Toggle Main Menu Toggle Search

Open Access padlockePrints

Common variants at 12p11, 12q24, 9p21, 9q31.2 and in ZNF365 are associated with breast cancer risk for BRCA1 and/or BRCA2 mutation carriers

Lookup NU author(s): Dr Fiona Douglas



Introduction: Several common alleles have been shown to be associated with breast and/or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers. Recent genome-wide association studies of breast cancer have identified eight additional breast cancer susceptibility loci: rs1011970 (9p21, CDKN2A/B), rs10995190 (ZNF365), rs704010 (ZMIZ1), rs2380205 (10p15), rs614367 (11q13), rs1292011 (12q24), rs10771399 (12p11 near PTHLH) and rs865686 (9q31.2). Methods: To evaluate whether these single nucleotide polymorphisms (SNPs) are associated with breast cancer risk for BRCA1 and BRCA2 carriers, we genotyped these SNPs in 12,599 BRCA1 and 7,132 BRCA2 mutation carriers and analysed the associations with breast cancer risk within a retrospective likelihood framework. Results: Only SNP rs10771399 near PTHLH was associated with breast cancer risk for BRCA1 mutation carriers (per-allele hazard ratio (HR) = 0.87, 95% CI: 0.81 to 0.94, P-trend = 3 x 10(-4)). The association was restricted to mutations proven or predicted to lead to absence of protein expression (HR = 0.82, 95% CI: 0.74 to 0.90, P-trend = 3.1 x 10(-5), P-difference = 0.03). Four SNPs were associated with the risk of breast cancer for BRCA2 mutation carriers: rs10995190, P-trend = 0.015; rs1011970, P-trend = 0.048; rs865686, 2df P = 0.007; rs1292011 2df P = 0.03. rs10771399 (PTHLH) was predominantly associated with estrogen receptor (ER)-negative breast cancer for BRCA1 mutation carriers (HR = 0.81, 95% CI: 0.74 to 0.90, P-trend = 4 x 10(-5)) and there was marginal evidence of association with ER- negative breast cancer for BRCA2 mutation carriers (HR = 0.78, 95% CI: 0.62 to 1.00, P-trend = 0.049). Conclusions: The present findings, in combination with previously identified modifiers of risk, will ultimately lead to more accurate risk prediction and an improved understanding of the disease etiology in BRCA1 and BRCA2 mutation carriers.

Publication metadata

Author(s): Antoniou AC, Kuchenbaecker KB, Soucy P, Beesley J, Chen XQ, McGuffog L, Lee A, Barrowdale D, Healey S, Sinilnikova OM, Caligo MA, Loman N, Harbst K, Lindblom A, Arver B, Rosenquist R, Karlsson P, Nathanson K, Domchek S, Rebbeck T, Jakubowska A, Lubinski J, Jaworska K, Durda K, Zlowowcka-Perlowska E, Osorio A, Duran M, Andres R, Benitez J, Hamann U, Hogervorst FB, van Os TA, Verhoef S, Meijers-Heijboer HEJ, Wijnen J, Garcia EBG, Ligtenberg MJ, Kriege M, Collee M, Ausems MGEM, Oosterwijk JC, Peock S, Frost D, Ellis SD, Platte R, Fineberg E, Evans DG, Lalloo F, Jacobs C, Eeles R, Adlard J, Davidson R, Cole T, Cook J, Paterson J, Douglas F, Brewer C, Hodgson S, Morrison PJ, Walker L, Rogers MT, Donaldson A, Dorkins H, Godwin AK, Bove B, Stoppa-Lyonnet D, Houdayer C, Buecher B, de Pauw A, Mazoyer S, Calender A, Leone M, Bressac-de Paillerets B, Caron O, Sobol H, Frenay M, Prieur F, Ferrer SF, Mortemousque I, Buys S, Daly M, Miron A, Terry MB, Hopper JL, John EM, Southey M, Goldgar D, Singer CF, Fink-Retter A, Tea MK, Kaulich DG, Hansen TVO, Nielsen FC, Barkardottir RB, Gaudet M, Kirchhoff T, Joseph V, Dutra-Clarke A, Offit K, Piedmonte M, Kirk J, Cohn D, Hurteau J, Byron J, Fiorica J, Toland AE, Montagna M, Oliani C, Imyanitov E, Isaacs C, Tihomirova L, Blanco I, Lazaro C, Teule A, Del Valle J, Gayther SA, Odunsi K, Gross J, Karlan BY, Olah E, Teo SH, Ganz PA, Beattie MS, Dorfling CM, van Rensburg EJ, Diez O, Kwong A, Schmutzler RK, Wappenschmidt B, Engel C, Meindl A, Ditsch N, Arnold N, Heidemann S, Niederacher D, Preisler-Adams S, Gadzicki D, Varon-Mateeva R, Deissler H, Gehrig A, Sutter C, Kast K, Fiebig B, Schafer D, Caldes T, de la Hoya M, Nevanlinna H, Muranen TA, Lesperance B, Spurdle AB, Neuhausen SL, Ding YC, Wang XS, Fredericksen Z, Pankratz VS, Lindor NM, Peterlongo P, Manoukian S, Peissel B, Zaffaroni D, Bonanni B, Bernard L, Dolcetti R, Papi L, Ottini L, Radice P, Greene MH, Loud JT, Andrulis IL, Ozcelik H, Mulligan AM, Glendon G, Thomassen M, Gerdes AM, Jensen UB, Skytte AB, Kruse TA, Chenevix-Trench G, Couch FJ, Simard J, Easton DF, CIMBA Study Collaborator, SWE-BRCA Study Collaborator, HEBON Study Collaborator, EMBRACE Study Collaborator, GEMO Study Collaborator, KConFab Investigators

Publication type: Article

Publication status: Published

Journal: Breast Cancer Research

Year: 2012

Volume: 14

Issue: 1

Print publication date: 20/02/2012

Date deposited: 24/10/2012

ISSN (electronic): 1465-542X

Publisher: BioMed Central Ltd.


DOI: 10.1186/bcr3121


Altmetrics provided by Altmetric


Funder referenceFunder name
Breast Cancer Family Registry (BCFR)
Breast Cancer Family Registry (BCFR) and Principal Investigators
Breast Cancer Research Foundation
Cancer Care Ontario
Cancer Councils of New South Wales, Tasmania
Cancer Foundation of Western Australia
Carlos III Health Institute
Catalan Health Institute
Eileen Stein Jacoby Fund while at FCCC
extramural (Community Oncology and Prevention Trials Program - COPTRG) NCI program
Familial Cancer Registry
Finnish Cancer Society
GOG's Cancer Prevention and Control Committee
Helsinki University Central Hospital Research Fund
Intramural Research Program of the US National Cancer Institute at the National Institutes of Health
Kansas Bioscience Authority Eminent Scholar Program
Ministero dell'Istruzione, dell'Universita e della Ricerca (MIUR)
National Health and Medical Research Council (NHMRC)
NHMRC Senior Research Fellowship
Spanish Health Research Fund
University of Kansas Cancer Center
"CIHR Team in Familial Risks of Breast Cancer" program
Asociacion Espanola Contra el Cancer
Autonomous Government of Catalonia
Canadian Institutes of Health Research for the "CIHR Team in Familial Risks of Breast Cancer" program
Cancer Association of South Africa
Cancer Councils of New South Wales, South Australia
Cancer Councils of New South Wales, Victoria
Ellen Li Charitable Foundation
Icelandic Association "Walking for Breast Cancer Research"
intramural (Clinical Genetics Branch, DCEG) NCI program
Komen Foundation
Landspitali University Hospital Research Fund
Morris and Horowitz Families Endowment
Mutua Madrile a Foundation
National Breast Cancer Foundation
National Cancer Institute
NEYE foundation
NIHR grant
Ohio State University Comprehensive Cancer Center
Principal Investigators
Queensland Cancer Fund
Sigrid Juselius Foundation
Swing Fore the Cure
US National Cancer Institute
019511Canadian Breast Cancer Research Alliance
10-04-92110Russian Federation for Basic Research
10-04-92601Russian Federation for Basic Research
11-04-00227Russian Federation for Basic Research
2009/0220/1DP/ Social Fund
132473Academy of Finland
16.512.11.2237Federal Agency for Science and Innovations
223175European Community's Seventh Framework Programme
ACC2/R6.9"Ministero della Salute" ("Progetto Tumouri Femminili)
628333Cancer Australia
CA 101165GOG Statistical and Data Center
CA-06-503National Institutes of Health under RFA
CA128978NIH grant
C12292/A11174Cancer Research UK
C1287/A10118Cancer Research UK
C1287/A11990Cancer Research UK
C5047/A8385Cancer Research UK
CA 27469GOG Tissue Bank
CA 37517GOG Statistical and Data Center
CA116201NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer
FIS PI08 1120Spanish Ministry of Science and Innovation
CK-80745Hungarian Research Grant KTIA-OTKA
HHSN261200744000CCancer Genetics Network
HU0115/NA/2008-3/P-9Norwegian EEA Financial Mechanism
JP090615Royal Society International Joint grant
HEALTH-F2-2009-223175European Community's Seventh Framework Programme
N02-CP-65504Westat, Inc, Rockville, MD
NKI1998-1854Dutch Cancer Society
NKI2004-3088Dutch Cancer Society
N02PC45022-46Research Triangle Institute Informatics Support Center
P30-CA051008Tissue Culture Shared Registry at Georgetown University (NIH/NCI)
NKI2007-3756Dutch Cancer Society
NO2-CP-11019-50Westat, Inc, Rockville, MD
R01 CA74415National Institutes of Health
RD06/0020/0021Instituto de Salud Carlos III
RFA-CA-06-503National Cancer Institute, National Institutes of Health
RFPS 2006-5-341353"Ministero della Salute" ("Progetto Tumouri Femminili)
U01 CA69398Columbia University
U01 CA69417Cancer Prevention Institute of California (formerly the Northern California Cancer Center)
U01 CA69446Huntsman Cancer Institute
U01 CA69631Fox Chase Cancer Center
RD06/0020/1160Red de Investigacion en Cancer
W81XWH-10-1-0341U.S. Department of Defence Ovarian Cancer Idea award
SAF201020493Spanish Ministry of Science and Innovation
SCIIIRETIC RD06/0020/1051
SIOP-06-258-COUNAmerican Cancer Society Clinical Research Professorship
U01 CA69467Cancer Care Ontario
U01 CA69638University of Melbourne