Evidence that the 5p12 Variant rs10941679 Confers Susceptibility to Estrogen-Receptor-Positive Breast Cancer through FGF10 and MRPS30 Regulation

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. 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. Strong evidence for the existence of a breast cancer (MIM: 114480) susceptibility locus at 5p12 has been observed through a GWAS in Iceland (SNP rs7703618),1Stacey S.N. Manolescu A. Sulem P. Rafnar T. Gudmundsson J. Gudjonsson S.A. Masson G. Jakobsdottir M. Thorlacius S. Helgason A. et al.Common variants on chromosomes 2q35 and 16q12 confer susceptibility to estrogen receptor-positive breast cancer.Nat. Genet. 2007; 39: 865-869Crossref PubMed Scopus (633) Google Scholar in the Breast Cancer Association Consortium (BCAC; SNP rs981782, 371 Kb centromeric),2Easton D.F. Pooley K.A. Dunning A.M. Pharoah P.D. Thompson D. Ballinger D.G. Struewing J.P. Morrison J. Field H. Luben R. et al.SEARCH collaboratorskConFabAOCS Management GroupGenome-wide association study identifies novel breast cancer susceptibility loci.Nature. 2007; 447: 1087-1093Crossref PubMed Scopus (1933) Google Scholar and in the Cancer GEnetic Markers of Susceptibility study (CGEMS; SNP rs4866929; 352 Kb centromeric; r2 = 0.18).3Hunter D.J. Kraft P. Jacobs K.B. Cox D.G. Yeager M. Hankinson S.E. Wacholder S. Wang Z. Welch R. Hutchinson A. et al.A genome-wide association study identifies alleles in FGFR2 associated with risk of sporadic postmenopausal breast cancer.Nat. Genet. 2007; 39: 870-874Crossref PubMed Scopus (1249) Google Scholar 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 rs10941679.4Stacey S.N. Manolescu A. Sulem P. Thorlacius S. Gudjonsson S.A. Jonsson G.F. Jakobsdottir M. Bergthorsson J.T. Gudmundsson J. Aben K.K. et al.Common variants on chromosome 5p12 confer susceptibility to estrogen receptor-positive breast cancer.Nat. Genet. 2008; 40: 703-706Crossref PubMed Scopus (391) Google Scholar More recently, a BCAC study confirmed that rs10941679 was associated with risk of lower-grade, progesterone receptor (PGR [MIM: 607311])-positive breast cancer tumors.5Milne R.L. Goode E.L. García-Closas M. Couch F.J. Severi G. Hein R. Fredericksen Z. Malats N. Zamora M.P. Arias Pérez J.I. et al.GENICA NetworkkConFab InvestigatorsAOCS GroupConfirmation of 5p12 as a susceptibility locus for progesterone-receptor-positive, lower grade breast cancer.Cancer Epidemiol. Biomarkers Prev. 2011; 20: 2222-2231Crossref PubMed Scopus (25) Google Scholar Here, we report the comprehensive fine-scale mapping of this locus in 104,660 subjects from 50 case-control studies participating in 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. Genotyping was conducted with the COGS array, a custom array comprising approximately 200,000 SNPs.6Michailidou K. Hall P. Gonzalez-Neira A. Ghoussaini M. Dennis J. Milne R.L. Schmidt M.K. Chang-Claude J. Bojesen S.E. Bolla M.K. et al.Breast and Ovarian Cancer Susceptibility CollaborationHereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)kConFab InvestigatorsAustralian Ovarian Cancer Study GroupGENICA (Gene Environment Interaction and Breast Cancer in Germany) NetworkLarge-scale genotyping identifies 41 new loci associated with breast cancer risk.Nat. Genet. 2013; 45: 353-361, e1–e2Crossref PubMed Scopus (836) Google Scholar After quality-control exclusions, we analyzed data from 48,155 case subjects and 43,612 control subjects of European ancestry and 6,269 case subjects and 6,624 control subjects of Asian ancestry. Estrogen receptor (ESR1 [MIM: 133430]) status of the primary tumor was available for 27,748 European and 4,997 Asian case subjects; of these, 7,646 (22%) European and 1,623 (32%) Asian case subjects were ER−. We examined a 1 Mb region (positions 44,394,495–45,364,167; NCBI build 37 assembly) in which the 1000 Genomes Project cataloged 1,811 variants (March 2010 Pilot version 60 CEU project data). We aimed to genotype all 628 SNPs with minor allele frequency (MAF) > 2% and correlated with rs981782 and rs10941679 at r2 > 0.1 (n = 424), plus a set of SNPs designed to tag all remaining SNPs with r2 > 0.9 (n = 184), but we managed to include 563 SNPs with a designability score (DS) > 0.9 and which passed QC.6Michailidou K. Hall P. Gonzalez-Neira A. Ghoussaini M. Dennis J. Milne R.L. Schmidt M.K. Chang-Claude J. Bojesen S.E. Bolla M.K. et al.Breast and Ovarian Cancer Susceptibility CollaborationHereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)kConFab InvestigatorsAustralian Ovarian Cancer Study GroupGENICA (Gene Environment Interaction and Breast Cancer in Germany) NetworkLarge-scale genotyping identifies 41 new loci associated with breast cancer risk.Nat. Genet. 2013; 45: 353-361, e1–e2Crossref PubMed Scopus (836) Google Scholar IMPUTE v.2.0 was used to impute genotypes of all known SNPs in the region using the 1000 Genome Project data (March 2012 version) as a reference panel. Case-control analyses were conducted on 3,365 SNPs (563 genotyped and 2,776 imputed at r2 > 0.3). In European-ancestry women, 461 of these SNPs were associated with overall breast cancer risk, 489 with ER+ and 38 with ER− breast cancer risk (p < 10−4; Table S1). SNP rs10941679 showed the strongest overall association (MAF = 0.27, per-minor (g) allele: OR = 1.12; 95% CI 1.10–1.14; p = 2.55 × 10−26; Figure 1, Tables 1 and S1). To identify additional association signals at this region, we conducted a forward stepwise logistic regression examining SNPs with univariate p < 0.1 (n = 1,040).6Michailidou K. Hall P. Gonzalez-Neira A. Ghoussaini M. Dennis J. Milne R.L. Schmidt M.K. Chang-Claude J. Bojesen S.E. Bolla M.K. et al.Breast and Ovarian Cancer Susceptibility CollaborationHereditary Breast and Ovarian Cancer Research Group Netherlands (HEBON)kConFab InvestigatorsAustralian Ovarian Cancer Study GroupGENICA (Gene Environment Interaction and Breast Cancer in Germany) NetworkLarge-scale genotyping identifies 41 new loci associated with breast cancer risk.Nat. Genet. 2013; 45: 353-361, e1–e2Crossref PubMed Scopus (836) Google Scholar The most parsimonious model included three variants: SNP1 rs10941679 (signal 1), SNP2 rs6864776 (signal 2; conditional p = 6.22 × 10−11), and SNP3 rs200229088 (signal 3; conditional p = 1.12 × 10−5, borderline significance; Table S2). SNP1 and SNP3 are weakly correlated (r2 = 0.15) but SNP2 was uncorrelated with the other two (r2 = 0.07 and 0.05).Table 1Associations of the Top SNPs from Each Signal with Overall Breast Cancer Risk and Bre

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