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Fine-mapping of a novel premenopausal breast cancer susceptibility locus at Chr4q31.22 in Caucasian women and validation in African and Chinese women

dc.contributor.authorKumaran, Mahalakshmi
dc.contributor.authorGhosh, Sunita
dc.contributor.authorJoy, Anil A.
dc.contributor.authorMackey, John R.
dc.contributor.authorCass, Carol E.
dc.contributor.authorZheng, Wei
dc.contributor.authorYasui, Yutaka
dc.contributor.authorDamaraju, Sambasivarao
dc.description.abstractWe previously identified a novel breast cancer susceptibility variant on chromosome 4q31.22 locus (rs1429142) conferring risk among women of European ancestry. Here, we report replication of findings, validation of the variant in diverse populations and fine-mapping of the associated locus in Caucasian population. The SNP rs1429142 (C/T, minor allele frequency 18%) showed association for the overall breast cancer risk in Stages 1-4 (n = 4,331 cases/4271 controls; p = 4.35 x 10(-8); odds ratio, ORC-allele,1.25), and an elevated risk among premenopausal women (n = 1,503 cases/4271 controls; p = 5.81 x 10(-10); ORC-allele 1.40) in European populations. SNP rs1429142 was associated with premenopausal breast cancer risk in women of African (T/C; p-value 1.45 x 10(-02); ORC-allele 1.2) but not from Chinese ancestry. Fine-mapping of the locus revealed several potential causal variants which are present within a single association signal, revealed from the conditional regression analysis. Functional annotation of the potential causal variants revealed three putative SNPs rs1366691, rs1429139 and rs7667633 with active enhancer functions inferred based on histone marks, DNase hypersensitive sites in breast cell line data. These putative variants were bound by transcription factors (C-FOS, STAT1/3 and POL2/3) with known roles in inflammatory pathways. Furthermore, Hi-C data revealed several short-range interactions in the fine-mapped locus harboring the putative variants. The fine mapped locus was predicted to be within a single topologically associated domain, potentially facilitating enhancer-promoter interactions possibly leading to the regulation of nearby genes.en_US
dc.publisherIntenational Journal of Canceren_US
dc.rightsThis is an open access article under the terms of the Creative Commons Attribution‐Non Commercial‐No Derivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
dc.subjectbreast canceren_US
dc.subjectgenome-wide association studiesen_US
dc.subjectsusceptibility variantsen_US
dc.subjectmenopausal statusen_US
dc.titleFine-mapping of a novel premenopausal breast cancer susceptibility locus at Chr4q31.22 in Caucasian women and validation in African and Chinese womenen_US

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