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

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

Author information

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

PMID:
28634199
PMCID:
PMC5762429
DOI:
10.1136/gutjnl-2016-313146
[Indexed for MEDLINE]
Free PMC Article

Conflict of interest statement

Competing interests: None declared.

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