Abstract 1646: Integrative analysis identifies functional prostate cancer risk SNPs in genomic regulatory regions defined as enhancers

Abstract

Abstract Prostate Cancer (PCa) genetic risk has recently been defined in numerous genome-wide association studies (GWASs), which have revealed more than 50 disease-associated single nucleotide polymorphs (SNP), known as tagSNPs, each at a different locus. More than 80% of these tagSNPs are in intergenic regions of the genome for which functionality remains unknown. Taking the 1000 genomes data into consideration, more than 10,000 correlated SNPs are revealed, which each define risk due to linkage disequilibrium (correlated to the tagSNP with an r2>0.5). The above therefore makes the identification of functional and/or causal SNPs not a trivial task. Therefore, we hypothesize that at least some of these SNPs affect non-coding genomic regulatory signatures, such as enhancers, insulators or repressors. In order to reduce the number of candidate functional SNPs, we developed an open-source (R/Bioconductor) package, called FunciSNP (Functional Integration of SNPs), which systematically integrates the 1000 genomes SNP data with chromatin features of interest. To define functionality in non-coding DNA associated with PCa risk we have utilized chromatin features generated by next-generation sequencing technologies, which capture regions genome-wide for which both open chromatin states and enhancers are likely. The open chromatin state (DnaseI, H3K9,14ac), enhancers (H3K4me1), and active/engaged enhancers (H3K27ac) were generated either by our lab, or harvested from the ENCODE project, or retrieved from recent publications. All chromatin features were identified in the same prostate cancer cell line (LNCaP). Thus, we have identified 113 PCa risk correlated SNPs at androgen receptor occupied regions (AROR), 1,545 at DNase1 sensitivity sites and 403 at histone modified regions [H3K4me1 (160 SNPs), H3K9,14 ac (121 SNPs), H3k27ac (122 SNPs)]; all features excluded transcription start sites of known annotated genes. Interestingly, the majority of the identified correlated SNPs (69%) are located in either chromosome 8 or 10. ARORs coinciding with DNase1 sites revealed four novel SNPs correlated with four GWAS tagSNPs. Of the four novel surrogate SNPs, two are located 4kb upstream from KLK3, one is located within the 3′ UTR of NKX3.1 and one is located within an intron of RUVBL1. DNase1 sites coinciding with any histone modification provided 17 novel SNPs correlated with 10 GWAS tagSNPs. Of the 17 novel SNPs, four are located in 8q24 genomic region and each are more than 100kb away from a known annotated gene. Each one of above-mentioned novel SNPs is assessed for effects on potential transcription factor response elements. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1646. doi:1538-7445.AM2012-1646