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ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein–Barr virus infection and microsatellite instability

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Abstract

The AT-rich interactive domain 1A gene (ARID1A), which encodes one of the subunits in the Switch/Sucrose Nonfermentable chromatin remodeling complex, carries mutations and is responsible for loss of protein expression in gastric carcinoma, particularly with Epstein–Barr virus (EBV) infection and a microsatellite instability-high phenotype. We used immunohistochemistry to investigate the significance of ARID1A loss in 857 gastric carcinoma cases, including 67 EBV(+) and 136 MLH1-lost gastric carcinomas (corresponding to a microsatellite instability-high phenotype). Loss of ARID1A expression was significantly more frequent in EBV(+) (23/67; 34 %) and MLH1-lost (40/136; 29 %) gastric carcinomas than in EBV(−)MLH1-preserved (32/657; 5 %) gastric carcinomas (P < 0.01). Loss of ARID1A correlated with larger tumor size, advanced invasion depth, lymph node metastasis, and poor prognosis in EBV(−)MLH1-preserved gastric carcinoma. A correlation was found only with tumor size and diffuse-type histology in MLH1-lost gastric carcinoma, but no correlation was observed in EBV(+) gastric carcinoma. Loss of ARID1A expression in EBV(+) gastric carcinoma was highly frequent in the early stage of gastric carcinoma, although EBV infection did not cause downregulation of ARID1A: EBV-positive nasopharyngeal carcinomas (n = 8) and lymphomas (n = 15) failed to show loss of ARID1A, and EBV infection did not cause loss of ARID1A in gastric carcinoma cell lines. Taken together, loss of ARID1A may be an early change in carcinogenesis and may precede EBV infection in gastric epithelial cells, while loss of ARID1A promotes cancer progression in gastric cancer cells without EBV infection or loss of MLH1 expression. Loss of ARID1A has different and pathway-dependent roles in gastric carcinoma.

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Acknowledgments

This work was supported by a grant-in-aid for scientific research (20249022) from the Ministry of Education, Culture, Science, Sports, and Technology, Japan.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

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

    Hiroyuki Abe, Daichi Maeda, Rumi Hino, Yuya Otake, Maya Isogai, Aya Shinozaki Ushiku, Keisuke Matsusaka, Akiko Kunita, Tetsuo Ushiku, Hiroshi Uozaki, Shumpei Ishikawa & Masashi Fukayama

  2. Division of Central Clinical Research Laboratory, Nissay Hospital, Osaka, Japan

    Yuya Otake

  3. Department of Pathology, Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital, Tokyo, Japan

    Yoko Tateishi & Tsunekazu Hishima

  4. Department of Surgery, Tokyo Metropolitan Cancer and Infectious diseases Center, Komagome Hospital, Tokyo, Japan

    Yoshiaki Iwasaki

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  1. Hiroyuki Abe
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Correspondence to Masashi Fukayama.

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Abe, H., Maeda, D., Hino, R. et al. ARID1A expression loss in gastric cancer: pathway-dependent roles with and without Epstein–Barr virus infection and microsatellite instability. Virchows Arch 461, 367–377 (2012). https://doi.org/10.1007/s00428-012-1303-2

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  • DOI: https://doi.org/10.1007/s00428-012-1303-2

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