Genome-wide association studies have identified more than 100 common single nucleotide polymorphisms (SNPs) that are associated with prostate cancer risk. However, the vast majority of these SNPs lie in noncoding regions of the genome. To test whether these risk SNPs regulate their target genes through long-range chromatin interactions, we applied capture-based 3C sequencing technology to investigate possible cis-interactions at ten prostate cancer risk loci in six cell lines. We identified significant physical interactions between risk regions and their potential target genes including CAPG at 2p11.2, C2orf43 at 2p24.1, RFX6 at 6q22.1, NFASC at 1q32.1, MYC at 8q24.1 and AGAP7P at 10q11.23. Most of the interaction peaks were co-localized to regions of active histone modification and transcription factor binding sites. Expression quantitative trait locus (eQTL) analysis showed suggestive eQTL signals at rs1446669, rs699664 and rs1078004 for CAPG (p < 0.004), rs13394027 for C2orf43 (p = 2.25E-27), rs10993994 and rs4631830 for AGAP7P (p < 8.02E-5). Further analysis revealed an enhancer activity at genomic region surrounding rs4631830 which was expected to disrupt HOXB-like DNA binding affinity. This study identifies a set of candidate genes and their potential regulatory variants, and provides additional evidence showing the role of long-range chromatin interactions in prostate cancer etiology.
Scientific reports. 2016 Jan 16*** epublish ***
Meijun Du, Lori Tillmans, Jianzhong Gao, Ping Gao, Tiezheng Yuan, Rachel L Dittmar, Wei Song, Yuehong Yang, Natasha Sahr, Tao Wang, Gong-Hong Wei, Stephen N Thibodeau, Liang Wang
Department of Pathology, MCW Cancer Center, Medical College of Wisconsin, Milwaukee, 53226, WI, USA., Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, 55905, MN, USA., Beijing 3H Medical Technology Co. Ltd., Beijing, 100176, China., Faculty of Biochemistry and Molecular Medicine and Biocenter Oulu, University of Oulu, Oulu, Finland., Division of Biostatistics, Institute for Health &Society, Medical College of Wisconsin, Milwaukee, 53226, WI, USA.