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

Mingfeng Zhang; Soren Lykke-Andersen; Bin Zhu; Wenming Xiao; Jason W Hoskins; Xijun Zhang; Lauren M Rost; Irene Collins; Martijn van de Bunt; Jinping Jia; Hemang Parikh; Tongwu Zhang; Lei Song; Ashley Jermusyk; Charles C Chung; Bin Zhu; Weiyin Zhou; Gail L Matters; Robert C Kurtz; Meredith Yeager; Torben Heick Jensen; Kevin M Brown; Halit Ongen; William R Bamlet; Bradley A Murray; Mark I McCarthy; Stephen J Chanock; Nilanjan Chatterjee; Brian M Wolpin; Jill P Smith; Sara H Olson; Gloria M Petersen; Jianxin Shi; Laufey Amundadottir

doi:10.1136/gutjnl-2016-313146

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

Gut. 2018 Mar;67(3):521-533. doi: 10.1136/gutjnl-2016-313146. Epub 2017 Jun 20.

Authors

Mingfeng Zhang¹, Soren Lykke-Andersen², Bin Zhu^{3

4}, Wenming Xiao⁵, Jason W Hoskins¹, Xijun Zhang^{3

6}, Lauren M Rost¹, Irene Collins¹, Martijn van de Bunt^{7

8}, Jinping Jia¹, Hemang Parikh^{1

9}, Tongwu Zhang¹, Lei Song⁴, Ashley Jermusyk¹, Charles C Chung^{3

6}, Bin Zhu^{3

6}, Weiyin Zhou^{3

6}, Gail L Matters¹⁰, Robert C Kurtz¹¹, Meredith Yeager^{3

6}, Torben Heick Jensen², Kevin M Brown¹, Halit Ongen¹², William R Bamlet¹³, Bradley A Murray¹⁴, Mark I McCarthy^{7

8

15}, Stephen J Chanock³, Nilanjan Chatterjee^{4

16}, Brian M Wolpin¹⁷, Jill P Smith¹⁸, Sara H Olson¹⁹, Gloria M Petersen¹³, Jianxin Shi⁴, Laufey Amundadottir¹

Affiliations

¹ Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
² Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark.
³ Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
⁴ Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
⁵ Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, FDA, Jefferson, Missouri, USA.
⁶ Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
⁷ Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
⁸ Oxford Centre for Diabetes, Endocrinology & Metabolism, University of Oxford, Oxford, UK.
⁹ Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida, USA.
¹⁰ Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA.
¹¹ Department of Medicine, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.
¹² Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
¹³ Department of Health Sciences Research, Division of Epidemiology, Mayo Clinic, Rochester, Minnesota, USA.
¹⁴ The Eli and Edythe L Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Cambridge, Massachusetts, USA.
¹⁵ Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.
¹⁶ Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
¹⁷ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
¹⁸ Division of Gastroenterology and Hepatology, Georgetown University Hospital, Washington, D.C., USA.
¹⁹ Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York City, New York, USA.

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.

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

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

ABO Blood-Group System / genetics*
Alleles
Chromosomes, Human, Pair 9
Gene Expression*
Genome-Wide Association Study
Genotype
Humans
Nonsense Mediated mRNA Decay
Pancreas*
Pancreatic Neoplasms / genetics*
Polymorphism, Single Nucleotide
Quantitative Trait Loci*
RNA, Neoplasm / analysis*
Regulatory Sequences, Nucleic Acid
Sequence Analysis, RNA
Transcriptome*

Substances

ABO Blood-Group System
RNA, Neoplasm

Abstract

Publication types

MeSH terms

Substances

Grants and funding