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Abstract
Functional characterization of cancer risk-associated single nucleotide polymorphism (SNP) identified by genome-wide association studies (GWAS) has become a big challenge. To identify the regulatory risk SNPs that can lead to transcriptional misregulation, we performed parallel reporter gene assays with both alleles of 213 prostate cancer risk-associated GWAS SNPs in 22Rv1 cells. We disclosed 32 regulatory SNPs that exhibited different regulatory activities with two alleles. For one of the regulatory SNPs, rs684232, we found that the variation altered chromatin binding of transcription factor FOXA1 on the DNA region and led to aberrant gene expression of VPS53, FAM57A, and GEMIN4, which play vital roles in prostate cancer malignancy. Our findings reveal the roles and underlying mechanism of rs684232 in prostate cancer progression and hold great promise in benefiting prostate cancer patients with prognostic prediction and target therapies.
Highlights
Up to 57.1% of genome-wide association studies (GWAS) single nucleotide polymorphism (SNP) are located in the DHSs (DNase hypersensitive sites), which indicates that most GWAS SNPs have potential regulatory functions themselves [25]
Considering that the typical transcription factors only occupy 6–12 bp DNA sequences [37], and short DNA stretches bearing transcription factor binding sites were widely used in the reporter gene assay [38], the 55 bp fragment will generally be enough to assess the effect of SNPs, even though we might not observe the full activity of the potential enhancer element
The results indicate that the rs684232 site might regulate gene expression of VPS53, FAM57A, and GEMIN4 by affecting
Summary
More than 2000 genome-wide association (GWASs) studies have been published, identifying many loci associated with susceptibility to over 1000 unique traits and common diseases since 2005 [1,2]. Prostate cancer (MIM:176807) is the second most common cancer in males and the fifth leading cause of cancer death in men worldwide [3,4]. As with other complex diseases, the genetic heritability of prostate cancer is caused by both rarely occurring but higher penetrant genetic variants and moderate to commonly occurring variants conferring lower risks. GWAS has identified over 170 low-penetrance prostate cancer susceptibility loci, including more than 1000 SNPs, predominantly in populations of mixed
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