Fine scale mapping of the 5q11.2 breast cancer locus reveals at least three independent risk variants regulating MAP3K1
Genome Wide Association Studies (GWAS) 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 analysed 909 genetic variants across the 5q11.2 locus in 103,991 breast cancer cases and controls from 52 studies in the Breast Cancer Association Consortium. Multiple logistic regression analyses identified three independent risk signals: The strongest associations are with 15 correlated variants (iCHAV1) where the minor allele of best candidate, rs62355902, associates with significantly increased risks of both estrogen receptor-positive (ER+: OR=1.24, 95% CI 1.21-1.27; P-trend=5.7×10-44) and estrogen receptor-negative tumors (ER-: OR=1.10, 95% CI 1.05-1.15; P-trend=3.0×10-4). After adjustment for rs62355902, we found evidence for the association of a further 173 variants (iCHAV2) containing three subsets with a range of effects, of which the strongest is SNP rs113317823 (P-cond=1.61×10-5); and five variants comprising iCHAV3 (lead rs11949391; ER+: OR=0.90, 95% CI 0.87-0.93; P-cond=1.4x10-4). Twenty six percent of the prioritized candidate variants coincide with four putative regulatory elements that interact with the MAP3K1 promoter through chromatin looping and affect MAP3K1 promoter activity. Functional analysis indicates the cancer risk alleles of four candidates increase MAP3K1 transcriptional activity: rs74345699 and rs62355900 (iCHAV1); rs16886397 (iCHAV2a); and rs17432750 (iCHAV3). 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 may promote breast cancer cell survival.
National Cancer Institute (NCI) (U19CA148065)
EC FP7 CP (223175)
Cancer Research UK (16565)
Cancer Research UK (CRUK-A10710)
Cancer Research UK (CRUK-A12014)
Cancer Research UK (CRUK-A10118)