Abstract
Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12. Here, we report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495–45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ER+) breast cancer (per-g allele OR ER+ = 1.15; 95% CI 1.13–1.18; p = 8.35 × 10−30). After adjustment for rs10941679, we detected signal 2, consisting of 38 SNPs more strongly associated with ER-negative (ER−) breast cancer (lead SNP rs6864776: per-a allele OR ER− = 1.10; 95% CI 1.05–1.14; p conditional = 1.44 × 10−12), and a single signal 3 SNP (rs200229088: per-t allele OR ER+ = 1.12; 95% CI 1.09–1.15; p conditional = 1.12 × 10−05). Expression quantitative trait locus analysis in normal breast tissues and breast tumors showed that the g (risk) allele of rs10941679 was associated with increased expression of FGF10 and MRPS30. Functional assays demonstrated that SNP rs10941679 maps to an enhancer element that physically interacts with the FGF10 and MRPS30 promoter regions in breast cancer cell lines. FGF10 is an oncogene that binds to FGFR2 and is overexpressed in ∼10% of human breast cancers, whereas MRPS30 plays a key role in apoptosis. These data suggest that the strongest signal of association at 5p12 is mediated through coordinated activation of FGF10 and MRPS30, two candidate genes for breast cancer pathogenesis.
Highlights
Genome-wide association studies (GWASs) have revealed increased breast cancer risk associated with multiple genetic variants at 5p12
We report the comprehensive fine-scale mapping of this locus in 104,660 subjects from 50 case-control studies participating in Breast Cancer Association Consortium (BCAC), including 41 studies from populations of European ancestry and nine of East Asian ancestry, and we explore the functional mechanisms underlying the associations in this region
Two of the excluded variants had been previously postulated as likely causative variants[4,7] and so we investigated these in more depth
Summary
Maya Ghoussaini,[1,98] Juliet D. We report the fine mapping of this locus using data from 104,660 subjects from 50 case-control studies in the Breast Cancer Association Consortium (BCAC). With data for 3,365 genotyped and imputed SNPs across a 1 Mb region (positions 44,394,495– 45,364,167; NCBI build 37), we found evidence for at least three independent signals: the strongest signal, consisting of a single SNP rs10941679, was associated with risk of estrogen-receptor-positive (ERþ) breast cancer (per-g allele OR ERþ 1⁄4 1.15; 95% CI 1.13–1.18; p 1⁄4 8.35 3 10À30). Centromeric; r2 1⁄4 0.18).[3] A subsequent study, using 22 SNPs in ~5,000 case subjects and ~33,000 control subjects of European ancestry, reported that risk at this locus could be explained by two SNPs: rs4415084 and rs10941679.4 More recently, a BCAC study confirmed that rs10941679 was associated with risk of lower-grade, progesterone receptor (PGR [MIM: 607311])-positive breast cancer tumors.[5].
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