Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma.
Promoter elements play important roles in isoform and cell type-specific expression. We surveyed the epigenomic promoter landscape of gastric adenocarcinoma, analyzing 110 chromatin profiles (H3K4me3, H3K4me1, H3K27ac) of primary gastric cancers, gastric cancer lines, and nonmalignant gastric tissues. We identified nearly 2,000 promoter alterations (somatic promoters), many deregulated in various epithelial malignancies and mapping frequently to alternative promoters within the same gene, generating potential pro-oncogenic isoforms (RASA3). Somatic promoter-associated N-terminal peptides displaying relative depletion in tumors exhibited high-affinity MHC binding predictions and elicited potent T-cell responsesin vitro, suggesting a mechanism for reducing tumor antigenicity. In multiple patient cohorts, gastric cancers with high somatic promoter usage also displayed reduced T-cell cytolytic marker expression. Somatic promoters are enriched in PRC2 occupancy, display sensitivity to EZH2 therapeutic inhibition, and are associated with novel cancer-associated transcripts. By generating tumor-specific isoforms and decreasing tumor antigenicity, epigenomic promoter alterations may thus drive intrinsic tumorigenesis and also allow nascent cancers to evade host immunity.Significance:We apply epigenomic profiling to demarcate the promoter landscape of gastric cancer. Many tumor-specific promoters activate different promoters in the same gene, some generating pro-oncogenic isoforms. Tumor-specific promoters also reduce tumor antigenicity by causing relative depletion of immunogenic peptides, contributing to cancer immunoediting and allowing tumors to evade host immune attack.Cancer Discov; 7(6); 630-51. ©2017 AACR.This article is highlighted in the In This Issue feature, p. 539.
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.|Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Aditi
A
Qamra
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
Manjie
M
Xing
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Nisha
N
Padmanabhan
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
Jeffrey Jun Ting
JJT
Kwok
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Shenli
S
Zhang
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Chang
C
Xu
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Yan Shan
YS
Leong
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
Ai Ping
AP
Lee Lim
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore.
Qianqao
Q
Tang
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
Wen Fong
WF
Ooi
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
Joyce
J
Suling Lin
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
Tannistha
T
Nandi
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
Xiaosai
X
Yao
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Xuewen
X
Ong
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Minghui
M
Lee
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Su Ting
ST
Tay
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Angie Tan Lay
ATL
Keng
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore.
Erna
E
Gondo Santoso
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore.
Cedric Chuan Young
CCY
Ng
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.|NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
Alvin
A
Ng
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
Apinya
A
Jusakul
Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee.
Duane
D
Smoot
Department of Medicine, Howard University, Washington, DC.
Hassan
H
Ashktorab
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
Sun Young
SY
Rha
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.|Department of Gastroenterology & Hepatology, National University Hospital, Singapore.
Khay Guan
KG
Yeoh
Department of Haematology-Oncology, National University Hospital of Singapore, Singapore.
Wei
W
Peng Yong
Department of General Surgery, Singapore General Hospital, Singapore.|Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.
Pierce K H
PKH
Chow
Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, Singapore.
Weng Hoong
WH
Chan
Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, Singapore.
Hock Soo
HS
Ong
Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.
Khee Chee
KC
Soo
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Kyoung-Mee
KM
Kim
Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, Singapore.
Wai Keong
WK
Wong
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.|SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.
Steven G
SG
Rozen
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore.|SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.
Bin Tean
BT
Teh
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Dennis
D
Kappei
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
Jeeyun
J
Lee
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.|Institute of Biomedical Studies, Baylor University, Waco, Texas.
John
J
Connolly
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore. gmstanp@duke-nus.edu.sg.|Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.|Cancer Science Institute of Singapore, National University of Singapore, Singapore.|SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.|Cellular and Molecular Research, National Cancer Centre, Singapore.
Patrick
P
Tan
D000230:Adenocarcinoma / Q000235:genetics*; D045744:Cell Line, Tumor; D057890:Epigenomics; D006801:Humans; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics*