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 Ng & 18 others Apinya Jusakul, Duane Smoot, Hassan Ashktorab, SunYoung 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

13 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

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Epigenomics
Stomach
Protein Isoforms
Adenocarcinoma
Genes
Stomach Neoplasms
Neoplasms
Carcinogens
T-Lymphocytes
Peptides
Chromatin
Immunity
Carcinogenesis

All Science Journal Classification (ASJC) codes

  • Oncology

Cite this

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 Discovery, 7(6), 630-651. https://doi.org/10.1158/2159-8290.CD-16-1022
Qamra, Aditi ; Xing, Manjie ; Padmanabhan, Nisha ; Kwok, Jeffrey Jun Ting ; Zhang, Shenli ; Xu, Chang ; Leong, Yan Shan ; Lim, Ai Ping Lee ; Tang, Qianqao ; Ooi, Wen Fong ; Lin, Joyce Suling ; Nandi, Tannistha ; Yao, Xiaosai ; Ong, Xuewen ; Lee, Minghui ; Tay, Su Ting ; Keng, Angie Tan Lay ; Santoso, Erna Gondo ; Ng, Cedric Chuan Young ; Ng, Alvin ; Jusakul, Apinya ; Smoot, Duane ; Ashktorab, Hassan ; Rha, SunYoung ; Yeoh, Khay Guan ; Yong, Wei Peng ; Chow, Pierce K.H. ; Chan, Weng Hoong ; Ong, Hock Soo ; Soo, Khee Chee ; Kim, Kyoung Mee ; Wong, Wai Keong ; Rozen, Steven G. ; Teh, Bin Tean ; Kappei, Dennis ; Lee, Jeeyun ; Connolly, John ; Tan, Patrick. / Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma. In: Cancer Discovery. 2017 ; Vol. 7, No. 6. pp. 630-651.
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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.",
author = "Aditi Qamra and Manjie Xing and Nisha Padmanabhan and Kwok, {Jeffrey Jun Ting} and Shenli Zhang and Chang Xu and Leong, {Yan Shan} and Lim, {Ai Ping Lee} and Qianqao Tang and Ooi, {Wen Fong} and Lin, {Joyce Suling} and Tannistha Nandi and Xiaosai Yao and Xuewen Ong and Minghui Lee and Tay, {Su Ting} and Keng, {Angie Tan Lay} and Santoso, {Erna Gondo} and Ng, {Cedric Chuan Young} and Alvin Ng and Apinya Jusakul and Duane Smoot and Hassan Ashktorab and SunYoung Rha and Yeoh, {Khay Guan} and Yong, {Wei Peng} and Chow, {Pierce K.H.} and Chan, {Weng Hoong} and Ong, {Hock Soo} and Soo, {Khee Chee} and Kim, {Kyoung Mee} and Wong, {Wai Keong} and Rozen, {Steven G.} and Teh, {Bin Tean} and Dennis Kappei and Jeeyun Lee and John Connolly and Patrick Tan",
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Qamra, A, Xing, M, Padmanabhan, N, Kwok, JJT, Zhang, S, Xu, C, Leong, YS, Lim, APL, Tang, Q, Ooi, WF, Lin, JS, Nandi, T, Yao, X, Ong, X, Lee, M, Tay, ST, Keng, ATL, Santoso, EG, Ng, CCY, Ng, A, Jusakul, A, Smoot, D, Ashktorab, H, Rha, S, Yeoh, KG, Yong, WP, Chow, PKH, Chan, WH, Ong, HS, Soo, KC, Kim, KM, Wong, WK, Rozen, SG, Teh, BT, Kappei, D, Lee, J, Connolly, J & Tan, P 2017, 'Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma', Cancer Discovery, vol. 7, no. 6, pp. 630-651. https://doi.org/10.1158/2159-8290.CD-16-1022

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

In: Cancer Discovery, Vol. 7, No. 6, 01.01.2017, p. 630-651.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Epigenomic promoter alterations amplify gene isoform and immunogenic diversity in gastric adenocarcinoma

AU - Qamra, Aditi

AU - Xing, Manjie

AU - Padmanabhan, Nisha

AU - Kwok, Jeffrey Jun Ting

AU - Zhang, Shenli

AU - Xu, Chang

AU - Leong, Yan Shan

AU - Lim, Ai Ping Lee

AU - Tang, Qianqao

AU - Ooi, Wen Fong

AU - Lin, Joyce Suling

AU - Nandi, Tannistha

AU - Yao, Xiaosai

AU - Ong, Xuewen

AU - Lee, Minghui

AU - Tay, Su Ting

AU - Keng, Angie Tan Lay

AU - Santoso, Erna Gondo

AU - Ng, Cedric Chuan Young

AU - Ng, Alvin

AU - Jusakul, Apinya

AU - Smoot, Duane

AU - Ashktorab, Hassan

AU - Rha, SunYoung

AU - Yeoh, Khay Guan

AU - Yong, Wei Peng

AU - Chow, Pierce K.H.

AU - Chan, Weng Hoong

AU - Ong, Hock Soo

AU - Soo, Khee Chee

AU - Kim, Kyoung Mee

AU - Wong, Wai Keong

AU - Rozen, Steven G.

AU - Teh, Bin Tean

AU - Kappei, Dennis

AU - Lee, Jeeyun

AU - Connolly, John

AU - Tan, Patrick

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

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