Abstract
Epstein-Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is a distinct molecular subtype of gastric cancer characterized by viral infection and cellular abnormalities, including loss of AT-rich interaction domain 1A (ARID1A) expression (lost ARID1A). To evaluate the significance of lost ARID1A in the development of EBVaGC, we performed in situ hybridization of EBV-encoded RNA (EBER) and immunohistochemistry of ARID1A in the non-neoplastic gastric mucosa and intramucosal cancer tissue of EBVaGC with in vitro infection analysis of ARID1A-knockdown and -knockout gastric cells. Screening of EBER by in situ 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. In vitro experiments using siRNA knockdown and the CRISPR/Cas9-knockout system demonstrated that transient reduction or permanent loss of ARID1A 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-host interactions in the carcinogenesis of EBVaGC.
Highlights
Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is one of four molecular subtypes of gastric cancer
The third source was derived from the file of one of the authors (TU), in which EBV-encoded RNAs (EBERs)-positive cells were identified in the non-neoplastic mucosa near the gastric cancer during the screening of EBV infection
Complex interaction between the virus and host is the primary issue in virus-associated neoplasms from the initial to the advanced stages of cancer development, which we termed the “gastritis infection carcinoma sequence of EBV-associated gastric cancer (EBVaGC)” [13]
Summary
Epstein–Barr virus (EBV)-associated gastric carcinoma (EBVaGC) is one of four molecular subtypes of gastric cancer. EBVaGC is defined as the clonal expansion of EBV-infected cells and is characterized by epigenetic and genetic abnormalities, such as the extensive DNA methylation of promoter regions and recurrent mutations of several genes. ARID1A is frequently mutated in two molecular subtypes, EBVaGC and MSI [1, 2]. We revealed that EBV infection did not induce the loss of ARID1A expression [11]. Based on these results, we hypothesized that ARID1A expression is lost at an early stage of carcinogenesis in EBVaGC, or in other words, within non-neoplastic glands [12, 13]
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