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Cancer Discov. 2017 Jun;7(6):630-651. doi: 10.1158/2159-8290.CD-16-1022. Epub 2017 Mar 20.

Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma.

Author information

1
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore.
2
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
3
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, Singapore.
4
NUS Graduate School for Integrative Sciences and Engineering, National University of Singapore, Singapore.
5
Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore.
6
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
7
Laboratory of Cancer Epigenome, Department of Medical Sciences, National Cancer Centre, Singapore.
8
Department of Internal Medicine, Meharry Medical College, Nashville, Tennessee.
9
Department of Medicine, Howard University, Washington, DC.
10
Department of Internal Medicine, Yonsei University College of Medicine, Seoul, South Korea.
11
Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore and National University Health System, Singapore.
12
Department of Gastroenterology & Hepatology, National University Hospital, Singapore.
13
Department of Haematology-Oncology, National University Hospital of Singapore, Singapore.
14
Department of General Surgery, Singapore General Hospital, Singapore.
15
Division of Surgical Oncology, National Cancer Centre Singapore, Singapore.
16
Department of Upper Gastrointestinal & Bariatric Surgery, Singapore General Hospital, Singapore.
17
Department of Pathology & Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
18
SingHealth/Duke-NUS Institute of Precision Medicine, National Heart Centre Singapore, Singapore.
19
Department of Medicine, Division of Hematology-Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
20
Institute of Biomedical Studies, Baylor University, Waco, Texas.
21
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, Singapore. gmstanp@duke-nus.edu.sg.
22
Cellular and Molecular Research, National Cancer Centre, Singapore.

Abstract

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 responses in 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.

PMID:
28320776
DOI:
10.1158/2159-8290.CD-16-1022
[Indexed for MEDLINE]
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