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To evaluate the significance of lost ARID1A in the development of EBVaGC, we performed <jats:italic>in situ<\/jats:italic> hybridization of EBV-encoded RNA (EBER) and immunohistochemistry of ARID1A in the non-neoplastic gastric mucosa and intramucosal cancer tissue of EBVaGC with <jats:italic>in vitro<\/jats:italic> infection analysis of <jats:italic>ARID1A<\/jats:italic>-knockdown and -knockout gastric cells. Screening of EBER by <jats:italic>in situ<\/jats:italic> hybridization revealed a frequency of approximately 0.2% EBER-positive epithelial cells in non-neoplastic gastric mucosa tissue samples. Six small foci of EBV-infected epithelial cells showed two types of histology: degenerated (n = 3) and metaplastic (n = 3) epithelial cells. ARID1A was lost in the former type. In intramucosal EBVaGC, there were ARID1A-lost (n = 5) and -preserved tumors (n = 7), suggesting that ARID1A-lost carcinomas are derived from ARID1A-lost precursor cells in the non-neoplastic mucosa. Lost ARID1A was also observed in non-neoplastic mucosa adjacent to an ARID1A-lost EBVaGC. <jats:italic>In vitro<\/jats:italic> experiments using siRNA knockdown and the CRISPR\/Cas9-knockout system demonstrated that transient reduction or permanent loss of <jats:italic>ARID1A<\/jats:italic> expression markedly increased the efficiency of EBV infection to stomach epithelial cells. Taken together, lost ARID1A plays a role in initiating EBV-driven carcinogenesis in stomach epithelial cells, which develop to a distinct subtype of EBVaGC within the proper mucosal layer. Lost ARID1A is one of the constituents of virus\u2013host interactions in the carcinogenesis of EBVaGC.<\/jats:p>","DOI":"10.1371\/journal.pone.0256440","type":"journal-article","created":{"date-parts":[[2021,9,1]],"date-time":"2021-09-01T17:31:39Z","timestamp":1630517499000},"page":"e0256440","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":11,"title":["Virus\u2013host interactions in carcinogenesis of Epstein-Barr virus-associated gastric carcinoma: Potential roles of lost ARID1A expression in its early 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