Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma

Aditi Qamra, Manjie Xing, Nisha Padmanabhan, Jeffrey Jun Ting Kwok, Shenli Zhang, Chang Xu, Yan Shan Leong, Ai Ping Lee Lim, Qianqao Tang, Wen Fong Ooi, Joyce Suling Lin, Tannistha Nandi, Xiaosai Yao, Xuewen Ong, Minghui Lee, Su Ting Tay, Angie Tan Lay Keng, Erna Gondo Santoso, Cedric Chuan Young Ng, Alvin NgApinya Jusakul, Duane Smoot, Hassan Ashktorab, Sun Young Rha, Khay Guan Yeoh, Wei Peng Yong, Pierce K.H. Chow, Weng Hoong Chan, Hock Soo Ong, Khee Chee Soo, Kyoung Mee Kim, Wai Keong Wong, Steven G. Rozen, Bin Tean Teh, Dennis Kappei, Jeeyun Lee, John Connolly, Patrick Tan

Research output: Contribution to journalArticle

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)630-651
Number of pages22
JournalCancer Discovery
Volume7
Issue number6
DOIs
Publication statusPublished - 2017 Jan 1

All Science Journal Classification (ASJC) codes

  • Oncology

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    Qamra, A., Xing, M., Padmanabhan, N., Kwok, J. J. T., Zhang, S., Xu, C., Leong, Y. S., Lim, A. P. L., Tang, Q., Ooi, W. F., Lin, J. S., Nandi, T., Yao, X., Ong, X., Lee, M., Tay, S. T., Keng, A. T. L., Santoso, E. G., Ng, C. C. Y., ... Tan, P. (2017). Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma. Cancer Discovery, 7(6), 630-651. https://doi.org/10.1158/2159-8290.CD-16-1022