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

Publication ,  Journal Article
Qamra, A; Xing, M; Padmanabhan, N; Kwok, JJT; Zhang, S; Xu, C; Leong, YS; Lee Lim, AP; Tang, Q; Ooi, WF; Suling Lin, J; Nandi, T; Yao, X ...
Published in: Cancer Discov
June 2017

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.

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Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

June 2017

Volume

7

Issue

6

Start / End Page

630 / 651

Location

United States

Related Subject Headings

  • Stomach Neoplasms
  • Promoter Regions, Genetic
  • Humans
  • Epigenomics
  • Cell Line, Tumor
  • Adenocarcinoma
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis
 

Citation

APA
Chicago
ICMJE
MLA
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Qamra, A., Xing, M., Padmanabhan, N., Kwok, J. J. T., Zhang, S., Xu, C., … Tan, P. (2017). Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma. Cancer Discov, 7(6), 630–651. https://doi.org/10.1158/2159-8290.CD-16-1022
Qamra, Aditi, Manjie Xing, Nisha Padmanabhan, Jeffrey Jun Ting Kwok, Shenli Zhang, Chang Xu, Yan Shan Leong, et al. “Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma.Cancer Discov 7, no. 6 (June 2017): 630–51. https://doi.org/10.1158/2159-8290.CD-16-1022.
Qamra A, Xing M, Padmanabhan N, Kwok JJT, Zhang S, Xu C, et al. Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma. Cancer Discov. 2017 Jun;7(6):630–51.
Qamra, Aditi, et al. “Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma.Cancer Discov, vol. 7, no. 6, June 2017, pp. 630–51. Pubmed, doi:10.1158/2159-8290.CD-16-1022.
Qamra A, Xing M, Padmanabhan N, Kwok JJT, Zhang S, Xu C, Leong YS, Lee Lim AP, Tang Q, Ooi WF, Suling Lin J, Nandi T, Yao X, Ong X, Lee M, Tay ST, Keng ATL, Gondo Santoso E, Ng CCY, Ng A, Jusakul A, Smoot D, Ashktorab H, Rha SY, Yeoh KG, Peng Yong W, Chow PKH, Chan WH, Ong HS, Soo KC, Kim K-M, Wong WK, Rozen SG, Teh BT, Kappei D, Lee J, Connolly J, Tan P. Epigenomic Promoter Alterations Amplify Gene Isoform and Immunogenic Diversity in Gastric Adenocarcinoma. Cancer Discov. 2017 Jun;7(6):630–651.

Published In

Cancer Discov

DOI

EISSN

2159-8290

Publication Date

June 2017

Volume

7

Issue

6

Start / End Page

630 / 651

Location

United States

Related Subject Headings

  • Stomach Neoplasms
  • Promoter Regions, Genetic
  • Humans
  • Epigenomics
  • Cell Line, Tumor
  • Adenocarcinoma
  • 3211 Oncology and carcinogenesis
  • 3101 Biochemistry and cell biology
  • 1112 Oncology and Carcinogenesis