638University of Melbourne

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