Abstract
Prostate cancer (PCa) is the second most common solid tumor for cancer related deaths in American men. Genome wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with the increased risk of PCa. Because most of the susceptibility SNPs are located in noncoding regions, little is known about their functional mechanisms. We hypothesize that functional SNPs reside in cell type-specific regulatory elements that mediate the binding of critical transcription factors (TFs), which in turn result in changes in target gene expression. Using PCa-specific functional genomics data, here we identify 38 regulatory candidate SNPs and their target genes in PCa. Through risk analysis by incorporating gene expression and clinical data, we identify 6 target genes (ZG16B, ANKRD5, RERE, FAM96B, NAALADL2 and GTPBP10) as significant predictors of PCa biochemical recurrence. In addition, 5 SNPs (rs2659051, rs10936845, rs9925556, rs6057110 and rs2742624) are selected for experimental validation using Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay in LNCaP cells, showing allele-specific enhancer activity. Furthermore, we delete the rs2742624-containing region using CRISPR/Cas9 genome editing and observe the drastic downregulation of its target gene UPK3A. Taken together, our results illustrate that this new methodology can be applied to identify regulatory SNPs and their target genes that likely impact PCa risk. We suggest that similar studies can be performed to characterize regulatory variants in other diseases.
Highlights
Prostate cancer (PCa) is the second most common cause of cancer deaths in American men [1]
Through overlapping with genomic positions of single nucleotide polymorphisms (SNPs) in Affymetrix Genome-Wide SNP Array 6.0 platform used in The Cancer Genome Atlas (TCGA) PCa project, we found that 7,197 SNPs are located in these PCa-specific regulatory regions
The data from the ENCODE consortium estimated that about 47% of the distal regulatory elements have interactions with the nearest expressed transcription start site (TSS) [37]. These analyses suggested that examining the nearby genes within ± 25 kb of SNPs may produce a relatively short but reasonable list of genes potentially regulated by eQTLs within PCa-specific enhancers
Summary
Prostate cancer (PCa) is the second most common cause of cancer deaths in American men [1]. Single nucleotide polymorphisms (SNPs) are known to underlie differences in our susceptibility to diseases, and it has attracted tremendous interest as potential biomarkers for PCa diagnostics and risk prediction in recent years. Common genetic variants in more than 70 genomic loci have been clearly associated to PCa by recent genome-wide association studies (GWAS), explaining approximately 30% of the familial risk for this disease [2]. Recent understanding of the control of gene expression have emerged as a key tool for connecting DNA sequence variation to phenotypes [3]. It is clear that regulatory variants can influence the individual steps of gene expression including transcription factor binding [4, 5], chromatin accessibility [6], histone modification [7], DNA methylation [8,9,10], alternative splicing [11] and so on
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