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Common germline polymorphisms associated with breast cancer-specific survival.


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Article

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Authors

Pirie, Ailith 
Guo, Qi 
Kraft, Peter 
Canisius, Sander 
Eccles, Diana M 

Abstract

INTRODUCTION: Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer-specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. METHODS: A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer-specific survival, overall survival and disease-free survival. All associations that reached the nominal significance level of P value <0.05 were included. Single nucleotide polymorphisms that had been previously reported as nominally associated with at least one survival outcome were evaluated in the pooled analysis of over 37,000 breast cancer cases for association with breast cancer-specific survival. Previous associations were evaluated using a one-sided test based on the reported direction of effect. RESULTS: Fifty-six variants from 45 previous publications were evaluated in the meta-analysis. Fifty-four of these were evaluated in the full set of 37,954 breast cancer cases with 2,900 events and the two additional variants were evaluated in a reduced sample size of 30,000 samples in order to ensure independence from the previously published studies. Five variants reached nominal significance (P <0.05) in the pooled GWAS data compared to 2.8 expected under the null hypothesis. Seven additional variants were associated (P <0.05) with ER-positive disease. CONCLUSIONS: Although no variants reached genome-wide significance (P <5 x 10(-8)), these results suggest that there is some evidence of association between candidate common germline variants and breast cancer prognosis. Larger studies from multinational collaborations are necessary to increase the power to detect associations, between common variants and prognosis, at more stringent significance levels.

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Keywords

Breast Neoplasms, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genome-Wide Association Study, Germ Cells, Humans, Polymorphism, Single Nucleotide, Prognosis

Journal Title

Breast Cancer Res

Conference Name

Journal ISSN

1465-5411
1465-542X

Volume Title

17

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research Uk (None)
Cancer Research Uk (None)
National Cancer Institute (U19CA148065)
National Cancer Institute (R01CA128978)
European Commission (223175)
Cancer Research Uk (None)
Cancer Research UK (6306)
Cancer Research UK (12014)
Cancer Research UK (10118)
Funding This work was supported by the following grants. 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 AP is funded by a MRC studentship. DE is a Principal Research Fellow of Cancer Research UK. JH is a National Health and Medical Research Council (NHMRC) Australia Fellow. MS. is a NHMRC Senior Research Fellow. GT 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); NIHR 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 Intramural Research Program of National Institutes of Health and 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).