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Fine-scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1.


Type

Article

Change log

Authors

Glubb, Dylan M 
Maranian, Mel J 
Michailidou, Kyriaki 
Pooley, Karen A 
Meyer, Kerstin B 

Abstract

Genome-wide association studies (GWASs) have revealed SNP rs889312 on 5q11.2 to be associated with breast cancer risk in women of European ancestry. In an attempt to identify the biologically relevant variants, we analyzed 909 genetic variants across 5q11.2 in 103,991 breast cancer individuals and control individuals from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: the strongest associations were with 15 correlated variants (iCHAV1), where the minor allele of the best candidate, rs62355902, associated with significantly increased risks of both estrogen-receptor-positive (ER(+): odds ratio [OR] = 1.24, 95% confidence interval [CI] = 1.21-1.27, ptrend = 5.7 × 10(-44)) and estrogen-receptor-negative (ER(-): OR = 1.10, 95% CI = 1.05-1.15, ptrend = 3.0 × 10(-4)) tumors. After adjustment for rs62355902, we found evidence of association of a further 173 variants (iCHAV2) containing three subsets with a range of effects (the strongest was rs113317823 [pcond = 1.61 × 10(-5)]) and five variants composing iCHAV3 (lead rs11949391; ER(+): OR = 0.90, 95% CI = 0.87-0.93, pcond = 1.4 × 10(-4)). Twenty-six percent of the prioritized candidate variants coincided with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicated that the cancer risk alleles of four candidates (rs74345699 and rs62355900 [iCHAV1], rs16886397 [iCHAV2a], and rs17432750 [iCHAV3]) increased MAP3K1 transcriptional activity. Chromatin immunoprecipitation analysis revealed diminished GATA3 binding to the minor (cancer-protective) allele of rs17432750, indicating a mechanism for its action. We propose that the cancer risk alleles act to increase MAP3K1 expression in vivo and might promote breast cancer cell survival.

Description

Keywords

Alleles, Breast Neoplasms, Case-Control Studies, Cell Line, Tumor, Chromosome Mapping, Chromosomes, Human, Pair 5, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Genotyping Techniques, Humans, MAP Kinase Kinase Kinase 1, MCF-7 Cells, Polymorphism, Single Nucleotide, Promoter Regions, Genetic, Quantitative Trait Loci, Racial Groups, Risk Factors

Journal Title

Am J Hum Genet

Conference Name

Journal ISSN

0002-9297
1537-6605

Volume Title

96

Publisher

Cell Press
Sponsorship
National Cancer Institute (R01CA128978)
National Cancer Institute (U19CA148065)
European Commission (223175)
Cancer Research UK (16565)
Cancer Research UK (A10710)
Cancer Research UK (A12014)
Cancer Research UK (A10118)
Manuscript writing group: DMG, MJM, KM, KAP, KBM, AMD, JDF. Locus SNP selection: MG, ED, AMD. iCOGS genotyping, calling and QC: MJM, SEB, SFN, AG-N, MRA, DH, JB, DCT, DV, FB, FR, SA, CL, CB, DC, JC, JD, CSH, JS, AMD, GC-T, DFE. Imputation: KM, DFE. Statistical analyses and programming: KM, KAP, DB, ED, JT, SK, DFE. Functional analysis and bioinformatics: DMG, SLE, KBM, SC, MO, MJM JAB, KMH, SK, JB and JDF. COGS coordination: PH, DFE, JB, AMD, BCAC coordination: DFE, GC-T, PDP. BCAC data management: MKB, QW. All other authors provided participant samples and phenotype information, and read and approved the manuscript. BCAC thanks all the individuals who took part in these studies and all the researchers, clinicians, technicians and administrative staff who have enabled this work to be carried out. BCAC is funded by Cancer Research UK [C1287/A10118, C1287/A12014] and by the European Community´s Seventh Framework Programme under grant agreement number 223175 (grant number HEALTH-F2-2009-223175) (COGS). Meetings of the BCAC have been funded by the European Union COST programme (BM0606). This study would not have been possible without the contributions of the following: Andrew Berchuck (OCAC), Rosalind A. Eeles, Ali Amin Al Olama, Zsofia Kote-Jarai, Sara Benlloch (PRACTICAL), Antonis Antoniou, Lesley McGuffog, and Ken Offit (CIMBA), Andrew Lee, Ed Dicks, and the staff of the Centre for Genetic Epidemiology Laboratory, the staff of the CNIO genotyping unit, Sylvie LaBoissière, Frederic Robidoux and the staff of the McGill University and Génome Québec Innovation Centre, the staff of the Copenhagen DNA laboratory, and Julie M. Cunningham, Sharon A. Windebank, Christopher A. Hilker, Jeffrey Meyer and the staff of Mayo Clinic Genotyping Core Facility. Genotyping of the iCOGS array was funded by the European Union (HEALTH-F2-2009-223175), Cancer Research UK (C1287/A10710), the Canadian Institutes of Health Research for the “CIHR Team in Familial Risks of Breast Cancer” program - grant #CRN-87521, and the Ministry of Economic Development, Innovation and Export Trade of Quebec – grant # PSR-SIIRI-701. This study makes use of data generated by the Molecular Taxonomy of Breast Cancer International Consortium. Funding for the project was provided by Cancer Research UK and the British Columbia Cancer Agency Branch. The QIMR Berghofer group was supported by project grants from the National Health and Medical Research Council of Australia (1021731, 1058415). The work by KBM, MO, SC and BJAP is supported by Cancer Research UK and the Breast Cancer Research Foundation. DFE is a Principal Research Fellow of CR-UK. GCT is an NHMRC Senior Principal Research Fellow. SLE and JDF are supported by Fellowships from the National Breast Cancer Foundation (NBCF) Australia. The funders have no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.