Epigenomic profiling of primary gastric adenocarcinoma reveals super-enhancer heterogeneity.
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.
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Wen Fong
WF
Ooi
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, 5 Lower Kent Ridge Road, Singapore 119074, Singapore.
Manjie
M
Xing
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.
Chang
C
Xu
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Xiaosai
X
Yao
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Muhammad Khairul
MK
Ramlee
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.
Mei Chee
MC
Lim
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.
Fan
F
Cao
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Kevin
K
Lim
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.
Deepak
D
Babu
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Lai-Fong
LF
Poon
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Joyce
J
Lin Suling
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive #04-01, Singapore 117597, Singapore.
Aditi
A
Qamra
Department of Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Astrid
A
Irwanto
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
James
J
Qu Zhengzhong
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Tannistha
T
Nandi
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Ai Ping
AP
Lee-Lim
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Yang Sun
YS
Chan
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Su Ting
ST
Tay
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Ming Hui
MH
Lee
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.
James O J
JO
Davies
Department of Upper Gastrointestinal &Bariatric Surgery, Singapore General Hospital, Singapore 169608, Singapore.
Wai Keong
WK
Wong
Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.
Khee Chee
KC
Soo
Department of Upper Gastrointestinal &Bariatric Surgery, Singapore General Hospital, Singapore 169608, Singapore.
Weng Hoong
WH
Chan
Department of Upper Gastrointestinal &Bariatric Surgery, Singapore General Hospital, Singapore 169608, Singapore.
Hock Soo
HS
Ong
Division of Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Drive, Singapore 169610, Singapore.|Department of General Surgery, Singapore General Hospital, Singapore 169608, Singapore.
Pierce
P
Chow
Department of General Surgery, Singapore General Hospital, Singapore 169608, Singapore.
Chow Yin
CY
Wong
Department of Medical Oncology, Yonsei University College of Medicine, Seoul 120-752, South Korea.
Sun Young
SY
Rha
Department of Human Genetics, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Jianjun
J
Liu
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.
Axel M
http://orcid.org/0000-0002-3381-7266
AM
Hillmer
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford OX3 9DS, UK.
Jim R
http://orcid.org/0000-0002-8955-7256
JR
Hughes
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.|SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 168752, Singapore.
Steve
http://orcid.org/0000-0002-4288-0056
S
Rozen
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.|SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 168752, Singapore.|Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
Bin Tean
BT
Teh
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.|School of Biological Sciences, Nanyang Technological University, Singapore 637551, Singapore.
Melissa Jane
MJ
Fullwood
Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.
Shang
S
Li
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Genome #02-01, Singapore 138672, Singapore.|Cancer and Stem Cell Biology Program, Duke-NUS Graduate Medical School, 8 College Road, Singapore 169857, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, #12-01, Singapore 117599, Singapore.|SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore 168752, Singapore.|Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore 169610, Singapore.
Patrick
P
Tan
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