**Epstein-Barr Virus–Associated Gastric Carcinoma: The Americas' Perspective The Americas' Perspective**

**Epstein-Barr Virus–Associated Gastric Carcinoma:** 

DOI: 10.5772/intechopen.70201

Alejandra Alarcón, Ursula Figueroa, Bastian

Alejandra Alarcón, Ursula Figueroa, Bastian Espinoza, Alejandra Sandoval, Gonzalo Carrasco-Aviño, Francisco R. Aguayo and Alejandro H. Corvalan Espinoza, Alejandra Sandoval, Gonzalo Carrasco-Aviño, Francisco R. Aguayo and Alejandro H. Corvalan Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70201

#### **Abstract**

Epstein-Barr virus (EBV) infection has been associated with different malignancies, and compelling evidence has shown that it may have a causative or at least contributing role in gastric carcinogenesis. EBV-associated gastric cancers have a unique molecular signature, which has defined this group of tumors as a distinctive molecular subtype of gastric cancer. This subtype has shown a greater incidence in the Americas than in the Asian countries. This chapter discusses about possible factors underlying these differences and the emerging roles of epigenetics in the pathogenesis of Epstein-Barr virus–associated gastric cancer.

**Keywords:** gastric cancer, Epstein-Barr virus, strains, phylogeographic diversity, epigenetic abnormalities

**1. Introduction: an overview of the Epstein-Barr virus**

Epstein-Barr virus (EBV) belongs to the human gammaherpesvirus and is a 175 kbp double-stranded linear DNA virus. EBV infection is associated with the development of different malignancies, including several lymphoid neoplasms like Burkitt's lymphoma, Hodgkin's lymphoma, and immunosuppression-related B-cell lymphoma; in addition, epithelial malignancies like nasopharyngeal carcinomas (NPC) and gastric carcinomas have also been associated with the EBV [1]. Primary EBV infection is most of the time asymptomatic, and like other members of the herpesvirus family, the EBV maintains its

Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

genome as extrachromosomal circular episomes with repression of genes involved in virus replication. If latent persistent infection is established, viral reactivation may occur with the expression of specific EBV genes defining the type of latency in the infected cell. Genes involved in these patterns are shown in **Figure 1** and include the EBV-encoded RNAs (EBERs), the EBV nuclear antigens (EBNAs), the BamH1-A rightward transcripts (BARTs) and the latent membrane protein (LMP)-1, 2A and 2B [3]. These latency-associated patterns have been associated with specific malignancies and in the case of gastric cancer, the virus shows a latency type I/IIab. The EBERs 1 and 2 genes are the most abundant small noncoding RNAs that interact with proteins of the host and are the standard target for EBV detection by in situ hybridization (ISH) [4]. The EBNA-1 and -2 genes are exclusive nuclear proteins expressed in latent infected gastric carcinoma cells and related to the disruption of promyelocytic leukemia nuclear bodies [5]. EBNA-1 is a DNAbinding protein that lacks enzymatic activity although it can interact with some cellular proteins such as CK2 and P32/TAP [6]. Interestingly, EBNA-1 is expressed in all of the EBV-associated tumors and is involved in viral DNA replication, mitotic segregation and transcriptional activation [7]. BART genes encode highly expressed multispliced RNAs whose protein-coding function is controversial [8]. Although some BARTs open reading frames (ORFs) have been predicted, currently it is not clear if any of them can be endogenously translated. In addition, BART genes, small as well as long noncoding RNAs, are highly expressed and associated with oncogenic transformation and immune evasion

**Figure 1.** Gene expression patterns at different stages of EBV latency states. The theoretical progression of EBV latency gene expression from initial infection to true latency is described from left to right. The EBV genome is shown in episomal form closed at the terminal repeats (TR). Promoters are shown as white boxes and include the EBNA promoters Cp, Wp and Qp as well as the bidirectional LMPp. Primary mRNA transcripts are shown as dotted lines, while coding regions have been simplified as colored boxes. An expanded list of viral genes expressed in each latency state is listed directly underneath the representative schematic. Taken from [2] with permission.

functions [9, 10] (for review, see [3, 11]). The LMP-1 and -2 encode for transmembrane proteins with a plethora of oncogenic functions with conflicted results in gastric carcinoma (for review, see [12]). It has been proposed that variations in its sequences might be related to phylogeographic diversity of EBV-associated gastric carcinoma (EBVaGC) strains worldwide [13]. Taken together, EBV latent genes not only define the type of latency but also are associated with oncogenic transformation, immune evasion and the genetic diversity of EBVaGC.
