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

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

Dokumenter

DOI

  • Mingfeng Zhang, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Soren Lykke-Andersen
  • Bin Zhu, Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
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  • Wenming Xiao, Division of Bioinformatics and Biostatistics, National Center for Toxicological Research, FDA, Jefferson, Missouri, USA.
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  • Jason W Hoskins, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Xijun Zhang, Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
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  • Lauren M Rost, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Irene Collins, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Martijn van de Bunt, Oxford Centre for Diabetes, Endocrinology and Metabolism, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
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  • Jinping Jia, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Hemang Parikh, University of South Florida
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  • Tongwu Zhang, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Lei Song, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Ashley Jermusyk, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Charles C Chung, Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
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  • Bin Zhu, Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
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  • Weiyin Zhou, Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
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  • Gail L Matters, Pennsylvania State University
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  • Robert C Kurtz, Memorial Sloan-Kettering Cancer Center
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  • Meredith Yeager, Cancer Genomics Research Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, USA.
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  • Torben Heick Jensen
  • Kevin M Brown, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Halit Ongen, University of Geneva
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  • William R Bamlet, Mayo Clinic Rochester, MN
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  • Bradley A Murray, The Eli and Edythe L Broad Institute of Massachusetts Institute of Technology and Harvard University Cambridge, Cambridge, Massachusetts, USA.
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  • Mark I. McCarthy, Oxford NIHR Biomedical Research Centre, Churchill Hospital, Headington, Oxford, UK.
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  • Stephen J Chanock, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Nilanjan Chatterjee, Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA.
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  • Brian M Wolpin, 1] Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA [2] Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02215, USA.
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  • Jill P Smith, Georgetown University
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  • Sara H Olson, Memorial Sloan-Kettering Cancer Center
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  • Gloria M Petersen, Mayo Clinic Rochester, MN
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  • Jianxin Shi, Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.
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  • Laufey Amundadottir, Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland, USA.

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 â '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.

OriginalsprogEngelsk
TidsskriftGut
Vol/bind67
Nummer3
Sider (fra-til)521-533
Antal sider13
ISSN0017-5749
DOI
StatusUdgivet - 1 mar. 2018

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