| Literature DB >> 28172817 |
Jason W Hoskins1, Abdisamad Ibrahim1, Mickey A Emmanuel1, Sarah M Manmiller1, Yinglun Wu1, Maura O'Neill2, Jinping Jia1, Irene Collins1, Mingfeng Zhang1, Janelle V Thomas1, Lauren M Rost1, Sudipto Das2, Hemang Parikh1,3, Jefferson M Haake4, Gail L Matters5, Robert C Kurtz6, William R Bamlet7, Alison Klein8,9, Rachael Stolzenberg-Solomon10, Brian M Wolpin11, Ronit Yarden4, Zhaoming Wang10,12, Jill Smith13, Sara H Olson3, Thorkell Andresson2, Gloria M Petersen7, Laufey T Amundadottir1.
Abstract
Genome-wide association studies (GWAS) have identified multiple common susceptibility loci for pancreatic cancer. Here we report fine-mapping and functional analysis of one such locus residing in a 610 kb gene desert on chr13q22.1 (marked by rs9543325). The closest candidate genes, KLF5, KLF12, PIBF1, DIS3 and BORA, range in distance from 265-586 kb. Sequencing three sub-regions containing the top ranked SNPs by imputation P-value revealed a 30 bp insertion/deletion (indel) variant that was significantly associated with pancreatic cancer risk (rs386772267, P = 2.30 × 10-11, OR = 1.22, 95% CI 1.15-1.28) and highly correlated to rs9543325 (r2 = 0.97 in the 1000 Genomes EUR population). This indel was the most significant cis-eQTL variant in a set of 222 histologically normal pancreatic tissue samples (β = 0.26, P = 0.004), with the insertion (risk-increasing) allele associated with reduced DIS3 expression. DIS3 encodes a catalytic subunit of the nuclear RNA exosome complex that mediates RNA processing and decay, and is mutated in several cancers. Chromosome conformation capture revealed a long range (570 kb) physical interaction between a sub-region of the risk locus, containing rs386772267, and a region ∼6 kb upstream of DIS3 Finally, repressor regulatory activity and allele-specific protein binding by transcription factors of the TCF/LEF family were observed for the risk-increasing allele of rs386772267, indicating that expression regulation at this risk locus may be influenced by the Wnt signaling pathway. In conclusion, we have identified a putative functional indel variant at chr13q22.1 that associates with decreased DIS3 expression in carriers of pancreatic cancer risk-increasing alleles, and could therefore affect nuclear RNA processing and/or decay. Published by Oxford University Press 2016. This work is written by US Government employees and is in the public domain in the US.Entities:
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Year: 2016 PMID： 28172817 PMCID： PMC5815622 DOI： 10.1093/hmg/ddw300
Source DB: PubMed Journal: Hum Mol Genet ISSN： 0964-6906 Impact factor: 6.150