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Nat Commun. 2016 Sep 28;7:12983. doi: 10.1038/ncomms12983.

Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity.

Author information

1
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
2
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
3
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
4
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.
5
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive #04-01, Singapore 117597, Singapore.
6
Department of Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
7
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.
8
Department of Upper Gastrointestinal &Bariatric Surgery, Singapore General Hospital, Singapore 169608, Singapore.
9
Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
10
Department of General Surgery, Singapore General Hospital, Singapore 169608, Singapore.
11
Department of Medical Oncology, Yonsei University College of Medicine, Seoul 120-752, South Korea.
12
SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 168752, Singapore.
13
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
14
School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
15
Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.

Abstract

Regulatory enhancer elements in solid tumours remain poorly characterized. Here we apply micro-scale chromatin profiling to survey the distal enhancer landscape of primary gastric adenocarcinoma (GC), a leading cause of global cancer mortality. Integrating 110 epigenomic profiles from primary GCs, normal gastric tissues and cell lines, we highlight 36,973 predicted enhancers and 3,759 predicted super-enhancers respectively. Cell-line-defined super-enhancers can be subclassified by their somatic alteration status into somatic gain, loss and unaltered categories, each displaying distinct epigenetic, transcriptional and pathway enrichments. Somatic gain super-enhancers are associated with complex chromatin interaction profiles, expression patterns correlated with patient outcome and dense co-occupancy of the transcription factors CDX2 and HNF4α. Somatic super-enhancers are also enriched in genetic risk SNPs associated with cancer predisposition. Our results reveal a genome-wide reprogramming of the GC enhancer and super-enhancer landscape during tumorigenesis, contributing to dysregulated local and regional cancer gene expression.

Conflict of interest statement

W.F.O., S.L. and P.T are authors on patent applications entitled ‘Epigenomic Profiling of Primary Gastric Adenocarcinoma Reveals Super-Enhancer Heterogeneity', SG patent application no. 10201601141X (2016) and 10201606828P (2016). The remaining authors declare no competing financial interests.

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