Literature DB >> 28634199

Characterising cis-regulatory variation in the transcriptome of histologically normal and tumour-derived pancreatic tissues.

Mingfeng Zhang1, Soren Lykke-Andersen2, Bin Zhu3,6, Wenming Xiao5, Jason W Hoskins1, Xijun Zhang3,6, Lauren M Rost1, Irene Collins1, Martijn van de Bunt7,8, Jinping Jia1, Hemang Parikh1,9, Tongwu Zhang1, Lei Song4, Ashley Jermusyk1, Charles C Chung3,6, Bin Zhu3,6, Weiyin Zhou3,6, Gail L Matters10, Robert C Kurtz11, Meredith Yeager3,6, Torben Heick Jensen2, Kevin M Brown1, Halit Ongen12, William R Bamlet13, Bradley A Murray14, Mark I McCarthy7,8,15, Stephen J Chanock3, Nilanjan Chatterjee4,16, Brian M Wolpin17, Jill P Smith18, Sara H Olson19, Gloria M Petersen13, Jianxin Shi4, Laufey Amundadottir1.   

Abstract

OBJECTIVE: To elucidate the genetic architecture of gene expression in pancreatic tissues.
DESIGN: We performed expression quantitative trait locus (eQTL) analysis in histologically normal pancreatic tissue samples (n=95) using RNA sequencing and the corresponding 1000 genomes imputed germline genotypes. Data from pancreatic tumour-derived tissue samples (n=115) from The Cancer Genome Atlas were included for comparison.
RESULTS: We identified 38 615 cis-eQTLs (in 484 genes) in histologically normal tissues and 39 713 cis-eQTL (in 237 genes) in tumour-derived tissues (false discovery rate <0.1), with the strongest effects seen near transcriptional start sites. Approximately 23% and 42% of genes with significant cis-eQTLs appeared to be specific for tumour-derived and normal-derived tissues, respectively. Significant enrichment of cis-eQTL variants was noted in non-coding regulatory regions, in particular for pancreatic tissues (1.53-fold to 3.12-fold, p≤0.0001), indicating tissue-specific functional relevance. A common pancreatic cancer risk locus on 9q34.2 (rs687289) was associated with ABO expression in histologically normal (p=5.8×10-8) and tumour-derived (p=8.3×10-5) tissues. The high linkage disequilibrium between this variant and the O blood group generating deletion variant in ABO (exon 6) suggested that nonsense-mediated decay (NMD) of the 'O' mRNA might explain this finding. However, knockdown 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 data set for further studies on gene expression and its regulation in pancreatic tissues. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

Entities:  

Keywords:  RNA-seq; allele specific expression.; eQTL; gene expression; pancreas

Mesh:

Substances:

Year:  2017        PMID: 28634199      PMCID: PMC5762429          DOI: 10.1136/gutjnl-2016-313146

Source DB:  PubMed          Journal:  Gut        ISSN: 0017-5749            Impact factor:   23.059


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