RESUMEN

Breast cancer is the most common malignant tumor in women. A previous genome-wide association study reports that rs72755295, a SNP locating at intron of EXO1 (exonuclease 1), is associated with breast cancer. Due to the complete linkage disequilibrium between rs72755295 and rs4149909, a nonsynonymous mutation for EXO1, rs4149909 is supposed to be the causal SNP. Since EXO1 is overexpressed in breast carcinoma samples, we hypothesized that the genetic variations in this locus might confer breast cancer risk by regulating EXO1 expression. To substantiate this, a functional genomics study was performed. The dual luciferase assay indicated that G of rs72755295 presents significantly higher relative enhancer activity than A, thus verifying that this SNP can influence gene expression in breast cell. Through chromosome conformation capture it was disclosed that the enhancer containing rs72755295 can interact with the EXO1 promoter. RNA-seq analysis indicated that EXO1 expression is dependent on the rs72755295 genotype. By chromatin immunoprecipitation, the transcription factor PAX6 (paired box 6) was recognized to bind the region spanning rs72755295. In electrophoretic mobility shift assay, G of rs72755295 displays obviously higher binding affinity with nuclear protein than A. Our results indicated that rs72755295 is a cis-regulatory variation for EXO1 and might confer breast cancer risk besides rs4149909.