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Thirty years of Epstein-Barr virus-associated gastric carcinoma

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Abstract

Thirty years have passed since a possible association of Epstein-Barr virus (EBV) with gastric carcinoma was reported. We now know EBV-associated gastric carcinoma to be a specific subtype of gastric carcinoma. Global epigenetic methylation and counteraction of the antitumour microenvironment are two major characteristics of this subtype of gastric carcinoma. Recent development of therapeutic modalities for gastric carcinoma, such as endoscopic mucosal dissection and immune checkpoint inhibitor therapy, has made the presence of EBV infection a biomarker for the treatment of gastric carcinoma. This review presents a portrait of EBV-associated gastric carcinoma from initiation to maturity that we define as the ‘gastritis-infection-cancer sequence’, followed by its molecular abnormalities and interactions with immune checkpoint molecules and the microenvironment. EBV non-coding RNAs (microRNA and circular RNA) and exosomes derived from EBV-infected cells that were previously behind the scenes are now recognized for their roles in EBV-associated gastric carcinoma. The virus utilizes cellular machinery skilfully to control infected cells and their microenvironment. We should thus strive to understand virus-host interactions more fully in the following years to overcome this virus-driven subtype of gastric carcinoma.

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Acknowledgements

We thank Gillian Campbell, PhD, from Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. We appreciate Mr. Francesco De Logu (University of Florence) for the beautiful and informative redrawing of Fig. 2.

Funding

This work was supported by Grants-in-Aid for Scientific Research (KAKENHI) from the Japan Society for the Promotion of Science (26253021 to M.F., 26860232 and 16 K19074 to H.A.) and from the Core Research for Evolutionary Science and Technology program from the Japan Science and Technology Agency to A.K. and M.F.

Author information

Author notes

  1. Masashi Fukayama

    Present address: Digital Pathology Centre, Asahi General Hospital, I-1326, Asahi City, Chiba, 289-2511, Japan

Authors and Affiliations

  1. Department of Pathology, Graduate School of Medicine, University of Tokyo, Hongo 7-3-1, Tokyo, 113-0033, Japan

    Masashi Fukayama, Hiroyuki Abe, Akiko Kunita, Aya Shinozaki-Ushiku & Tetsuo Ushiku

  2. Department of Pathology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Keisuke Matsusaka

  3. Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

    Keisuke Matsusaka & Atsushi Kaneda

Authors
  1. Masashi Fukayama
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  2. Hiroyuki Abe
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  3. Akiko Kunita
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  4. Aya Shinozaki-Ushiku
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  5. Keisuke Matsusaka
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  6. Tetsuo Ushiku
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  7. Atsushi Kaneda
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Contributions

All authors (MF, HA, AKu, AS-U, KM, TU and AK) contributed to the idea of the review. The first draft was written by MF, and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Masashi Fukayama.

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The authors declare that they have no conflict of interest.

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Fukayama, M., Abe, H., Kunita, A. et al. Thirty years of Epstein-Barr virus-associated gastric carcinoma. Virchows Arch 476, 353–365 (2020). https://doi.org/10.1007/s00428-019-02724-4

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