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Identification of novel genetic markers of breast cancer survival.


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Authors

Guo, Qi 
Schmidt, Marjanka K 
Kraft, Peter 
Canisius, Sander 
Chen, Constance 

Abstract

BACKGROUND: Survival after a diagnosis of breast cancer varies considerably between patients, and some of this variation may be because of germline genetic variation. We aimed to identify genetic markers associated with breast cancer-specific survival. METHODS: We conducted a large meta-analysis of studies in populations of European ancestry, including 37954 patients with 2900 deaths from breast cancer. Each study had been genotyped for between 200000 and 900000 single nucleotide polymorphisms (SNPs) across the genome; genotypes for nine million common variants were imputed using a common reference panel from the 1000 Genomes Project. We also carried out subtype-specific analyses based on 6881 estrogen receptor (ER)-negative patients (920 events) and 23059 ER-positive patients (1333 events). All statistical tests were two-sided. RESULTS: We identified one new locus (rs2059614 at 11q24.2) associated with survival in ER-negative breast cancer cases (hazard ratio [HR] = 1.95, 95% confidence interval [CI] = 1.55 to 2.47, P = 1.91 x 10(-8)). Genotyping a subset of 2113 case patients, of which 300 were ER negative, provided supporting evidence for the quality of the imputation. The association in this set of case patients was stronger for the observed genotypes than for the imputed genotypes. A second locus (rs148760487 at 2q24.2) was associated at genome-wide statistical significance in initial analyses; the association was similar in ER-positive and ER-negative case patients. Here the results of genotyping suggested that the finding was less robust. CONCLUSIONS: This is currently the largest study investigating genetic variation associated with breast cancer survival. Our results have potential clinical implications, as they confirm that germline genotype can provide prognostic information in addition to standard tumor prognostic factors.

Description

Keywords

Breast Neoplasms, Female, Genetic Markers, Genetic Predisposition to Disease, Genotype, Humans, Polymorphism, Single Nucleotide, Prognosis, Receptors, Estrogen, Survival Analysis, White People

Journal Title

J Natl Cancer Inst

Conference Name

Journal ISSN

0027-8874
1460-2105

Volume Title

107

Publisher

Oxford University Press (OUP)
Sponsorship
Cancer Research Uk (None)
Cancer Research Uk (None)
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
European Commission (223175)
Cancer Research UK (6306)
Cancer Research UK (12014)
Cancer Research UK (10118)
Cancer Research Uk (None)
Higher-level funding: The COGS project was funded through a European Commission’s Seventh Framework Programme grant (agreement number 223175 - HEALTH-F2-2009–223175). The Breast Cancer Association Consortium (BCAC) is funded by Cancer Research-UK (C1287/A10118 and C1287/A12014). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). ELAN Program of the University Hospital Erlangen (BBCC). Personal support: DFE is a Principal Research Fellow of Cancer Research UK. JLH is a National Health and Medical Research Council (NHMRC) Australia Fellow. MCS is an NHMRC Senior Research Fellow. GCT is an NHMRC Senior Principal Research Fellow. DL is supported by the FWO and the KULPFV/10/016-SymBioSysII. JL is a UNESCO-L’Oréal International Fellow. RB was a Cancer Institute NSW Fellow. KAP is a National Breast Cancer Foundation Fellow (Australia). Funding of constituent studies (these are listed by funding agency, with each grant number in parentheses): Academy of Finland (266528); Addenbrookes Charitable Trust; Agency for Science, Technology and Research of Singapore; Asociación Española Contra el Cáncer and the Fondo de Investigación Sanitario (PI11/00923, PI08/1120); Baden Württemberg Ministry of Science, Research and Arts; Breast Cancer Campaign (2009PR42); Breast Cancer Research Foundation; Canadian Institutes of Health Research (CIHR Team in Familial Risks of Breast Cancer program); Cancer Australia; Cancer Councils of New South Wales, Victoria, Tasmania and South Australia; Cancer Foundation of Western Australia; Cancer Fund of North Savo; Cancer Research UK (C1287/A10118, C1287/A12014, A7572, A10124, A11699, A16561, C507/A6306, C10097/A7484,C1275/A11699); Chief Physician Johan Boserup and Lise Boserup Fund; Danish Breast Cancer Group; Danish Medical Research Council; Deutsche Krebshilfe (70-2892-BR I, PBZ_KBN_122/P05/2004); Dietmar-Hopp Foundation; Dutch Cancer Society (1997-1505, 2004–3124, NKI2007-3839, 2009–4318, NKI2009-4363); Dutch government (NWO 184.021.007); Dutch National Genomics Initiative; ELAN-Fond of the University Hospital of Erlangen; European Community′s Seventh Framework Programme (HEALTH-F2-2009–223175); Federal Ministry of Education and Research, Germany (01KH0402); Finnish Cancer Society; Fondazione IRCCS Istituto Nazionale Tumori; Genome Spain Foundation; German Cancer Research Center (DKFZ); Hamburg Cancer Society; Helmholtz Society; Helsinki University Central Hospital Research Fund; Italian Association for Cancer Research (AIRC); Kuopio University Hospital special Government Funding; National Health and Medical Research Council of Australia (209057, 251553 and 504711); National Breast Cancer Foundation (Australia); National Institute for Health Research, Cambridge Biomedical Research Centre; Nordic Cancer Union; Märit and Hans Rausings Initiative Against Breast Cancer; Nordic Cancer Union; Polish Foundation of Science (PBZ_KBN_122/P05/2004); Queensland Cancer Fund; Red Temática de Investigación Cooperativa en Cáncer; Sigrid Juselius Foundation; Susan G. Komen Breast Cancer Foundation; Stichting tegen Kanker (232–2008 and 196–2010); United States National Institutes of Health (BBMRI-NL-CP16, CA69638, CA69417, CA06503, CA116201, CA122340, CA128978, CA63464, CA54281, CA098758, CA132839, CA164920, CA98216, CA098233, CA148065, CA98710, CA98758, and the Intramural Research Program of the National Institutes of Health and the National Cancer Institute); UK National Institute for Health Research Biomedical Research Centres at the University of Cambridge, Guy’s & St. Thomas’ NHS Foundation Trust in partnership with King’s College London, and University of Oxford; University of Eastern Finland strategic funding; Victorian Health Promotion Foundation; Victorian Breast Cancer Research Consortium; Yorkshire Cancer Research (S295, S299, S305PA).