Abstract 1442: Analysis of cis-eQTLs in normal and tumor-derived pancreatic tissues reveals functional insights, including for the 9q34.1 ABO pancreatic cancer risk locus
Authors: Amundadottir Laufey T. , Andresen Soren Lykke , Xiao Wenming , Hoskins Jason , Jermusyk Ashley , Rost Lauren , Collins Irene , Jia Jinping , Mobaraki Michael , Zhu Bin , Kurtz Robert , Parikh Hemang , Song Lei , Yeager Meredith , Jensen Torben , Bamlet William , Chatterjee Nilanjan , Wolpin Brian , Smith Jill , Olson Sara , Petersen Gloria , Shi Jianxin , Zhang Mingfeng 
Published: July 2017

Abstract
Objective: To elucidate the genetic architecture of gene expression in pancreatic tissues.
Design: We performed expression quantitative trait locus (eQTL) and allele specific expression (ASE) analyses using RNA-sequence data and 1000 Genomes (1000G) imputed GWAS genotypes from 95 fresh frozen histologically normal pancreatic tissue samples. Data from 115 pancreatic tumor-derived tissue samples from The Cancer Genome Atlas (TCGA) was included for comparison.
Results: We identified 38,615 cis-eQTLs (corresponding to 484 Genes) in histologically normal tissues and 39,713 cis-eQTL (corresponding to 237 Genes) in tumor tissues (FDR&lt;0.1), with the strongest effects seen near transcriptional start sites (TSS). Approximately 23% and 42% of genes with significant cis-eQTLs (eGenes) appeared to be specific for tumor and normal derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in noncoding regulatory regions marked by modified histones, DNAse hypersensitivity and bound transcription factors, in particular for pancreatic tissues (1.53-3.12 fold, P≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 in the ABO gene (rs687289) was associated with ABO expression in histologically normal (P=5.8x10-8) and tumor-derived (P=8.3x10-5) pancreatic tissues. The high linkage disequilibrium (LD) between this variant and the O blood group generating deletion variant in exon 6 of ABO suggested that nonsense-mediated decay (NMD) of the “O” mRNA could explain the eQTL. However, knock-down of crucial NMD regulators did not influence decay of the ABO “O” mRNA, indicating that a gene regulatory element influenced by pancreatic cancer risk alleles may underlie the eQTL.
Conclusions: We have identified cis-eQTLs representing potential functional regulatory variants in the pancreas and generated a rich dataset for further studies on gene expression and regulation in pancreatic tissues.
Citation Format: Laufey T. Amundadottir, Soren Lykke Andresen, Wenming Xiao, Jason Hoskins, Ashley Jermusyk, Lauren Rost, Irene Collins, Jinping Jia, Michael Mobaraki, Bin Zhu, Robert Kurtz, Hemang Parikh, Lei Song, Meredith Yeager, Torben Jensen, William Bamlet, Nilanjan Chatterjee, Brian Wolpin, Jill Smith, Sara Olson, Gloria Petersen, Jianxin Shi, Mingfeng Zhang. Analysis of cis-eQTLs in normal and tumor-derived pancreatic tissues reveals functional insights, including for the 9q34.1 ABO pancreatic cancer risk locus [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1442. doi:10.1158/1538-7445.AM2017-1442