• COVID-19 as a potential Epstein-Barr virus associated gastric cancer agent
  • Ali Yousefzadeh Dastjerd,1 Ali Rezaei,2 Seyed Masoud Hosseini,3 Seyed Reza Mohebbi,4,*
    1. Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
    2. Department of Cell and Molecular Biology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
    3. Department of Microbiology and Microbial Biotechnology, Faculty of Life Sciences and Biotechnology, Shahid Beheshti University, Tehran, Iran
    4. Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran


  • Introduction: Recent studies indicate a decline in CD8+ T lymphocytes in COVID-19 patients implying immunosuppression and reactivation of opportunistic viruses respectively. Epstein-Barr virus (EBV), formerly known as Human gammaherpesvirus 4, is an oppurtunistic double-stranded DNA virus and a causative agent of infectious mononucleosis with a subclinical distribution in 90% to 95% of the world population. EBV-associated gastric cancer (EBVaGC) is a distinct subtype of gastrointestinal cancers in terms of carcinogenesis with characteristic clinical and pathological features, including a male predominance, a proximal location in the stomach, and a lymphoepithelioma-like histology. The goal of this review is to discuss reactivation of EBV subsequent to Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and highlight the potential role of the latter in EBVaGC.
  • Methods: To conduct this research, we studied 15 articles regarding “EBV reactivation”, “COVID-19” and “gastric cancer” on NCBI and Google Scholar. We searched for studies published up to September 2023.
  • Results: Recent studies indicate that 30% of the COVID-19 patients have evidence of EBV reactivation. Researchers found that the proportion of individuals who were simultaneously positive for EBV early antigen (EA) IgG and viral capsid antigen (VCA) IgG was significantly higher in severe COVID-19 patients (25.3%) than in healthy controls (less than 4.22%). This evidence suggests a potential role of COVID-19 infection in EBVaGC emergence. Recent advances in genome-wide and comprehensive molecular analyses have demonstrated that both genetic and epigenetic alterations contribute to EBVaGC carcinogenesis. Genetic modifications that are characteristic of EBVaGC comprise frequent mutations in PIK3CA and ARID1A and amplification of JAK2 and PD-L1/L2. Additionally, Global CpG island hypermethylation, which triggers epigenetic silencing of tumor suppressor genes is also a unique feature of EBVaGC and is considered to be crucial for its carcinogenesis. Post-transcriptional gene expression regulation by cellular and EBV-derived microRNAs has also been shown to play a critical role in EBVaGC carcinogenesis. These abnormalities result in significant alterations in gene expression related to cell proliferation, apoptosis, migration, and immune signaling pathways.
  • Conclusion: Limited data and ambiguity of the EBVaGC encourages generation of novel hypothesis regarding its pathogenesis pathways. As discussed above, Severe COVID-19 makes extensive contribution to EBV reactivation through suppressing immune system. Genetic alterations due to EBV reactivation can stimulate the development of EBVaGC by promoting cell growth and survival in addition to suppressing immune response to tumorigenesis. The study of EBVaGC is a rapidly evolving field; As a result, further studies are encouraged to elevate our understanding of EBVaGC and the potential role of COVID-19 infection in its progression in the years to come.
  • Keywords: Gastric Cancer, Epstein-Barr virus, COVID-19