Abstract
Genome-wide association studies (GWAS) have identified more than 2000 single nucleotide polymorphisms (SNPs) associated with breast cancer susceptibility, most of which are located in the non-coding region. However, the causal SNPs functioning as gene regulatory elements still remain largely undisclosed. Here, we applied a Dinucleotide Parallel Reporter sequencing (DiR-seq) assay to evaluate 288 breast cancer risk SNPs in nine different breast cancer cell lines. Further multi-omics analysis with the ATAC-seq (Assay for Transposase-Accessible Chromatin using sequencing), DNase-seq (DNase I hypersensitive sites sequencing) and histone modification ChIP-seq (Chromatin Immunoprecipitation sequencing) nominated seven functional SNPs in breast cancer cells. Functional investigations show that rs4808611 affects breast cancer progression by altering the gene expression of NR2F6. For the other site, rs2236007, the alteration promotes the binding of the suppressive transcription factor EGR1 and results in the downregulation of PAX9 expression. The downregulated expression of PAX9 causes cancer malignancies and is associated with the poor prognosis of breast cancer patients. Our findings contribute to defining the functional risk SNPs and the related genes for breast cancer risk prediction.
Highlights
Breast cancer is the most commonly diagnosed malignancy and the main cause of cancer-related mortality in women [1]
288 single nucleotide polymorphisms (SNPs) (Table S4) that have been reported for associations with breast cancer susceptibility were enlisted in the Dinucleotide Parallel Reporter sequencing (DiR-seq) analysis
In the online eQTL analysis with the GenotypeTissue Expression (GTEx) database, we found that the PAX9 gene was highly associated with the rs2236007 variation in the thyroid, tibial, and skin tissues (Figure S6), with the
Summary
Breast cancer is the most commonly diagnosed malignancy and the main cause of cancer-related mortality in women [1]. SNPs, highlighting that genetic factors make a great contribution to breast cancer susceptibility. Functional studies of the risk SNPs have resulted in successful findings of regulatory SNPs and elucidation of the thereof mechanisms in complex diseases [8,9,10,11,12,13,14,15,16,17,18,19]. Accumulating studies show that the functional risk SNP sites usually alter the chromatin binding of the transcription factors and result in the abnormal expression of the target gene [8,12,18,20,21,22,23,24,25,26]. The majority of these GWAS SNPs remain unclear with respect to their biological function and underlying mechanisms
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