Open access peer-reviewed chapter

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

Written By

Alejandra Alarcón, Ursula Figueroa, Bastian Espinoza, Alejandra Sandoval, Gonzalo Carrasco-Aviño, Francisco R. Aguayo and Alejandro H. Corvalan

Reviewed: 23 June 2017 Published: 20 September 2017

DOI: 10.5772/intechopen.70201

From the Edited Volume

Gastric Cancer

Edited by Gyula Mózsik and Oszkár Karádi

Chapter metrics overview

1,739 Chapter Downloads

View Full Metrics

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 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 DNA-binding 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 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.

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.

Advertisement

2. Gastric cancer: novel molecular classifications

The molecular bases of gastric cancer have begun to be unraveled by a comprehensive molecular evaluation of primary tumors [1420]. As shown in Figure 2, the Cancer Genome Atlas (TCGA) network has proposed a novel molecular classification of gastric carcinoma that recognized for the first time a subtype of tumor positive for Epstein-Barr virus, the EBV-associated gastric carcinoma (EBVaGC). This novel subtype of gastric cancer is characterized by frequent PIK3CA gene mutations, amplification of JAK2, CD274 (PD-L1) and PDCD1LG2 (PD-L2), and a unique CpG island methylator phenotype (CIMP) [14, 21].

Figure 2.

Major features of molecular classification of gastric cancer as proposed by the tumor cancer genome atlas (TCGA) are CIMP: CpG island methylator phenotype, EBV: Epstein-Barr virus, MSI: microsatellite instability, GS: genomically stable and CIN: chromosomal instability. Taken from [20] with permission.

Advertisement

3. EBV-associated gastric carcinoma: the Americas’ perspective

Worldwide studies show higher EBVaGC prevalence in the Americas than in Asia [22]. These observations suggest a phylogeographic diversity of Epstein-Barr virus strains along with host and environmental associations [13]. In the Americas, the first report of gastric tumors positive for Epstein-Barr virus comes from Shibata and coworkers [23] (Figure 3). These authors, based on the histological resemblance between rare variant of undifferentiated gastric carcinomas with intense lymphoid infiltration (so-called lymphoepithelioma-like carcinoma [LELC]) and nasopharyngeal lymphoepithelioma, a well-established EBV-associated disease, detected EBV sequences in seven of eight LELC cases. EBV genomes were uniformly present only in carcinoma cells but not in reactive lymphoid infiltrate or normal gastric mucosa. Furthermore, the presence of a single genotype in each LELC cell was consistent with a clonal process, suggesting that EBV infection occurs before malignant transformation. Later, the same group expanded these findings to conventional gastric cancer, detecting EBV sequences in 22 of 138 (16%) cases [24]. In all these cases, the EBV genome was expressed, exclusively in gastric tumor cells. No EBV sequences were detected in surrounding lymphocytes, or precancerous lesions such as intestinal metaplasia and chronic gastritis. In addition, EBVaGC cases were most often detected in males than in females (p = 0.007). To define the clinicopathological characteristics of this novel molecular subtype of gastric cancer, a long-term, well-characterized cohort of Japanese-Americans living in Hawaii [32, 33] was evaluated. Unfortunately, beyond male predominance, no other clinicopathological characteristic, including survival, was found [32]. A high incidence of EBVaGC has been reported in Santiago, Chile, with 31 (16.8%) EBV-positive cases identified among 185 consecutive gastric cancer patients [25]. In this series, associations with the diffuse-type histology (p < 0.001) and nonantrum location (p = 0.01) were the most significant findings. Among Mexican descendants living in the USA, Gulley and coworkers and Vo and coworkers have reported 20 out of 138 (14.5%) EBVaGC cases [26, 27]. Interestingly, prevalence of EBV was 26.4% among Mexican descendants in comparison with 4.5% among white/non-Hispanic cases. In addition, male predominance was found exclusively in those with Hispanic ancestry (p = 0.01) [27]. Koriyama et al. [28] examined 151 non–Japanese-Brazilian and 149 Japanese-Brazilian gastric carcinoma cases to identify an 11.2% prevalence among non–Japanese-Brazilian but only 4.7% among Japanese-Brazilian residents (p = 0.01). EBV-associated gastric carcinoma was predominant in males only in the non–Japanese-Brazilian cases (p = 0.047). Taken together, these findings suggest human phylogeographic diversity in the prevalence of EBVaGC.

Figure 3.

A consolidated overview of EBVaGC in the Americas. Phylogeographic diversity of EBV strains along with host and environmental associations might explain the high incidence of EBVaGC in the Americas [2431].

Among other countries in Latin America, Carrascal et al. [29], in Cali, Colombia, examined 178 consecutive gastric carcinoma cases identifying 23 (13%) cases of EBVaGCs. In this series, EBVaGC also revealed a male (p = 0.004) and nonantrum (p = 0.009) predominance. Herrera-Goepfert et al. [30] identified 24 of 330 (7.3%) cases in Mexico City. In this series, no male predominance was confirmed, although all cases were of diffuse-type histology. The lowest frequency reported in Latin America was in Peru, where 254 gastric cancer cases from Japanese descendants were evaluated by Yoshiwara et al. [31]. In this analysis, only 3.9% (10 cases) of EBV infection was found, with no male or histological subtype predominance detected. A consolidated overview of EBVaGC in the Americas is shown in Figure 3.

A recent meta-analysis estimated a prevalence of 11.49% (95% CI = 8.46–15.43), with high heterogeneity among the aforementioned studies (I2 = 73.3%; p < 0.001). Although heterogeneity for predominant sex, location and histology was low (I2 = 16.5% [p = 0.35], 0% [p = 0.68] and 33.7% [p = 0.16], respectively), these authors showed male predominance (p < 0.001) and diffuse-type histology (p < 0.001) as the most significant features of EBVaGC in the Americas (Figures 4 and 5) [13].

Figure 4.

An estimated odds ratio (95% CI) for male predominance of EBV-associated gastric cancer in the Americas. Meta-analyses were performed by a random effects model with the inverse variance method, using the DerSimonian-Laird estimator, a logit transformation and the Clopper-Pearson confidence interval for individual studies. The results are shown in a log-scale. Taken from [4] with permission.

Figure 5.

An estimated odds ratio (95% CI) for diffuse-type histology of EBV-associated gastric carcinoma in the Americas. Meta-analyses were performed by a random effects model with the inverse variance method, using the DerSimonian-Laird estimator, a logit transformation and the Clopper-Pearson confidence interval for individual studies. The results are shown in a log-scale. Taken from [13] with permission.

In Asia, low prevalence of EBV-associated gastric carcinoma has been described. The reported prevalence ranges from 6.1% in Northern China [34] to 9.1% in Southern China [35]. In Japan and Korea, the reported prevalence is 6.6 and 6.9%, respectively [35, 36]. Among European countries, Russia and the Republics of the former Soviet Union, 8.7% prevalence has been reported [37]. Interestingly, distribution of EBV-positive GCs by sex, site and histological type was similar to that in Japan. In a study carried out in Holland, EBV was detected in 7.2% of the gastric carcinomas from the Dutch D1D2 trial (N = 566; mean follow-up, 9 years) [38]. In France, only 5.8% of 85 cases of gastric adenocarcinomas were EBV-associated adenocarcinomas, from which 4 cases were of the intestinal histological type [39].

Advertisement

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 [4044]. 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 [4750]. 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.

Advertisement

5. Epigenetic abnormalities of EBV-associated gastric carcinoma: DNA methylation

EBV-associated gastric cancer has been reported as the most extensive CpG island methylation at both human and viral genomes, being more extensive than any other tumor type from the TCGA network [14, 21, 57, 58]. CpG island methylation is an epigenetic mechanism of gene expression regulation, affecting all cellular pathways [59]. It consists of methyl groups attached to the 5′ position of cytosines, which are followed by a guanine nucleotide (CpG site) [60] (Figure 6). More than 50% of human genes contain CpG site in the promoter region and are known as CpG islands [62]. Methylation of CpG sites within a promoter region may inhibit the binding of transcription factors in their consensus sequence of tumor suppressor genes, thus precluding the transcription of the gene, and resulting in gene silencing [63]. Methylation of tumor suppressor genes is usually seen at early stages of gastric cancer and increases during the stomach carcinogenesis [64]. These observations suggest that the silencing of these genes by DNA methylation mechanisms plays an important role in the gastric carcinogenesis. In addition, aberrant methylation is unusually detected in EBVaGC nonneoplastic surrounding mucosa, which might indicate a critical role of EBV in tumorigenesis mechanisms [65]. Although the extensive CpG island methylation is present in EBVaGC, a distinctive pattern of methylation has been suggested, as promoter methylation of tumor suppressor gene CDKN2A, but not promoter methylation of MLH1, characteristic of the microsatellite instability (MSI) GC subtype [21, 27, 6671]. Individual methylation of p14ARF and p16INK4a, alternative reading frames of CDKN2A locus, has also been described, and many studies have proved a significant association between their methylation and EBV positivity [72, 73]. Ushiku et al. [74] observed a uniform methylation of all CpG sites on promoter regions of both genes in EBVaGC, whereas it was variable in EBV-negative tumors. In addition, methylation frequency of p16INK4a appears to be about three times higher in EBVaGC than in EBV-negative tumors [65, 75]. CDH1, p15 and p73 tumor suppressor genes are also frequently methylated in EBVaGC, representing one of the most common abnormalities described in this tumor [65, 74].

Figure 6.

DNA methylation. (A) CpG methylation mechanism is mediated by DNA methyltransferases and consists in the addition of a methyl group to the carbon in the 5th position of cytosines that precedes guanine nucleotides. (B) CpG islands are DNA sequences rich in CpG sites (>50% CpG sites within a 200bp sequence). Methylation of CpG islands inside a promoter region may control gene expression.

Despite EBV-induced host gene methylation in EBVaGC is well established, the exact underlying mechanisms are not entirely understood. It has been proposed that when the host cell detects the viral genome, it defends itself by starting a host-driven extensive methylation of the foreign genome, which may trigger the subsequent host genome methylation [7577]. However, based on the specific methylation patterns observed, a possible participation of EBV in maintenance and de novo methylation has been proposed [72, 74]. Several studies have shown that EBV can modulate the expression of DNA methyltransferases (DNMT), which catalyze the transfer of methyl groups to DNA. Specifically, LMP-2A, EBV latent gene, has been shown to upregulate DNMT1 and DNMT3b expression in gastric cancer cell lines, which further induced methylation of several tumor suppressor genes, such as PTEN [78, 79]. Therefore, LMP-2A may play an essential role in the epigenetic abnormalities in host cells and in the development and maintenance of EBV-associated cancer.

Advertisement

6. Epigenetic abnormalities of EBV-associated gastric carcinoma: microRNAs

MicroRNAs (miRNAs) are small (~22 nt) noncoding RNAs and fundamental in posttranscriptional regulation of a broad range of biological processes of different organisms. This fundamental regulation is achieved through specific complementary binding to the 3′ untranslated region (3′UTR) of one or more target mRNAs, allowing regulation of multiple genes simultaneously [80] (Figure 7). Increasing evidence has shown that dysregulation of specific miRNAs has a crucial role in tumorigenesis. In fact, microRNAs involved in this process are usually called oncomiRs and anti-oncomiRs, acting similar to onco- and tumor-suppressor genes [11]. Particularly, in gastric cancer, cellular miRNAs have gained special interest because they have shown differential expression between distinct cancer subtypes and have been related to progression and prognosis of the disease (for a review, see [80]). Viral microRNAs were first described in EBV [81]. It is now known that diverse virus families 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 [8689]. 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 mechanisms of downregulation of these miRNAs [93, 95].

Figure 7.

Canonical pathway of miRNA biogenesis in human. miRNAs are transcribed by RNA polymerase II (RNAP II) from intergenic, intronic or polycistronic loci to long primary transcript, called primary miRNA (pri-miRNA), which consists in a stem, a terminal loop and single-stranded RNA segments at both the 5′- and 3′-UTR sides. Microprocessor complex (Drosha and DGCR8 cofactor) cleaves the stem-loop and releases a small hairpin-shaped RNA, called precursor miRNA (pre-miRNA). Following, pre-miRNA is exported into the cytoplasm by the transport complex formed by protein exportin 5 (EXP5) and GTP-binding nuclear protein RAN•GTP. Subsequently, pre-miRNAs are cleaved by a ternary complex formed by dicer, TAR RNA-binding protein (TRBP) and protein activator of PKR (PACT), producing a small RNA duplexes (miRNA-miRNA*). Next, these are loaded onto an Argonaute protein (AGO) to form an immature RNA-induced silencing complex (RISC) or pre-RISC, in a process mediated for heat shock cognate 70 (Hsc70)-heat shock protein (Hsp90) chaperone complex. AGO protein separates the two strands to generate a mature RISC effector. Finally, RISC binds the target mRNA through complementary binding of six to eight base pairs of the miRNA, with a specific sequence of the target resulting in the gene silencing. Taken from [80] with permission.

Advertisement

7. Summary and conclusions

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 EBVaGC.

Advertisement

Disclaimer

The funders had no role in study design, data collection and analysis, decision to publish or preparation of the paper.

Advertisement

Authors’ contribution

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.

Advertisement

Acknowledgments

This study was funded by Fondecyt grant nos. 1151411 and 1161219 from the Government of Chile.

Conflict of interest

The authors declare that there is no conflict of interest regarding the publication of this paper.

References

  1. 1. Stanfield BA, Luftig MA. Recent advances in understanding Epstein-Barr virus. F1000Research. 2017;6:386. DOI: 10.12688/f1000research.10591.1
  2. 2. Price AM, Luftig MA. To be or not IIb: a multi-step process for Epstein-Barr virus latency establishment and consequences for B cell tumorigenesis. PLoS Pathogens. 2015;11:e1004656. DOI: 10.1371/journal.ppat.1004656
  3. 3. Tsao SW, Tsang CM, To KF, Lo KW. The role of Epstein-Barr virus in epithelial malignancies. The Journal of Pathology. 2015;235:323-333. DOI: 10.1002/path.4448
  4. 4. Weiss LM, Chen YY. EBER in situ hybridization for Epstein-Barr virus. Methods in Molecular Biology. 2013;999:223-230. DOI: 10.1007/978-1-62703-357-2_16
  5. 5. Sivachandran N, Wang X, Frappier L. Functions of the Epstein-Barr virus EBNA1 protein in viral reactivation and lytic infection. Journal of Virology. 2012;86:6146-6158. DOI: JVI.00013-12 [pii]
  6. 6. Malik-Soni N, Frappier L. Proteomic profiling of EBNA1-host protein interactions in latent and lytic Epstein-Barr virus infections. Journal of Virology. 2012;86:6999-7002. DOI: 10.1128/jvi.00194-12
  7. 7. Shire K, Wong AI, Tatham MH, Anderson OF, Ripsman D, Gulstene S, Moffat J, Hay RT, Frappier L. Identification of RNF168 as a PML nuclear body regulator. Journal of Cell Science. 2016;129:580-591. DOI: 10.1242/jcs.176446
  8. 8. Skalsky RL, Cullen BR. EBV noncoding RNAs. Current Topics in Microbiology and Immunology. 2015;391:181-217. DOI: 10.1007/978-3-319-22834-1_6
  9. 9. Marquitz AR, Mathur A, Nam CS, Raab-Traub N. The Epstein-Barr virus BART microRNAs target the pro-apoptotic protein Bim. Virology. 2011;412:392-400. DOI: S0042-6822(11)00042-0 [pii]
  10. 10. Marquitz AR, Mathur A, Edwards RH, Raab-Traub N. Host gene expression is regulated by two types of noncoding RNAs transcribed from the Epstein-Barr virus BamHI a rightward transcript region. Journal of Virology. 2015;89:11256-11268 DOI: JVI.01492-15 [pii]
  11. 11. Shinozaki-Ushiku A, Kunita A, Fukayama M. Update on Epstein-Barr virus and gastric cancer (review). International Journal of Oncology. 2015;46:1421-1434. DOI: 10.3892/ijo.2015.2856
  12. 12. Kang MS, Kieff E. Epstein-Barr virus latent genes. Experimental & Molecular Medicine. 2015;47:e131. DOI: 10.1038/emm.2014.84
  13. 13. Carrasco-Avino G, Riquelme I, Padilla O, Villaseca M, Aguayo FR, Corvalan AH. The conundrum of the Epstein-Barr virus-associated gastric carcinoma in the Americas. Oncotarget. 2017.DOI: 10.18632/oncotarget.18497
  14. 14. Bass AJ. Comprehensive molecular characterization of gastric adenocarcinoma. Nature. 2014;513:202-209 DOI: nature13480 [pii]10.1038/nature13480
  15. 15. Cristescu R, Lee J, Nebozhyn M, Kim KM, Ting JC, Wong SS, Liu J, Yue YG, Wang J, Yu K, Ye XS, Do IG, Liu S, et al. Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes. Natural Medicine. 2015;21:449-456. DOI: nm.3850 [pii]10.1038/nm.3850
  16. 16. Liu N, Liu X, Zhou N, Wu Q, Zhou L, Li Q. Gene expression profiling and bioinformatics analysis of gastric carcinoma. Experimental and Molecular Pathology. 2014;96:361-366. DOI: S0014-4800(14)00022-7 [pii]10.1016/j.yexmp.2014.02.007
  17. 17. Shah MA, Khanin R, Tang L, Janjigian YY, Klimstra DS, Gerdes H, Kelsen DP. Molecular classification of gastric cancer: A new paradigm. Clinical Cancer Research. 2011;17:2693-2701. DOI: 1078-0432.CCR-10-2203 [pii]10.1158/1078-0432.CCR-10-2203
  18. 18. Lei Z, Tan IB, Das K, Deng N, Zouridis H, Pattison S, Chua C, Feng Z, Guan YK, Ooi CH, Ivanova T, Zhang S, Lee M, et al. Identification of molecular subtypes of gastric cancer with different responses to PI3-kinase inhibitors and 5-fluorouracil. Gastroenterology. 2013;145:554-565. DOI: S0016-5085(13)00722-1 [pii]10.1053/j.gastro.2013.05.010
  19. 19. Tan IB, Ivanova T, Lim KH, Ong CW, Deng N, Lee J, Tan SH, Wu J, Lee MH, Ooi CH, Rha SY, Wong WK, Boussioutas A, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology. 2011;141:476-485, 85 e1-11. DOI: S0016-5085(11)00597-X [pii]
  20. 20. Riquelme I, Saavedra K, Espinoza JA, Weber H, Garcia P, Nervi B, Garrido M, Corvalan AH, Roa JC, Bizama C. Molecular classification of gastric cancer: Towards a pathway-driven targeted therapy. Oncotarget. 2015;6((28)):24750-24779. DOI: 10.18632/oncotarget.4990
  21. 21. Gulley ML. Genomic assays for Epstein-Barr virus-positive gastric adenocarcinoma. Experimental & Molecular Medicine. 2015;47:e134. DOI: emm201493 [pii]
  22. 22. Camargo MC, Anderson WF, King JB, Correa P, Thomas CC, Rosenberg PS, Eheman CR, Rabkin CS. Divergent trends for gastric cancer incidence by anatomical subsite in US adults. Gut. 2011;60:1644-1649. DOI: gut.2010.236737 [pii]10.1136/gut.2010.236737
  23. 23. Shibata D, Tokunaga M, Uemura Y, Sato E, Tanaka S, Weiss LM. Association of Epstein-Barr virus with undifferentiated gastric carcinomas with intense lymphoid infiltration: Lymphoepithelioma-like carcinoma. The American Journal of Pathology. 1991;139:469-474
  24. 24. Shibata D, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma. The American Journal of Pathology. 1992;140:769-774
  25. 25. Corvalán AH, Koriyama C, Akiba S, Eizuru Y, Backhouse C, Palma M, Argandona J, Tokunaga M. Epstein-Barr virus in gastric carcinoma is associated with location in the cardia and with a diffuse histology: A study in one area of Chile. International Journal of Cancer. 2001;94:527-530. DOI: 10.1002/ijc.1510
  26. 26. Gulley ML, Pulitzer DR, Eagan PA, Schneider BG. Epstein-Barr virus infection is an early event in gastric carcinogenesis and is independent of bcl-2 expression and p53 accumulation. Human Pathology. 1996;27:20-27
  27. 27. Vo QN, Geradts J, Gulley ML, Boudreau DA, Bravo JC, Schneider BG. Epstein-Barr virus in gastric adenocarcinomas: Association with ethnicity and CDKN2A promoter methylation. Journal of Clinical Pathology. 2002;55:669-675
  28. 28. Koriyama C, Akiba S, Iriya K, Yamaguti T, Hamada GS, Itoh T, Eizuru Y, Aikou T, Watanabe S, Tsugane S, Tokunaga M. Epstein-Barr virus-associated gastric carcinoma in Japanese Brazilians and non-Japanese Brazilians in Sao Paulo. Japanese Journal of Cancer Research. 2001;92:911-917
  29. 29. Carrascal E, Koriyama C, Akiba S, Tamayo O, Itoh T, Eizuru Y, Garcia F, Sera M, Carrasquilla G, Piazuelo MB, Florez L, Bravo JC. Epstein-Barr virus-associated gastric carcinoma in Cali, Colombia. Oncology Reports. 2003;10:1059-1062
  30. 30. Herrera-Goepfert R, Akiba S, Koriyama C, Ding S, Reyes E, Itoh T, Minakami Y, Eizuru Y. Epstein-Barr virus-associated gastric carcinoma: Evidence of age-dependence among a Mexican population. World Journal of Gastroenterology. 2005;11:6096-6103
  31. 31. Yoshiwara E, Koriyama C, Akiba S, Itoh T, Minakami Y, Chirinos JL, Watanabe J, Takano J, Miyagui J, Hidalgo H, Chacon P, Linares V, Eizuru Y. Epstein-Barr virus-associated gastric carcinoma in Lima, Peru. Journal of Experimental and Clinical Cancer Research. 2005;24:49-54
  32. 32. Shibata D, Hawes D, Stemmermann GN, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma among Japanese Americans in Hawaii. Cancer Epidemiology, Biomarkers & Prevention. 1993;2:213-217
  33. 33. Nomura AM, Stemmermann GN, Chyou PH. Gastric cancer among the Japanese in Hawaii. Japanese Journal of Cancer Research. 1995;86:916-923 DOI: 0910505095967854 [pii]
  34. 34. Hao Z, Koriyama C, Akiba S, Li J, Luo X, Itoh T, Eizuru Y, Zou J. The Epstein-Barr virus-associated gastric carcinoma in southern and northern China. Oncology Reports. 2002;9:1293-1298
  35. 35. Lee HS, Chang MS, Yang HK, Lee BL, Kim WH. Epstein-barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with Epstein-Barr virus-negative carcinoma. Clinical Cancer Research. 2004;10:1698-1705
  36. 36. Koriyama C, Akiba S, Corvalán AH, Carrascal E, Itoh T, Herrera-Goepfert R, Eizuru Y, Tokunaga M. Histology-specific gender, age and tumor-location distributions of Epstein-Barr virus-associated gastric carcinoma in Japan. Oncology Reports. 2004;12:543-547
  37. 37. Galetsky SA, Tsvetnov VV, Land CE, Afanasieva TA, Petrovichev NN, Gurtsevitch VE, Tokunaga M. Epstein-Barr-virus-associated gastric cancer in Russia. International Journal of Cancer. 1997;73:786-789. DOI: 10.1002/(SICI)1097-0215(19971210)73:6<786::AID-IJC2>3.0.CO;2-Z [pii]
  38. 38. van Beek J, zur Hausen A, Klein Kranenbarg E, van de Velde CJ, Middeldorp JM, van den Brule AJ, Meijer CJ, Bloemena E. EBV-positive gastric adenocarcinomas: A distinct clinicopathologic entity with a low frequency of lymph node involvement. Journal of Clinical Oncology. 2004;22:664-670. DOI: 10.1200/jco.2004.08.061
  39. 39. Kerroucha R, Hervieu V, Chambonniere ML, Mege-Lechevallier F, Poncet G, Boulez J, Taniere P, Scoazec JY. Adenocarcinomas of the stomach and distal esophagus. Incidence and phenotypic characteristics of EBV-associated cases in the Lyons area, France. Annales de Pathologie. 2004;24:228-235
  40. 40. Liu Y, Yang W, Pan Y, Ji J, Lu Z, Ke Y. Genome-wide analysis of Epstein-Barr virus (EBV) isolated from EBV-associated gastric carcinoma (EBVaGC). Oncotarget. 2016;7:4903-4914. DOI: 6751 [pii]
  41. 41. Baer R, Bankier AT, Biggin MD, Deininger PL, Farrell PJ, Gibson TJ, Hatfull G, Hudson GS, Satchwell SC, Seguin C, et al. DNA sequence and expression of the B95-8 Epstein-Barr virus genome. Nature. 1984;310:207-211
  42. 42. de Jesus O, Smith PR, Spender LC, Elgueta Karstegl C, Niller HH, Huang D, Farrell PJ. Updated Epstein-Barr virus (EBV) DNA sequence and analysis of a promoter for the BART (CST, BARF0) RNAs of EBV. The Journal of General Virology. 2003;84:1443-1450. DOI: 10.1099/vir.0.19054-0
  43. 43. Lei H, Li T, Hung GC, Li B, Tsai S, Lo SC. Identification and characterization of EBV genomes in spontaneously immortalized human peripheral blood B lymphocytes by NGS technology. BMC Genomics. 2013;14:804. DOI: 10.1186/1471-2164-14-8041471-2164-14-804 [pii]
  44. 44. Santpere G, Darre F, Blanco S, Alcami A, Villoslada P, Mar Alba M, Navarro A. Genome-wide analysis of wild-type Epstein-Barr virus genomes derived from healthy individuals of the 1000 genomes project. Genome Biology and Evolution. 2014;6:846-860 DOI: evu054 [pii]
  45. 45. Zimber U, Adldinger HK, Lenoir GM, Vuillaume M, Knebel-Doeberitz MV, Laux G, Desgranges C, Wittmann P, Freese UK, Schneider U, et al. Geographical prevalence of two types of Epstein-Barr virus. Virology. 1986;154:56-66
  46. 46. Young LS, Yao QY, Rooney CM, Sculley TB, Moss DJ, Rupani H, Laux G, Bornkamm GW, Rickinson AB. New type B isolates of Epstein-Barr virus from Burkitt’s lymphoma and from normal individuals in endemic areas. The Journal of General Virology. 1987;68(Pt 11):2853-2862. DOI: 10.1099/0022-1317-68-11-2853
  47. 47. Lung ML, Chang RS, Jones JH. Genetic polymorphism of natural Epstein-Barr virus isolates from infectious mononucleosis patients and healthy carriers. Journal of Virology. 1988;62:3862-3866
  48. 48. Lung ML, Chang GC. Detection of distinct Epstein-Barr virus genotypes in NPC biopsies from southern Chinese and Caucasians. International Journal of Cancer. 1992;52:34-37
  49. 49. Sidagis J, Ueno K, Tokunaga M, Ohyama M, Eizuru Y. Molecular epidemiology of Epstein-Barr virus (EBV) in EBV-related malignancies. International Journal of Cancer. 1997;72:72-76. DOI: 10.1002/(SICI)1097-0215(19970703)72:1<72::AID-IJC11>3.0.CO;2-C [pii]
  50. 50. Lung ML, Chang RS, Huang ML, Guo HY, Choy D, Sham J, Tsao SY, Cheng P, Ng MH. Epstein-Barr virus genotypes associated with nasopharyngeal carcinoma in southern China. Virology. 1990;177:44-53
  51. 51. Abdel-Hamid M, Chen JJ, Constantine N, Massoud M, Raab-Traub N. EBV strain variation: Geographical distribution and relation to disease state. Virology. 1992;190:168-175 DOI: 0042-6822(92)91202-6 [pii]
  52. 52. Lung ML, Lam WP, Sham J, Choy D, Yong-Sheng Z, Guo HY, Ng MH. Detection and prevalence of the “f” variant of Epstein-Barr virus in southern China. Virology. 1991;185:67-71 DOI: 0042-6822(91)90754-Y [pii]
  53. 53. Khanim F, Yao QY, Niedobitek G, Sihota S, Rickinson AB, Young LS. Analysis of Epstein-Barr virus gene polymorphisms in normal donors and in virus-associated tumors from different geographic locations. Blood. 1996;88:3491-3501
  54. 54. Wohlford EM, Asito AS, Chelimo K, Sumba PO, Baresel PC, Oot RA, Moormann AM, Rochford R. Identification of a novel variant of LMP-1 of EBV in patients with endemic Burkitt lymphoma in western Kenya. Infectious Agents and Cancer. 2013;8:34. DOI: 10.1186/1750-9378-8-34
  55. 55. Santon A, Manzanal AI, Campo E, Bellas C. Deletions in the Epstein-Barr virus latent membrane protein-1 oncogene in Hodgkin’s disease. Clinical Molecular Pathology. 1995;48:M184-M187
  56. 56. Corvalán AH, Ding S, Koriyama C, Carrascal E, Carrasquilla G, Backhouse C, Urzua L, Argandona J, Palma M, Eizuru Y, Akiba S. Association of a distinctive strain of Epstein-Barr virus with gastric cancer. International Journal of Cancer. 2006;118:1736-1742. DOI: 10.1002/ijc.21530
  57. 57. Zouridis H, Deng N, Ivanova T, Zhu Y, Wong B, Huang D, Wu YH, Wu Y, Tan IB, Liem N, Gopalakrishnan V, Luo Q, Wu J, et al. Methylation subtypes and large-scale epigenetic alterations in gastric cancer. Science Translational Medicine. 2012;4:156ra140. DOI: 4/156/156ra140 [pii]
  58. 58. Loh M, Liem N, Vaithilingam A, Lim PL, Sapari NS, Elahi E, Mok ZY, Cheng CL, Yan B, Pang B, Salto-Tellez M, Yong WP, Iacopetta B, et al. DNA methylation subgroups and the CpG island methylator phenotype in gastric cancer: A comprehensive profiling approach. BMC Gastroenterology. 2014;14:55. DOI: 1471-230X-14-55 [pii]
  59. 59. Cech TR, Steitz JA. The noncoding RNA revolution-trashing old rules to forge new ones. Cell. 2014;157:77-94. DOI: 10.1016/j.cell.2014.03.008
  60. 60. Chen ZX, Riggs AD. DNA methylation and demethylation in mammals. The Journal of Biological Chemistry. 2011;286:18347-18353. DOI: 10.1074/jbc.R110.205286
  61. 61. Collas P, Noer A, Timoskainen S. Programming the genome in embryonic and somatic stem cells. Journal of Cellular and Molecular Medicine. 2007;11:602-620. DOI: 10.1111/j.1582-4934.2007.00079.x
  62. 62. Vavouri T, Lehner B. Human genes with CpG island promoters have a distinct transcription-associated chromatin organization. Genome Biology. 2012;13:R110. DOI: 10.1186/gb-2012-13-11-r110
  63. 63. Padmanabhan N, Ushijima T, Tan P. How to stomach an epigenetic insult: The gastric cancer epigenome. Nature Reviews. Gastroenterology & Hepatology. 2017;14:467-478. DOI: 10.1038/nrgastro.2017.53
  64. 64. Oue N, Mitani Y, Motoshita J, Matsumura S, Yoshida K, Kuniyasu H, Nakayama H, Yasui W. Accumulation of DNA methylation is associated with tumor stage in gastric cancer. Cancer. 2006;106:1250-1259. DOI: 10.1002/cncr.21754
  65. 65. Akiba S, Koriyama C, Herrera-Goepfert R, Eizuru Y. Epstein-Barr virus associated gastric carcinoma: Epidemiological and clinicopathological features. Cancer Science. 2008;99:195-201 DOI: CAS674 [pii]
  66. 66. Ryan JL, Jones RJ, Kenney SC, Rivenbark AG, Tang W, Knight ER, Coleman WB, Gulley ML. Epstein-Barr virus-specific methylation of human genes in gastric cancer cells. Infectious Agents and Cancer. 2010;5:27. DOI: 1750-9378-5-27 [pii]
  67. 67. Ferrasi AC, Pinheiro NA, Rabenhorst SH, Caballero OL, Rodrigues MA, de Carvalho F, Leite CV, Ferreira MV, Barros MA, Pardini MI. Helicobacter pylori and EBV in gastric carcinomas: Methylation status and microsatellite instability. World Journal of Gastroenterology. 2010;16:312-319
  68. 68. Bernal C, Vargas M, Ossandon F, Santibanez E, Urrutia J, Luengo V, Zavala LF, Backhouse C, Palma M, Argandona J, Aguayo F, Corvalán AH. DNA methylation profile in diffuse type gastric cancer: Evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis. Biological Research. 2008;41:303-315
  69. 69. McCormick TM, Canedo NH, Furtado YL, Silveira FA, de Lima RJ, Rosman AD, Almeida Filho GL, Carvalho MG. Association between human papillomavirus and Epstein-Barr virus DNA and gene promoter methylation of RB1 and CDH1 in the cervical lesions: A transversal study. Diagnostic Pathology. 2015;10:59. DOI: 10.1186/s13000-015-0283-3
  70. 70. He D, Zhang YW, Zhang NN, Zhou L, Chen JN, Jiang Y, Shao CK. Aberrant gene promoter methylation of p16, FHIT, CRBP1, WWOX, and DLC-1 in Epstein-Barr virus-associated gastric carcinomas. Medical Oncology 2015;32:92. DOI: 10.1007/s12032-015-0525-y
  71. 71. Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clinica Chimica Acta. 2013;424:53-65. DOI: 10.1016/j.cca.2013.05.002
  72. 72. Chong JM, Sakuma K, Sudo M, Ushiku T, Uozaki H, Shibahara J, Nagai H, Funata N, Taniguchi H, Aburatani H, Fukayama M. Global and non-random CpG-island methylation in gastric carcinoma associated with Epstein-Barr Virus. Cancer Science. 2003;94:76-80
  73. 73. Geddert H, Zur Hausen A, Gabbert HE, Sarbia M. EBV-infection in cardiac and non-cardiac gastric adenocarcinomas is associated with promoter methylation of p16, p14 and APC, but not hMLH1. Analytical cellular pathology (Amsterdam). 2010;33:143-149. DOI: 10.3233/acp-clo-2010-0540
  74. 74. Ushiku T, Chong JM, Uozaki H, Hino R, Chang MS, Sudo M, Rani BR, Sakuma K, Nagai H, Fukayama M. p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma. International Journal of Cancer. 2007;120:60-66. DOI: 10.1002/ijc.22275
  75. 75. Kang GH, Lee S, Kim WH, Lee HW, Kim JC, Rhyu MG, Ro JY. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. The American Journal of Pathology. 2002;160:787-794. DOI: S0002-9440(10)64901-2 [pii]10.1016/S0002-9440(10)64901-2
  76. 76. Zong L, Seto Y. CpG island methylator phenotype, helicobacter pylori, Epstein-Barr virus, and microsatellite instability and prognosis in gastric cancer: A systematic review and meta-analysis. PLoS One 2014;9:e86097. DOI: 10.1371/journal.pone.0086097
  77. 77. Kaneda A, Matsusaka K, Aburatani H, Fukayama M. Epstein-Barr virus infection as an epigenetic driver of tumorigenesis. Cancer Research. 2012;72:3445-3450. DOI: 0008-5472.CAN-11-3919 [pii]10.1158/0008-5472.CAN-11-3919
  78. 78. Hino R, Uozaki H, Murakami N, Ushiku T, Shinozaki A, Ishikawa S, Morikawa T, Nakaya T, Sakatani T, Takada K, Fukayama M. Activation of DNA methyltransferase 1 by EBV latent membrane protein 2A leads to promoter hypermethylation of PTEN gene in gastric carcinoma. Cancer Research. 2009;69:2766-2774. DOI: 0008-5472.CAN-08-3070 [pii]10.1158/0008-5472.CAN-08-3070
  79. 79. Zhao J, Liang Q, Cheung KF, Kang W, Lung RW, Tong JH, To KF, Sung JJ, Yu J. Genome-wide identification of Epstein-Barr virus-driven promoter methylation profiles of human genes in gastric cancer cells. Cancer. 2013;119:304-312. DOI: 10.1002/cncr.27724
  80. 80. Sandoval-Borquez A, Saavedra K, Carrasco-Aviño G, Garcia-Bloj B, Fry J, Wichmann I, Corvalan AH. Noncoding genomics in gastric cancer and the gastric precancerous cascade: Pathogenesis and biomarkers. Disease Markers. 2015;2015:14. DOI: 10.1155/2015/503762
  81. 81. Pfeffer S, Zavolan M, Grasser FA, Chien M, Russo JJ, Ju J, John B, Enright AJ, Marks D, Sander C, Tuschl T. Identification of virus-encoded microRNAs. Science. 2004;304:734-736. DOI: 10.1126/science.1096781
  82. 82. Grundhoff A, Sullivan CS. Virus-encoded microRNAs. Virology. 2011;411:325-343. DOI: 10.1016/j.virol.2011.01.002
  83. 83. Klinke O, Feederle R, Delecluse HJ. Genetics of Epstein-Barr virus microRNAs. Seminars in Cancer Biology. 2014;26:52-59. DOI: 10.1016/j.semcancer.2014.02.002
  84. 84. Kozomara A, Griffiths-Jones S. miRBase: Annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Research. 2014;42:D68-D73. DOI: 10.1093/nar/gkt1181
  85. 85. Lung RW, Tong JH, To KF. Emerging roles of small Epstein-Barr virus derived non-coding RNAs in epithelial malignancy. International Journal of Molecular Sciences. 2013;14:17378-17409 DOI: ijms140917378 [pii]
  86. 86. Edwards RH, Marquitz AR, Raab-Traub N. Epstein-Barr virus BART microRNAs are produced from a large intron prior to splicing. Journal of Virology. 2008;82:9094-9106. DOI: 10.1128/jvi.00785-08
  87. 87. Kim do N, Chae HS, Oh ST, Kang JH, Park CH, Park WS, Takada K, Lee JM, Lee WK, Lee SK. Expression of viral microRNAs in Epstein-Barr virus-associated gastric carcinoma. Journal of Virology. 2007;81:1033-1036. DOI: JVI.02271-06 [pii]10.1128/JVI.02271-06
  88. 88. Marquitz AR, Mathur A, Chugh PE, Dittmer DP, Raab-Traub N. Expression profile of microRNAs in Epstein-Barr virus-infected AGS gastric carcinoma cells. Journal of Virology. 2014;88:1389-1393 DOI: JVI.02662-13 [pii]
  89. 89. Treece AL, Duncan DL, Tang W, Elmore S, Morgan DR, Dominguez RL, Speck O, Meyers MO, Gulley ML. Gastric adenocarcinoma microRNA profiles in fixed tissue and in plasma reveal cancer-associated and Epstein-Barr virus-related expression patterns. Laboratory Investigation. 2016;96:661-671. DOI: 10.1038/labinvest.2016.33
  90. 90. Kang D, Skalsky RL, Cullen BR. EBV BART MicroRNAs target multiple pro-apoptotic cellular genes to promote epithelial cell survival. PLoS Pathogens. 2015;11:e1004979. DOI: 10.1371/journal.ppat.1004979
  91. 91. Shinozaki-Ushiku A, Kunita A, Isogai M, Hibiya T, Ushiku T, Takada K, Fukayama M. Profiling of virus-encoded MicroRNAs in Epstein-Barr virus-associated gastric carcinoma and their roles in gastric carcinogenesis. Journal of Virology. 2015;89:5581-5591 JVI.03639-14 [pii]
  92. 92. Choy EY, Siu KL, Kok KH, Lung RW, Tsang CM, To KF, Kwong DL, Tsao SW, Jin DY. An Epstein-Barr virus-encoded microRNA targets PUMA to promote host cell survival. The Journal of Experimental Medicine. 2008;205:2551-2560. DOI: 10.1084/jem.20072581
  93. 93. Shinozaki A, Sakatani T, Ushiku T, Hino R, Isogai M, Ishikawa S, Uozaki H, Takada K, Fukayama M. Downregulation of microRNA-200 in EBV-associated gastric carcinoma. Cancer Research. 2010;70:4719-4727. DOI: 10.1158/0008-5472.can-09-4620
  94. 94. Du Y, Xu Y, Ding L, Yao H, Yu H, Zhou T, Si J. Down-regulation of miR-141 in gastric cancer and its involvement in cell growth. Journal of Gastroenterology. 2009;44:556-561. DOI: 10.1007/s00535-009-0037-7
  95. 95. Yau TO, Tang CM, Yu J. Epigenetic dysregulation in Epstein-Barr virus-associated gastric carcinoma: Disease and treatments. World Journal of Gastroenterology. 2014;20:6448-6456. DOI: 10.3748/wjg.v20.i21.6448

Written By

Alejandra Alarcón, Ursula Figueroa, Bastian Espinoza, Alejandra Sandoval, Gonzalo Carrasco-Aviño, Francisco R. Aguayo and Alejandro H. Corvalan

Reviewed: 23 June 2017 Published: 20 September 2017