**Authors' contribution**

encode miRNAs and that they are capable of targeting both cellular and viral genes [82]. EBV-miRNA expression is dependent on the host cellular miRNA processing machinery for its biogenesis. EBV miRNAs are encoded in two clusters within the EBV genome. As shown in **Figure 1**, the first cluster is localized in the Bam HI fragment H rightward open reading frame 1 (BHRF1) gene and originates four mature miRNAs, which express only during lytic infection and in latency type IIb/III [83]. The second cluster is localized among the Bam HI-A region rightward transcript (BART) gene, encoding 40 mature miRNAs [84], which are expressed in all EBV latency types [83]. However, variable expression patterns of BART miRNAs have been reported in different EBV-associated malignancies or cell types [83, 85]. Additionally, discrepant reports exist concerning specific BART miRNAs' relative expression within the same cellular context, which could be in part a result of different EBV strains studied [86–89]. Most BART miRNAs host targets, identified so far, are involved in proapoptotic and immune response pathways, suggesting a crucial role in promoting host cell survival [90]. For instance, EBVaGC highly expressed miRBART4-5p and miRBART5-5p that have been shown to target and downregulate the BH3-interacting domain death agonist (BID) protein [91] and the p53-upregulated modulator of apoptosis (PUMA) [92], respectively. Furthermore, EBV not only expresses its own miRNAs but also alters miRNAs' expression of the host cells. Particularly, miR-200 family has been shown to be consistently downregulated both in GC cell lines and in EBVaGC tumor samples compared to normal adjacent mucosa and other GC subtypes [93, 94]. Aberrant DNA methylation following EBV infection and viral proteins such as BRAF0, EBER, and LMP-2A have been proposed as the main mecha-

Novel molecular classifications and meta-analyses identified Epstein-Barr virus (EBV) as a distinct etiological agent for gastric cancer. An important characteristic of EBV-associated gastric carcinoma (EBVaGC) is the difference in incidence in Asia and the Americas. Specific EBV genes such as EBERs, EBNAs, BARTs and LMP are the most actively expressed in EBVaGC, and variations in its sequences might be associated with phylogeographic diversity of EBV strains across the world. Polymorphisms at BamHI W1/I1 boundary region and XhoI RFLPs at exon 1 of the LMP-1 gene have been found in healthy donors reflecting the mixing of different ethnic populations in the Americas. However, this is not the case for gastric cancer, since almost all types of EBVaGC studied harbor exclusively the western genotypes (subtype D and kept XhoI site). These findings propose that a disrupted coevolution between a pathogen and its healthy population might contribute to a phylogeographic origin of disease. DNA methylation and cellular and viral microRNAs play an emerging role in the pathogenesis of

The funders had no role in study design, data collection and analysis, decision to publish or

nisms of downregulation of these miRNAs [93, 95].

**7. Summary and conclusions**

EBVaGC.

18 Gastric Cancer

**Disclaimer**

preparation of the paper.

Alejandra Alarcón: Conception or design of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, final approval of the version to be published; Ursula Figueroa: Conception or design of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, final approval of the version to be published; Bastian Espinoza: Conception or design of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, final approval of the version to be published; Gonzalo Carrasco-Aviño: Conception or design of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, final approval of the version to be published; Francisco R. Aguayo: Drafting the article, critical revision of the article, final approval of the version to be published; Alejandro H. Corvalan: Conception or design of the work, data collection, data analysis and interpretation, drafting the article, critical revision of the article, final approval of the version to be published.
