**4. EBV strains and EBV-associated gastric carcinoma**

Previous restriction fragment length polymorphism (RFLP) studies and the recently completed genome sequencing of 31 viruses head to the first global approach of the diversity of EBV. Seven of these sequences were obtained from healthy donors or benign lesions and twenty-five from strains present in tumors including nine EBVaGC [40–44]. By this approach, the genome diversity of EBV can be classified into five types (A–F). A substitution of 1.8 kb in the C-terminal part of the EBNA-2 gene defines types A and B [45]. Subtype A is the most common strain in the West and in Asia, while subtype B is the most common one in Africa [45, 46]. Polymorphisms at BamHI W1/I1 boundary region identify C and D subtypes. The lack of the BamHI site defines subtype C that predominates in Asia among healthy people and EBV-associated diseases [47– 50]. On the other hand, the presence of the BamHI restriction site defines subtype D that prevails in the West [47, 51]. Lastly, polymorphism at BamHI site identifies subtype F with worldwide distribution. However, the presence of an extra site defines the "f" variant and is found only in cases of nasopharyngeal carcinomas (NPC) [52]. Two more variants of EBV associated with the LMP-1 gene have been described. Polymorphisms at XhoI restriction site in position 169,425 of the LMP-1 gene define Western and Asian strains. Healthy people and EBV-associated diseases in Asia lack the XhoI restriction site [47], while in Western countries, the presence of the XhoI site is frequent [53]. The second variant in the LMP-1 gene is the deletion of 30-base pair at C-terminal (position 168,287–168,256) [54]. This variant confers an aggressive clinical behavior in Hodgkin's disease [55].

In the Americas, both polymorphisms at BamHI W1/I1 boundary region (C and D types) and XhoI RFLPs at exon 1 of the LMP-1 gene are present in healthy donors at similar proportions [56]. These authors also identified two unique novel recombinant strains (C type/kept XhoI site and D type/lack of XhoI site) [56]. As shown in **Figure 3**, these findings might reflect the mixing of different ethnic populations in this continent as has been reported in Texas and Louisiana, USA [26, 27] and Brazil [28]. Conversely of what has been found in Asian and Western countries, this mixing did not reflect in the case of EBVaGC, since almost all EBV strains studied in tumors harbored exclusively the western genotype (D type and kept XhoI site) (OR 16.3 [95% CI 2.5–685]) [56]. **Figure 3** shows a consolidated overview of phylogeographic diversity of Epstein-Barr virus strains in the Americas.
