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Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2

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Breast Cancer Association Consortium (Including: Muir, Kenneth (Kenneth R.), Lophatananon, Artitaya and Stewart-Brown, Sarah L.). (2015) Fine-mapping identifies two additional breast cancer susceptibility loci at 9q31.2. Human Molecular Genetics, Volume 24 (Number 10). pp. 2966-2984. Article number 2966. doi:10.1093/hmg/ddv035

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Official URL: http://dx.doi.org/10.1093/hmg/ddv035

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Abstract

We recently identified a novel susceptibility variant, rs865686, for estrogen-receptor positive breast cancer at 9q31.2. Here, we report a fine-mapping analysis of the 9q31.2 susceptibility locus using 43 160 cases and 42 600 controls of European ancestry ascertained from 52 studies and a further 5795 cases and 6624 controls of Asian ancestry from nine studies. Single nucleotide polymorphism (SNP) rs676256 was most strongly associated with risk in Europeans (odds ratios [OR] = 0.90 [0.88-0.92]; P-value = 1.58 × 10(-25)). This SNP is one of a cluster of highly correlated variants, including rs865686, that spans ∼14.5 kb. We identified two additional independent association signals demarcated by SNPs rs10816625 (OR = 1.12 [1.08-1.17]; P-value = 7.89 × 10(-09)) and rs13294895 (OR = 1.09 [1.06-1.12]; P-value = 2.97 × 10(-11)). SNP rs10816625, but not rs13294895, was also associated with risk of breast cancer in Asian individuals (OR = 1.12 [1.06-1.18]; P-value = 2.77 × 10(-05)). Functional genomic annotation using data derived from breast cancer cell-line models indicates that these SNPs localise to putative enhancer elements that bind known drivers of hormone-dependent breast cancer, including ER-α, FOXA1 and GATA-3. In vitro analyses indicate that rs10816625 and rs13294895 have allele-specific effects on enhancer activity and suggest chromatin interactions with the KLF4 gene locus. These results demonstrate the power of dense genotyping in large studies to identify independent susceptibility variants. Analysis of associations using subjects with different ancestry, combined with bioinformatic and genomic characterisation, can provide strong evidence for the likely causative alleles and their functional basis.

Item Type: Journal Article
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions: Faculty of Medicine > Warwick Medical School > Health Sciences
Faculty of Medicine > Warwick Medical School > Health Sciences > Statistics and Epidemiology
Faculty of Medicine > Warwick Medical School
Library of Congress Subject Headings (LCSH): Breast -- Cancer -- Susceptibility, Breast -- Cancer -- Genetic aspects
Journal or Publication Title: Human Molecular Genetics
Publisher: Oxford University Press
ISSN: 0964-6906
Official Date: 15 May 2015
Dates:
DateEvent
15 May 2015Published
4 February 2015Available
30 January 2015Accepted
22 December 2014Submitted
Date of first compliant deposit: 29 December 2015
Volume: Volume 24
Number: Number 10
Page Range: pp. 2966-2984
Article Number: Article number 2966
DOI: 10.1093/hmg/ddv035
Status: Peer Reviewed
Publication Status: Published
Access rights to Published version: Open Access
Funder: Cancer Research UK (CRUK), Seventh Framework Programme (European Commission) (FP7), European Union (EU), Canadian Institutes of Health Research (CIHR), Québec (Province). Ministry of Economic Development, Innovation and Export Trade, National Institutes of Health (U.S.) (NIH), National Cancer Institute (U.S.) (NCI), United States. Department of Defense (DoD), Susan G. Komen for the Cure, Breast Cancer Research Foundation, Ovarian Cancer Research Fund, National Health and Medical Research Council (Australia) (NHMRC) , New South Wales State Cancer Council, Victorian Health Promotion Foundation (VHPF), Victorian Breast Cancer Research Consortium, KWF Kankerbestrijding [Dutch Cancer Society], Breast Cancer Research Trust (Great Britain), Universitätsklinikum Erlangen, Breakthrough Breast Cancer, National Institute for Health Research (Great Britain) (NIHR), Oxford Biomedical Research Centre, Dietmar Hopp Stiftung, Hermann von Helmholtz-Gemeinschaft Deutscher Forschungszentren (HGF), German Cancer Research Center, Fondation de France (FF), Institut National Du Cancer (France), Ligue nationale contre le cancer (France) (LNCC), French agency for Food, Environmental and Occupational Health Safety (ANSES), France. Agence nationale de la recherche (ANR), Fondation ARC pour la Recherche sur le Cancer, Chief Physician Johan Boserup and Lise Boserup's Fund, Statens lægevidenskabelige forskningsråd (Denmark) [Danish Medical Research Council] (SLF), Herlev Hospital [Denmark], Genome Spain Foundation, Red Temática de investigación cooperativa en cáncer, Asociación Española contra el Cáncer, Fondo de Investigaciones Sanitarias (Spain), Instituto de Salud Carlos III, Michael Manzella Foundation, California Breast Cancer Research Program, Lon V Smith Foundation, Baden-Württemberg (Germany). Ministerium für Wissenschaft, Forschung und Kunst, Deutsche Krebshilfe [German Cancer Aid], Germany. Bundesministerium für Bildung und Forschung (BMBF), Robert Bosch Stiftung, Deutsches Krebsforschungszentrum Heidelberg (DKFZ), Ruhr-Universität Bochum. Institut für Prävention und Arbeitsmedizin der Deutschen Gesetzlichen Unfallversicherung, Johanniter-Krankenhaus Bonn. Abteilung Innere Medizin, Helsingin yliopistollinen keskussairaala [Helsinki University Central Hospital], Suomen Akatemia [Academy of Finland], Suomen Syöpäyhdistys [Cancer Society of Finland], Nordic Cancer Union, Sigrid Jusélius stiftelse, Japan. Monbu Kagakushō [Japan. Ministry of Education, Culture, Sports, Science and Technology] (MK), Japan. Kōsei Rōdōshō [Japan. Ministry of Health, Labour and Welfare], Takeda Kagaku Shinkō Zaidan [Takeda Science Foundation], Kokuritsu Gan Sentā [Japan. National Cancer Center], Deutscher Akademischer Austauschdienst (DAAD), Friends of Hannover Medical School, Stockholms län (Sweden). Landstinget, Karolinska institutet, Stockholm Cancer Foundation, Cancerfonden, Kuopion yliopistollinen Keskussairaala (Finland) [Kuopio University Hospital], Cancer Fund of North Savo, Itä-Suomen yliopisto [University of Eastern Finland], National Breast Cancer Foundation, Queensland Cancer Fund, Cancer Council Victoria, Cancer Council Tasmania, Cancer Council South Australia, Cancer Foundation of Western Australia, United States. Army Medical Research and Materiel Command (DAMD), California. Department of Health, Stichting tegen Kanker (Belgium), Hamburg Cancer Society, Associazione italiana per la ricerca sul cancro, David F and Margaret T Grohne Family Foundation, Ting Tsung and Wei Fong Chao Foundation, Quebec Breast Cancer Foundation, Malaysia. Kementerian Sains, Teknologi dan Inovasi (MOTSI), Malaysia. Kementerian Pengajian Tinggi [Malaysia. Ministry of Higher Education], Cancer Research Initiatives Foundation (CARIF), Singapore. Biomedical Research Council, Singapore. National Medical Research Council, Norges forskningsråd [Norwegian Research Council], Oulun yliopisto [University of Oulu], Oulun yliopistollinen sairaala (OYS), Biobanking and Biomolecular Resources Research Infrastructure (BBMRI), Marit and Hans Rausing initiative against breast cancer, Sweden. Vetenskapsrådet [Research Council], Singapore. Agency for Science, Technology and Research (ASTAR), Riksföreningen mot cancer [Swedish Cancer Society], Yorkshire Cancer Research Campaign, National Program of Cancer Registries (U.S.), Fundacja na rzecz Nauki Polskiej [Foundation for Polish Science] (FNP), Ohio State University. Comprehensive Cancer Center, Stefanie Spielman Fund for Breast Cancer Research, Greece. General Secretariat of Research and Technology, Zhong yang yan jiu yuan [Academia Sinica (Taipei, Taiwan)], Guo jia ke xue wei yuan hui [National Science Council (Taiwan)], Institute of Cancer Research (London, England)
Grant number: C1287/A10118 (CRUK), C1287/A12014 (CRUK), 223175 (FP7), BM0606 (EU), C1287/A10710 (CRUK), PSR-SIIRI-701 (MEDIET), CA128978 (NIH), 1U19 CA148537 (NCI), 1U19 CA148065 (NCI), 1U19 CA148112 (NCI), W81XWH-10-1-0341 (DoD), UM1 CA164920 (NCI), NKI2007-3839 (KWF)
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