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Association between Epstein-Barr virus infection and gastric cancer: a systematic review and meta-analysis

Abstract

Background

Numerous studies conducted over the past 30 years have pointed to the presence of Epstein–Barr virus (EBV) in gastric cancer samples. This study was aimed to provide a meta-analytic review of the prevalence of EBV in gastric cancer patients, and to clarify the relationship between EBV infection and gastric cancer.

Methods

A literature search was performed electronically using online databases for English language publications until July 1, 2019. The pooled EBV prevalence and 95% confidence intervals (CIs) were estimated using a random-effects model. To determine the association between EBV and gastric cancer, pooled odds ratio (OR) and its 95% CI were computed for case-control studies. Two separate analyses were performed on data from case-control studies with matched and non-match pairs designs to calculate the pooled estimates of ORs.

Results

The pooled prevalence of EBV in 20,361 gastric cancer patients was 8.77% (95% CI: 7.73–9.92%; I2 = 83.2%). There were 20 studies with matched pairs design, including tumor and tumor-adjacent normal tissue pairs from 4116 gastric cancer patients. The pooled ORs were 18.56 (95% CI: 15.68–21.97; I2 = 55.4%) for studies with matched pairs design and 3.31 (95% CI: 0.95–11.54; I2 = 55.0%) for studies with non-matched pairs design. The proportion of EBV-associated gastric cancer among male cases was significantly higher than among female cases (10.83%, vs. 5.72%) (P < 0.0001). However, the pooled OR estimate for EBV-associated gastric cancer was significantly higher among females (21.47; 95% CI: 15.55–29.63; I2 = 0%) than in males (14.07; 95% CI: 10.46–18.93; I2 = 49.0%) (P = 0.06). EBV was more prevalent in the cardia (12.47%) and the body (11.68%) compared to the antrum (6.29%) (P = 0.0002).

Conclusions

EBV infection is associated with more than 18 times increase the risk of gastric cancer. Although the prevalence of EBV was higher in male patients than in female patients with gastric cancer, women are more likely than men to develop EBV-associated gastric cancer. Our findings showed that using tumor-adjacent normal tissues as the control group provides more robust and accurate results regarding the relationship between EBV infection and gastric cancer.

Peer Review reports

Background

According to GLOBOCAN statistics in 2018, gastric cancer is the fifth most frequently diagnosed cancer and the third leading cause of cancer-related mortality in the world accounted for 8.2% of all cancer deaths. Over 1,000,000 new cases of gastric cancer diagnosed in 2018 around the world, with an estimated 783,000 deaths [1]. Gastric cancer arises from a combination of multiple environmental and genetic risk factors, and infectious agents are one of the critical environmental factors which contribute to an increased risk of developing several malignancies [2].

Epstein-Barr virus (EBV), as a member of the Herpesviridae family, is the first described human cancer virus and is responsible for approximately 1.8% of all human cancers, including Hodgkin lymphoma, Burkitt lymphoma, NK/T cell lymphoma, and nasopharyngeal carcinoma [3]. However, the role of EBV in the development of other malignancies is still under investigation. At the beginning of the 1990s, the association between EBV and gastric carcinomas was found. The first report was made by Burke et al. in a case of lymphoepithelial-like gastric carcinoma [4], and afterwards, the association was observed in gastric adenocarcinoma [5]. Subsequently, numerous studies demonstrated an essential role of EBV in gastric carcinogenesis.

To date, the mechanisms of EBV-associated gastric cancer are still not comprehensively clarified. Generally, virologic aspects, in conjunction with host genome abnormalities, co-potentiate the cancer progression. Regarding the virologic background, the EBV genome encodes oncoproteins, which target important cellular pathways. EBV-associated gastric cancer belongs to latency type I infection, in which only EBNA1, EBER, BamHI A rightward transcript (BART), and BART miRNAs are highly expressed, while the latent membrane protein 2A (LMP2A) can be detected in 40% of cases [6]. Evidence suggests that latent infection by EBV and the expression of the EBV latent genes lead to the host genome abnormalities like aberrant DNA methylation, which has attracted more attention in recent years [7].

The gold standard for the diagnosis of EBV infection in histopathologic samples is ISH, which detects EBV-encoded small RNA-1 (EBER1). EBER1 is highly expressed in latently EBV-infected cells (up to 107 copies per cell) [8]. EBER1 signals are commonly identified in the nuclei of nearly all carcinoma cells in EBV-associated gastric carcinoma [9]. PCR-based methods are also widely used for the diagnosis of EBV infection. Although PCR is a cost-efficient and simple technique for the detection of EBV infection, it is prone to false-positive results due to its low specificity. The low specificity of PCR can be explained by the fact that memory cells and/or non-tumor, bystander lymphocytes may also be investigated for the presence of the EBV genome. Therefore, PCR-based methods are more sensitive but less specific than the gold standard ISH method to detect EBV [10, 11].

There are several published meta-analyses addressing the prevalence of EBV among gastric cancer patients [12,13,14,15,16], however, their results are out of date and only descriptive. On the other hand, they did not perform any analysis to estimate the association between the EBV and gastric cancer risk. The last meta-analysis conducted by Bae et al. focused on the results of case-control studies published up to 2014 to prove the relationship between EBV and gastric cancer for the first time [17]. However, some important variables such as gender, type of samples, and tumor anatomical location did not include in their meta-analysis. Our meta-analysis aims to determine the association of EBV infection with gastric cancer and to provide an updated pooled prevalence of EBV infection among gastric cancer patients. It is anticipated that the results of the present study will direct future experimental studies toward elucidating the role of EBV infection in the carcinogenesis of gastric cancer, and will inform clinicians and policy-makers to improve preventive intervention and control.

Methods

The present systematic review and meta-analysis was performed according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement [18].

Search strategy

A rigorous literature search was conducted using PubMed, Web of Science, Scopus, EMBASE, and Google scholar to identify all published articles reporting the prevalence of EBV in patients with gastric cancer. Databases were searched from inception to July 1, 2019. The bibliographies of all articles obtained were also reviewed for additional relevant publications. The list of keywords used for this systematic review and meta-analysis is provided in Additional file 1.

Study selection

All records were imported to EndNote software version X8 (Thomson Reuters, California, USA), and duplicate entries were removed. The screening of the title and abstract of the remaining records was independently conducted by two researchers. The full-texts of the remaining records were then retrieved and reviewed, and any disagreements were resolved through discussion by a third investigator.

Eligibility criteria

Studies were considered eligible for inclusion in the present meta-analysis, if they met the following criteria: (1) Studies using cross-sectional and case-control designs reporting the prevalence of EBV infection in patients with different types of gastric carcinoma; (2) Studies using EBER-ISH technique to detect the presence of EBV transcripts or nucleic acids; (3) Studies using the formalin-fixed paraffin-embedded (FFPE) tissues and biopsies samples; (4) Studies published in peer-reviewed journals in the English language.

Studies with following characteristics were excluded from the present meta-analysis: (1) Studies using serological techniques such as enzyme-linked immunosorbent assay (ELISA) to detect circulating antibodies to EBV infection; (2) Studies evaluating the presence of EBV in serum, plasma or peripheral blood mononuclear cell (PBMC) samples; (3) Studies assessing the presence of EBV in gastric carcinoma patients with underlying disorders; (4) Studies evaluating the presence of EBV by molecular methods such as PCR, nested-PCR and Real-Time PCR; (5) Studies addressing remnant gastric cancer, gastric lymphoma, and other types of gastric malignancies; (6) Studies using techniques other than EBER-ISH, (7) Studies published in languages other than English; (8) Reviews, letters to the editor, abstracts, and case reports.

Data extraction and quality assessment

Two investigators independently extracted data from all eligible studies in a pre-designed data extraction form using Microsoft Excel 2013 (Microsoft Corporation, Redmond, Washington, USA). The two investigators cross-checked each other’s data extraction, and any disagreements were resolved by a third investigator. After retrieving the eligible articles, a modified checklist based on the guidelines of the strengthening the reporting of observational studies in epidemiology (STROBE) was used for assessing the risk of bias of the included studies [19, 20]. The checklist includes 12 questions that cover different methodological aspects. According to the checklist, the highest score was 12, representing the highest quality, and the minimum acceptable score was 8. Lastly, studies obtained the minimum score, and more were considered eligible to include in the main meta-analysis. The following characters were extracted from each study: first author’s name, publication date, study location, study design, sample size, sex, type of specimen, histological type, number of EBV-positive samples, tumor anatomical location, depth of invasion, tumor stage, and lymph node invasion.

Statistical analysis

The present meta-analysis had two primary purposes; first, providing an updated estimate of the pooled prevalence of EBV among patients with gastric cancer, and secondly, investigating the association between EBV and the development of gastric cancer. A random-effect meta-analysis using the inverse variance method was applied to estimate the pooled prevalence of EBV (DerSimonian-Laird method) [21]. The logit transformation was used for stabilizing the variance and data normalization, and the Clopper-Pearson method was applied to determine the 95% confidence intervals (CIs) for proportions [22].

To evaluate the strength of the association between EBV infection and gastric cancer risk, the pooled odds ratios (ORs) with 95% CIs were generated from a random-effects model based on the DerSimonian-Laird method. For studies with a zero cell, a continuity correction of 0.5 was applied. We also conducted subgroup analyses to identify the possible sources of heterogeneity. The heterogeneity among the studies was assessed through I2 statistics [23]. To explore potential publication bias and symmetric assumption among the included studies, a Begg’s funnel plot was constructed [24]. All the above-mentioned analyses were conducted using the R package “meta” (version 3.5.3 [2019-03-11]) [25, 26], and P values less than 0.05 were considered statistically significant. Furthermore, for each case-control study with matched pairs design, we separately computed matched-pairs OR and its corresponding variance using the “escalc” function in the R “metafor” package [27] (version 2.1–0 [2019-05-13]. The obtained results were then used for performing meta-analysis to calculate the matched pairs pooled OR.

Results

Literature selection

The electronic database searches were identified 597 articles, and additional 14 relevant records were found through bibliographic hand searching. Of these 611 articles, 151 duplicates were excluded, so a total of 460 articles was screened according to their title and abstract. A total of 353 articles was eliminated after reading the title and abstract due to apparent irrelevance. The remaining 107 articles were assessed for agreement with the inclusion and exclusion criteria by the full-text review, and 72 papers met the scope criteria. Based on the modified STROBE checklist, 71 papers were deemed to have good quality (obtained scores of 8 and above), and only one paper [28] was failed to reach score 8. Finally, 71 papers were included in this systematic review and meta-analysis. Figure 1 shows the process of literature retrieval and screening using a flow chart.

Fig. 1
figure1

Flowchart presenting the steps of literature search and selection

Study characteristics

Table 1 shows the characteristics of eligible studies included in the systematic review and meta-analysis. Out of 71 studies, 30 were case-control, and 41 were cross-sectional in design. Publication dates ranged from 1993 to 2019, and over half of the studies (59.1%) described specimens recruited before 2005. Among the studies included in this meta-analysis, four were from Africa, 16 were from America, 35 were from Asia, and 17 were from Europe. Of the 72 studies included, 46 provided information on patients’ sex, 40 studies provided data on histological type, and 35 had data on tumor anatomical location. The most extensive study included 2226 gastric cancer cases, and the smallest covered 19 cases. Most studies were from Japan (n = 15).

Table 1 Characteristics of the included studies in this systematic review and meta-analysis

The prevalence of EBV among gastric cancer patients

The first aim of the current study was to determine the pooled prevalence of EBV in 20,361 gastric cancer patients from 26 countries, and the range was from 1.69 to 43.75% of the selected individual studies. Figure 2 shows the prevalence of EBV and 95% CI estimates from individual studies according to the random-effects model. The pooled prevalence of EBV among gastric cancer patients was 8.77% (95% CI: 7.73–9.92%; I2 = 83.2%). The highest and lowest prevalence of EBV were found in gastric cancer patients from Poland and the United Kingdom, respectively (25.57, 95%CI: 6.13–64.36% vs. 2.78, 95%CI: 1.51–5.06%). The proportion of EBV-positive gastric cancer among male cases was significantly higher than among female cases (10.83, 95%CI: 9.43–12.40% vs 5.72, 95%CI: 4.27–7.64%) (P < 0.0001) (Fig. 3). Table 2 presents more detailed information on the prevalence of EBV infection in gastric cancer patients for subgroups.

Fig. 2
figure2

Forest plot of the prevalence of EBV infection among gastric cancer patients, according to the random effect model

Fig. 3
figure3

Forest plot of the prevalence of EBV infection among gastric cancer patients, according to the random effect model in females (a) and males (b)

Table 2 Subgroup analysis of the prevalence of EBV infection in gastric cancer patients

The association between EBV and gastric cancer

Among 30 case-control studies, 20 had matched pairs design, including tumor and tumor-adjacent normal tissue pairs from 4116 gastric cancer patients. The remaining ten non-matched case-control studies included 911 cases of gastric cancer and 436 controls. Using data obtained from studies with non-matched pairs design, the pooled OR of EBV infection was 3.31 (95% CI: 0.95–11.54; I2 = 55.0%), whereas the pooled OR for studies with matched pairs design was 18.56 (95% CI: 15.68–21.97; I2 = 55.4%), indicating a solid significant positive relationship between EBV infection and gastric cancer (Fig. 4). So, we further performed a subgroup analysis for studies with matched pairs design. Table 3 presents details on the association between EBV infection and gastric cancer risk for subgroups. Finally, the analysis of the funnel plot did not show evidence of asymmetry (Fig. 5), and Begg’s test indicated an absence of publication bias among all the studies included in this meta-analysis (P = 0.18).

Fig. 4
figure4

Forest plot of the association between EBV infection and gastric cancer risk (according to random effect model) in studies with match pairs design (a) and non-match pairs design (b)

Table 3 Subgroup analysis of association between EBV infection and gastric cancer risk
Fig. 5
figure5

Funnel plot for assessment of publication bias

Discussion

Our meta-analysis showed that the pooled prevalence of EBV among gastric cancer patients from 26 countries is 8.77% (95% CI: 7.73–9.92%; I2 = 83.2%). We chose strict inclusion and exclusion criteria to obtain pertinent studies and to increase the chance of finding a valid conclusion. The pooled prevalence and OR obtained in this meta-analysis were calculated from studies that detected EBV infection with the ISH method. All studies that investigated the presence of EBV by other methods, including different types of PCR assays, and even immunohistochemistry (IHC), did not consider in our analysis. The reason for this stems from the fact that the sensitivity and specificity of each detection method are different, and it is not reliable to draw a conclusion using the pooled data.

The gold standard technique for the detection of EBV in tissues is ISH with EBV EBERs (EBER-ISH) due to its high sensitivity and specificity to determine the precise intranuclear localization of the EBV-infected cells. The diagnosis of EBV-associated gastric cancer is confirmed by the presence of EBER within the tumor cells and its absence in the normal tissue adjacent to the tumor [3]. Many studies have reported the higher prevalence of EBV among gastric cancer patients by PCR assay than the EBER-ISH technique [17]. However, PCR is unable to discriminate between cancer cells and lymphocytes infiltrating in tumor stromal, and thus it is impossible to know from where the EBV genome is amplified. It should be noted that the vast majority of people (nearly 90%) are EBV carriers, and their lymphocytes probably contain EBV genomes [11]. Regarding the statements above, our meta-analysis exclusively focused on the positivity of the EBV-associated gastric cancers by ISH only.

One of the major strong points in this meta-analysis is that the pooled estimates of ORs were calculated from studies with matched pairs and non-matched pairs designs, separately, with different statistical methods. The detailed descriptions about the analysis of data for matched pairs and non-matched pairs studies are available in several previous studies [98]. It has been recommended that a matched-pairs analysis should be used to assess effect sizes for studies with matched pairs design. Accordingly, the pooled OR determined for studies with non-matched pairs and matched pairs designs were 3.31 (95% CI: 0.95–11.54; I2 = 55.0%) and 18.56 (95% CI: 15.68–21.97; I2 = 55.4%), respectively. We performed two separate analyses for studies with match pairs and non-match pairs designs to demonstrate that the strength of association (ORs) between EBV infection and gastric cancer is the highest when tumor-adjacent normal tissues are used as a control group. This is due to the fact that confounding variables are eliminated from data analysis. Therefore, we can obtain more accurate and robust estimates of the association between EBV and gastric cancer. This finding of our study will be beneficial for researchers to design their future case-control studies appropriately. Using the tumor-adjacent normal tissues as the control group will provide more accurate results regarding the relationship between EBV infection and gastric cancer.

To date, several studies have attempted to discover the role of EBV infection in gastric cancer progression. EBV enters B lymphocytes in oropharyngeal lymphoid tissues. The virus then enters the gastric epithelial cells, either by the cell-to-cell contact between B lymphocytes and gastric epithelial cells or by direct entry into the gastric epithelia [99]. It has been reported that EBV entry into the gastric epithelial cells is facilitated by the previous mucosal damage [68]. After the virus enters the cell, EBV establishes type I latency in which a limited set of the latent gene is expressed [79]. A recent systematic review study showed that the most of the EBV latent proteins expressed in gastric cancer cases were EBNA1 (98.1%) and LMP2A (53.8%), whereas LMP1 and LMP2B were detected in only 10% of EBV-associated gastric cancer cases. Some of the lytic proteins, such as BARF1, were also reported to be present in almost half of EBV-associated gastric cancer cases [100]. It is shown that the EBV-encoded BARF1 acts as an oncogene and promotes cell proliferation in gastric cancer through upregulation of NF-κB signaling and reduction of the cell cycle inhibitor p21 [101]. It is well known that DNA methylation plays a crucial role in gastric cancer development and progression [102]. Methylation of both viral and cellular genome is one of the critical mechanisms involved in the development and maintenance of EBV-associated gastric cancer. It is well documented that EBV latent membrane protein 2A (LMP2A) plays a variety of key roles in the epigenetic abnormalities such as aberrant DNA methylation in host stomach cells, and the development and maintenance of EBV-associated gastric cancer [9].

Another interesting finding of our meta-analysis is that the prevalence of EBV was 1.9-fold higher in male patients than in female patients with gastric cancer (P < 0.0001). However, the OR estimate for EBV-associated gastric cancer was significantly higher among females than in males (P = 0.06). According to these results, we concluded that women are more likely than men (1.5-fold) to develop EBV-associated gastric cancer. This novel finding can be explained by different genetic backgrounds, lifestyles, or hormonal conditions between the two genders.

Subgroup analyses based on the tumor anatomical location indicate an anatomic preference for EBV during gastric carcinogenesis. Indeed, EBV-associated gastric cancers were significantly more prevalent in the cardia and the body of the stomach than in the antrum (P = 0.0002) (Table 2). However, the situation was different when OR was calculated. So that the OR estimate for EBV-associated gastric cancer was remarkably higher in the antrum than in the cardia and in the body (Table 3), although the difference was not statistically significant. This feature can be justified by the fact that the various parts of the stomach have different physiological conditions.

One prominent finding of the present meta-analysis is that EBV was detected more frequently in biopsy samples than in FFPE specimens from gastric cancer patients (2.4-fold, P < 0.0001). It is well documented that there are several challenges when working with FFPE samples, such as the low amount of extracted nucleic acids, and fragmentation of genomes and transcripts during the processes of fixation and embedding in paraffin. Therefore, to prevent false-negative results, using biopsy samples is recommended.

According to Lauren’s histological classification, gastric carcinoma is classified into two distinct types, namely intestinal and diffuse types. There are many differences between intestinal and diffuse types based on their epidemiology, etiology, and pathology [82]. However, the current meta-analysis showed that the prevalence of EBV was similar in intestinal and diffuse types (8.10 and 9.41%, respectively), and no significant association of EBV infection with the histological type was found (P = 0.31).

Similarly, our results did not indicate any significant difference in the prevalence of EBV-associated gastric cancer among different geographic regions, even between developed and developing countries. The same prevalence in developed and developing countries demonstrates that economic conditions are not related to EBV-associated gastric cancer risk.

There are some limitations in this study arose from the nature of the data sources used in the meta-analysis. Gastric cancer is a multifactorial disease affected by several risk factors. Age is considered as a risk factor for the development of EBV-associated gastric carcinoma. However, the majority of studies included in the current meta-analysis did not categorize EBV-infected and -uninfected gastric cancer patients based on the age group. Subsequently, we were not able to perform a subgroup analysis in this regard. Besides, there are some reports on the association between Helicobacter pylori infection and gastric cancer. Nevertheless, we did not consider data regarding the co-infection of EBV and Helicobacter pylori.

Conclusions

To sum up, our meta-analysis suggests that the pooled prevalence of EBV among patients with gastric cancer was 8.77%. To determine the association between EBV infection and gastric cancer, a matched-pairs analysis from case-control studies was performed, and the pooled OR was calculated 18.56. This finding indicates a robust positive association between EBV infection and gastric cancer risk. We recommend using biopsy instead of FFPE samples and the ISH technique instead of PCR methods to ensure the validity of results.

Furthermore, the pooled prevalence of EBV was obtained from data from 26 countries in the world. Therefore, conducting studies in other geographical regions is strongly recommended to get more reliable estimates. Furthermore, we suggest that researchers use the tumor-adjacent normal tissues as the control group for their case-control studies to achieve more accurate results regarding the relationship between EBV infection and gastric cancer.

Availability of data and materials

All data generated or analyzed during this study are included in this article.

Abbreviations

EBV:

Epstein–Barr virus

CI:

Confidence interval

OR:

Odds ratio

EBER:

EBV-encoded small RNA

ISH:

In situ hybridization

PCR:

Polymerase chain reaction

FFPE:

Formalin-fixed paraffin-embedded

ELISA:

Enzyme-linked immunosorbent assay

PBMC:

Peripheral blood mononuclear cell

IHC:

Immunohistochemistry

LMP:

Latent membrane protein

BARF-1:

BamH1-A Reading Frame-1

NF-κB:

Nuclear factor kappa B

EBNA-1:

Epstein–Barr nuclear antigen 1

References

  1. 1.

    Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.

    PubMed  PubMed Central  Article  Google Scholar 

  2. 2.

    BenAyed-Guerfali D, Ayadi W, Miladi-Abdennadher I, Khabir A, Sellami-Boudawara T, Gargouri A, et al. Characteristics of epstein barr virus variants associated with gastric carcinoma in Southern Tunisia. Virol J. 2011;8(1):1–9.

    Article  Google Scholar 

  3. 3.

    Ribeiro J, Oliveira A, Malta M, Oliveira C, Silva F, Galaghar A, et al. Clinical and pathological characterization of Epstein-Barr virus-associated gastric carcinomas in Portugal. World J Gastroenterol. 2017;23(40):7292–302.

    PubMed  PubMed Central  Article  Google Scholar 

  4. 4.

    Burke A, Yen T, Shekitka K, Sobin L. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 1990;3(3):377–80.

    CAS  PubMed  Google Scholar 

  5. 5.

    Shibata D, Weiss L. Epstein-Barr virus-associated gastric adenocarcinoma. Am J Pathol. 1992;140(4):769–74.

    CAS  PubMed  PubMed Central  Google Scholar 

  6. 6.

    Iizasa H, Nanbo A, Nishikawa J, Jinushi M, Yoshiyama H. Epstein-Barr Virus (EBV)-associated gastric carcinoma. Viruses. 2012;4(12):3420–39.

    PubMed  PubMed Central  Article  Google Scholar 

  7. 7.

    Kang W, To KF. Are Epstein-Barr virus-positive and-negative gastric carcinomas, with lymphoid stroma, single entity or different entities? Clin Gastroenterol Hepatol. 2015;13(10):1745–7.

    PubMed  Article  Google Scholar 

  8. 8.

    Shinozaki-Ushiku A, Kunita A, Fukayama M. Update on Epstein-Barr virus and gastric cancer. Int J Oncol. 2015;46(4):1421–34.

    CAS  PubMed  Article  Google Scholar 

  9. 9.

    Nishikawa J, Iizasa H, Yoshiyama H, Shimokuri K, Kobayashi Y, Sasaki S, et al. Clinical importance of Epstein–Barr virus-associated gastric cancer. Cancers. 2018;10(6):1–13.

    Article  CAS  Google Scholar 

  10. 10.

    Deyhimi P, Kalantari M. Study of Epstein-Barr virus expression in Burkitt's lymphoma by polymerase chain reaction and in situ hybridization: a study in Iran. Dent Res J. 2014;11(3):380–5.

    Google Scholar 

  11. 11.

    Chen X-Z, Chen H, Castro FA, Hu J-K, Brenner H. Epstein–Barr virus infection and gastric cancer: a systematic review. Medicine. 2015;94(20):1–9.

    Article  CAS  Google Scholar 

  12. 12.

    Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein–Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137(3):824–33.

    PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Li S, Du H, Wang Z, Zhou L, Zhao X, Zeng Y. Meta-analysis of the relationship between Epstein-Barr virus infection and clinicopathological features of patients with gastric carcinoma. Sci China Life Sci. 2010;53(4):524–30.

    PubMed  Article  Google Scholar 

  14. 14.

    Lee JH, Kim SH, Han SH, An JS, Lee ES, Kim YS. Clinicopathological and molecular characteristics of Epstein–Barr virus-associated gastric carcinoma: a meta-analysis. J Gastroenterol Hepatol. 2009;24(3):354–65.

    PubMed  Article  Google Scholar 

  15. 15.

    Sousa H, Pinto-Correia AL, Medeiros R, Dinis-Ribeiro M. Epstein-Barr virus is associated with gastric carcinoma: the question is what is the significance? World J Gastroenterol. 2008;14(27):4347–51.

    PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    Camargo M, Murphy G, Koriyama C, Pfeiffer R, Kim WH, Herrera-Goepfert R, et al. Determinants of Epstein-Barr virus-positive gastric cancer: an international pooled analysis. Br J Cancer. 2011;105(1):38–43.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  17. 17.

    Bae J-M, Kim EH. Epstein-Barr virus and gastric cancer risk: a meta-analysis with meta-regression of case-control studies. J Prev Med Public Health. 2016;49(2):97–107.

    PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med. 2009;151(4):264–9.

    Article  Google Scholar 

  19. 19.

    Eslamipour F, Afshari Z, Najimi A. Prevalence of orthodontic treatment need in permanent dentition of Iranian population: a systematic review and meta-analysis of observational studies. Dent Res J. 2018;15(1):1–10.

    Article  Google Scholar 

  20. 20.

    Moosazadeh M, Nekoei-moghadam M, Emrani Z, Amiresmaili M. Prevalence of unwanted pregnancy in Iran: a systematic review and meta-analysis. Int J Health Plann Manag. 2014;29(3):e277–90.

    Article  Google Scholar 

  21. 21.

    DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7(3):177–88.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  22. 22.

    Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 1998;17(8):857–72.

    CAS  PubMed  Article  Google Scholar 

  23. 23.

    Higgins JP, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in meta-analyses. BMJ. 2003;327(7414):557–60.

    PubMed  PubMed Central  Article  Google Scholar 

  24. 24.

    Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994;50(4):1088–101.

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Core Team R. R: a language and environment for statistical computing. Vienna: R Foundation for Statistical Computing; 2018. https://www.R-project.org.

    Google Scholar 

  26. 26.

    Schwarzer G. meta: an R package for meta-analysis. R News. 2007;7(3):40–5.

    Google Scholar 

  27. 27.

    Viechtbauer W. Conducting meta-analyses in R with the metafor package. J Stat Softw. 2010;36(3):1–48.

    Article  Google Scholar 

  28. 28.

    Karim N, Pallesen G. Epstein-Barr virus (EBV) and gastric carcinoma in Malaysian patients. Malays J Pathol. 2003;25(1):45–7.

    PubMed  Google Scholar 

  29. 29.

    Rowlands D, Ito M, Mangham D, Reynolds G, Herbst H, Hallissey M, et al. Epstein-Barr virus and carcinomas: rare association of the virus with gastric adenocarcinomas. Br J Cancer. 1993;68(5):1014–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  30. 30.

    Shibata D, Hawes D, Stemmermann GN, Weiss LM. Epstein-Barr virus-associated gastric adenocarcinoma among Japanese Americans in Hawaii. Cancer Epidemiol Biomark Prev. 1993;2(3):213–7.

    CAS  Google Scholar 

  31. 31.

    Tokunaga M, Uemura Y, Tokudome T, Ishidate T, Masuda H, Okazaki E, et al. Epstein-Barr virus related gastric cancer in Japan: a molecular patho-epidemiological study. Pathol Int. 1993;43(10):574–81.

    CAS  Article  Google Scholar 

  32. 32.

    Tokunaga M, Land C, Uemura Y, Tokudome T, Tanaka S, Sato E. Epstein-Barr virus in gastric carcinoma. Am J Pathol. 1993;143(5):1250–4.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. 33.

    Imai S, Koizumi S, Sugiura M, Tokunaga M, Uemura Y, Yamamoto N, et al. Monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc Natl Acad Sci. 1994;91(19):9131–5.

    CAS  PubMed  Article  Google Scholar 

  34. 34.

    Ott G, Kirchner T, Müller-Hermelink H. Monoclonal Epstein-Barr virus genomes but lack of EBV-related protein expression in different types of gastric carcinoma. Histopathology. 1994;25(4):323–9.

    CAS  PubMed  Article  Google Scholar 

  35. 35.

    Shousha S, Luqmani Y. Epstein-Barr virus in gastric carcinoma and adjacent normal gastric and duodenal mucosa. J Clin Pathol. 1994;47(8):695–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  36. 36.

    Yuen S, Chung L, Leung S, Luk I, Chan S, Ho J. In situ detection of Epstein-Barr virus in gastric and colorectal adenocarcinomas. Am J Surg Pathol. 1994;18(11):1158–63.

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Harn H-J, Chang J-Y, Wang M-W, Ho L-I, Lee H-S, Chiang J-H, et al. Epstein-Barr virus-associated gastric adenocarcinoma in Taiwan. Hum Pathol. 1995;26(3):267–71.

    CAS  PubMed  Article  Google Scholar 

  38. 38.

    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. Hum Pathol. 1996;27(1):20–7.

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Moritani S, Kushima R, Sugihara H, Hattori T. Phenotypic characteristics of Epstein-Barr-virus-associated gastric carcinomas. J Cancer Res Clin Oncol. 1996;122(12):750–6.

    CAS  PubMed  Article  Google Scholar 

  40. 40.

    Selves J, Bibeau F, Brousset P, Meggetto F, Mazerolles C, Voigt JJ, et al. Epstein-Barr virus latent and replicative gene expression in gastric carcinoma. Histopathology. 1996;28(2):121–7.

    CAS  PubMed  Article  Google Scholar 

  41. 41.

    Shin WS, Kang MW, Kang JH, Choi MK, Ahn BM, Kim JK, et al. Epstein-Barr virus-associated gastric adenocarcinomas among Koreans. Am J Clin Pathol. 1996;105(2):174–81.

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Galetsky SA, Tsvetnov VV, Land CE, Afanasieva TA, Petrovichev NN, Gurtsevitch VE, et al. Epstein-Barr-virus-associated gastric cancer in Russia. Int J Cancer. 1997;73(6):786–9.

    CAS  PubMed  Article  Google Scholar 

  43. 43.

    Clark GD, Lee YS, Min K-W, Dunn ST. Epstein-Barr virus in gastric carcinomas from Singapore. Int J Surg Pathol. 1996;4(3):149–58.

    Article  Google Scholar 

  44. 44.

    Ojima H, Fukuda T, Nakajima T, Nagamachi Y. Infrequent overexpression of p53 protein in Epstein-Barr virus-associated gastric carcinomas. Jpn J Cancer Res. 1997;88(3):262–6.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Yanai H, Nishikawa J, Mizugaki Y, Shimizu N, Takada K, Matsusaki K, et al. Endoscopic and pathologic features of Epstein-Barr virus–associated gastric carcinoma. Gastrointest Endosc. 1997;45(3):236–42.

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Herrera-Goepfert R, Reyes E, Hernández-Avila M, Mohar A, Shinkura R, Fujiyama C, et al. Epstein-Barr virus-associated gastric carcinoma in Mexico: analysis of 135 consecutive gastrectomies in two hospitals. Mod Pathol. 1999;12(9):873–8.

    CAS  PubMed  Google Scholar 

  47. 47.

    Kume T, Oshima K, Shinohara T, Takeo H, Yamashita Y, Shirakusa T, et al. Low rate of apoptosis and overexpression of bcl-2 in Epstein–Barr virus-associated gastric carcinoma. Histopathology. 1999;34(6):502–9.

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Takano Y, Kato Y, Saegusa M, Mori S, Shiota M, Masuda M, et al. The role of the Epstein-Barr virus in the oncogenesis of EBV (+) gastric carcinomas. Virchows Arch. 1999;434(1):17–22.

    CAS  PubMed  Article  Google Scholar 

  49. 49.

    Wan R, Gao M-Q, Gao L-Y, Chen B-F, Cai Q-K. In situ detection of Epstein-Barr virus in gastric carcinoma tissue in China highrisk area. World J Gastroenterol. 1999;5(6):531–2.

    PubMed  PubMed Central  Article  Google Scholar 

  50. 50.

    Chapel F, Fabiani B, Davi F, Raphael M, Tepper M, Champault G, et al. Epstein-Barr virus and gastric carcinoma in Western patients: comparison of pathological parameters and p53 expression in EBV-positive and negative tumours. Histopathology. 2000;36(3):252–61.

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Wu MS, Shun CT, Wu CC, Hsu TY, Lin MT, Chang MC, et al. Epstein–Barr virus—associated gastric carcinomas: relation to H. pylori infection and genetic alterations. Gastroenterology. 2000;118(6):1031–8.

    CAS  PubMed  Article  Google Scholar 

  52. 52.

    Corvalan A, Koriyama C, Akiba S, Eizuru Y, Backhouse C, Palma M, et al. 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. Int J Cancer. 2001;94(4):527–30.

    CAS  PubMed  Article  Google Scholar 

  53. 53.

    Kijima Y, Hokita S, Takao S, Baba M, Natsugoe S, Yoshinaka H, et al. Epstein-Barr virus involvement is mainly restricted to lymphoepithelial type of gastric carcinoma among various epithelial neoplasms. J Med Virol. 2001;64(4):513–8.

    CAS  PubMed  Article  Google Scholar 

  54. 54.

    Ishii H, Gobe G, Kawakubo Y, Sato Y, Ebihara Y. Interrelationship between Epstein–Barr virus infection in gastric carcinomas and the expression of apoptosis-associated proteins. Histopathology. 2001;38(2):111–9.

    CAS  PubMed  Article  Google Scholar 

  55. 55.

    Koriyama C, Akiba S, Iriya K, Yamaguti T, Hamada GS, Itoh T, et al. Epstein-Barr virus-associated gastric carcinoma in Japanese Brazilians and non-Japanese Brazilians in Sao Paulo. Jpn J Cancer Res. 2001;92(9):911–7.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Luqmani YA, Linjawi SO, Shousha S. Detection of Epstein-Barr virus in gastrectomy specimens. Oncol Rep. 2001;8(5):995–9.

    CAS  PubMed  Google Scholar 

  57. 57.

    Burgess D, Woodman C, Flavell K, Rowlands D, Crocker J, Scott K, et al. Low prevalence of Epstein–Barr virus in incident gastric adenocarcinomas from the United Kingdom. Br J Cancer. 2002;86(5):702–4.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. 58.

    Kang GH, Lee S, Kim WH, Lee HW, Kim JC, Rhyu M-G, et al. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol. 2002;160(3):787–94.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  59. 59.

    Kattoor J, Koriyama C, Akiba S, Itoh T, Ding S, Eizuru Y, et al. Epstein-Barr virus-associated gastric carcinoma in southern India: a comparison with a large-scale Japanese series. J Med Virol. 2002;68(3):384–9.

    PubMed  Article  Google Scholar 

  60. 60.

    Vo Q, Geradts J, Gulley M, Boudreau D, Bravo J, Schneider B. Epstein-Barr virus in gastric adenocarcinomas: association with ethnicity and CDKN2A promoter methylation. J Clin Pathol. 2002;55(9):669–75.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Czopek JP, Stojak M, Sińczak A, Popiela T, Kulig J, Rudzki Z, et al. EBV-positive gastric carcinomas in Poland. Pol J Pathol. 2003;54(2):123–8.

    PubMed  Google Scholar 

  62. 62.

    Oda K, Koda K, Takiguchi N, Nunomura M, Seike K, Miyazaki M. Detection of Epstein-Barr virus in gastric carcinoma cells and surrounding lymphocytes. Gastric Cancer. 2003;6(3):173–8.

    PubMed  Article  Google Scholar 

  63. 63.

    Ishii H, Gobe G, Yoneyama J, Mukaide M, Ebihara Y. Role of p53, apoptosis, and cell proliferation in early stage Epstein-Barr virus positive and negative gastric carcinomas. J Clin Pathol. 2004;57(12):1306–11.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. 64.

    Lee HS, Chang MS, Yang H-K, Lee BL, Kim WH. Epstein-Barr virus-positive gastric carcinoma has a distinct protein expression profile in comparison with Epstein-Barr virus-negative carcinoma. Clin Cancer Res. 2004;10(5):1698–705.

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Lopes L, Bacchi MM, Elgui-de-Oliveira D, Zanati S, Alvarenga M, Bacchi CE. Epstein-Barr virus infection and gastric carcinoma in São Paulo State, Brazil. Braz J Med Biol Res. 2004;37(11):1707–12.

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    van Beek J, Zur Hausen A, Klein Kranenbarg E, van de Velde CJ, Middeldorp JM, van den Brule AJ, et al. EBV-positive gastric adenocarcinomas: a distinct clinicopathologic entity with a low frequency of lymph node involvement. J Clin Oncol. 2004;22(4):664–70.

    PubMed  Article  Google Scholar 

  67. 67.

    Alipov G, Nakayama T, Nakashima M, Wen C-Y, Niino D, Kondo H, et al. Epstein-Barr virus-associated gastric carcinoma in Kazakhstan. World J Gastroenterol. 2005;11(1):27–30.

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

    Herrera-Goepfert R, Akiba S, Koriyama C, Ding S, Reyes E, Itoh T, et al. Epstein-Barr virus-associated gastric carcinoma: evidence of age-dependence among a Mexican population. World J Gastroenterol. 2005;11(39):6096–103.

    PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Luo B, Wang Y, Wang X-F, Liang H, Yan L-P, Huang B-H, et al. Expression of Epstein-Barr virus genes in EBV-associated gastric carcinomas. World J Gastroenterol. 2005;11(5):629–33.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  70. 70.

    Yoshiwara E, Koriyama C, Akiba S, Itoh T, Minakami Y, Chirinos J, et al. Epstein-Barr virus-associated gastric carcinoma in Lima, Peru. J Exp Clin Cancer Res. 2005;24(1):49–54.

    CAS  PubMed  Google Scholar 

  71. 71.

    Campos FI, Koriyama C, Akiba S, Carrasquilla G, Serra M, Carrascal E, et al. Environmental factors related to gastric cancer associated with Epstein-Barr virus in Colombia. Asian Pac J Cancer Prev. 2006;7(4):633–7.

    PubMed  Google Scholar 

  72. 72.

    Szkaradkiewicz A, Majewski W, Wal M, Czyżak M, Majewski P, Bierła J, et al. Epstein-Barr virus (EBV) infection and p53 protein expression in gastric carcinoma. Virus Res. 2006;118(1–2):115–9.

    CAS  PubMed  Article  Google Scholar 

  73. 73.

    Luo B, Wang Y, Wang X-F, Gao Y, Huang B-H, Zhao P. Correlation of Epstein-Barr virus and its encoded proteins with helicobacter pylori and expression of c-met and c-myc in gastric carcinoma. World J Gastroenterol. 2006;12(12):1842–8.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  74. 74.

    von Rahden BH, Langner C, Brücher BL, Stein HJ, Sarbia M. No association of primary adenocarcinomas of the small bowel with Epstein-Barr virus infection. Mol Carcinog. 2006;45(5):349–52.

    Article  CAS  Google Scholar 

  75. 75.

    Abdirad A, Ghaderi-Sohi S, Shuyama K, Koriyama C, Nadimi-Barforoosh H, Emami S, et al. Epstein-Barr virus associated gastric carcinoma: a report from Iran in the last four decades. Diagn Pathol. 2007;2(1):1–9.

    Article  Google Scholar 

  76. 76.

    Jung IM, Chung JK, Kim YA, Kim JE, Heo SC, Ahn YJ, et al. Epstein-Barr virus, beta-catenin, and E-cadherin in gastric carcinomas. J Korean Med Sci. 2007;22(5):855–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  77. 77.

    Lima VP, de Lima MAP, André AR, Ferreira MVP, Barros MAP, Rabenhorst SHB. H pylori (CagA) and Epstein-Barr virus infection in gastric carcinomas: correlation with p53 mutation and c-Myc, Bcl-2 and Bax expression. World J Gastroenterol. 2008;14(6):884–91.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  78. 78.

    Ryan JL, Morgan DR, Dominguez RL, Thorne LB, Elmore SH, Mino-Kenudson M, et al. High levels of Epstein–Barr virus DNA in latently infected gastric adenocarcinoma. Lab Investig. 2009;89(1):80–90.

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Trimeche M, Ksiâa F, Ziadi S, Mestiri S, Hachana M, Gacem RB, et al. Prevalence and characteristics of Epstein–Barr virus-associated gastric carcinomas in Tunisia. Eur J Gastroenterol Hepatol. 2009;21(9):1001–7.

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Truong CD, Feng W, Li W, Khoury T, Li Q, Alrawi S, et al. Characteristics of Epstein-Barr virus-associated gastric cancer: a study of 235 cases at a comprehensive cancer center in USA. J Exp Clin Cancer Res. 2009;28(1):1–9.

    Article  Google Scholar 

  81. 81.

    Ferrasi AC, Pinheiro NA, Rabenhorst SHB, Caballero OL, Rodrigues MAM, Carvalho F, et al. Helicobacter pylori and EBV in gastric carcinomas: methylation status and microsatellite instability. World J Gastroenterol. 2010;16(3):312–9.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  82. 82.

    Koriyama C, Akiba S, Shimaoka S, Itoh T, Akiyama S-I, Eizuru Y. Frequent expression of thymidine phosphorylase in Epstein-Barr virus-associated gastric carcinoma of diffuse type. Anticancer Res. 2010;30(6):2431–7.

    PubMed  Google Scholar 

  83. 83.

    Chen JN, Ding YG, Feng ZY, Li HG, He D, Du H, et al. Association of distinctive Epstein–Barr virus variants with gastric carcinoma in Guangzhou, southern China. J Med Virol. 2010;82(4):658–67.

    CAS  PubMed  Article  Google Scholar 

  84. 84.

    Boysen T, Friborg J, Stribolt K, Hamilton-Dutoit S, Goertz S, Wohlfahrt J, et al. Epstein-Barr virus-associated gastric carcinoma among patients with pernicious anemia. Int J Cancer. 2011;129(11):2756–60.

    CAS  PubMed  Article  Google Scholar 

  85. 85.

    Lima MAP, Ferreira MVP, Barros MAP, Pardini MIMC, Ferrasi AC, Rabenhorst SHB. Epstein-Barr virus-associated gastric carcinoma in Brazil: comparison between in situ hybridization and polymerase chain reaction detection. Braz J Microbiol. 2012;43(1):393–404.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  86. 86.

    Ksiaa F, Ziadi S, Gacem R, Dhiab M, Trimeche M. Correlation between DNA methyltransferases expression and Epstein-Barr virus, JC polyomavirus and helicobacter pylori infections in gastric carcinomas. Neoplasma. 2014;61(6):710–7.

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Aslane M, Al Haj A, Henneb A, Khenchouche A, Houali K. Characteristics of gastric carcinoma associated with Epstein Barr virus in Algeria. Pharm Lett. 2016;8(17):169–78.

    CAS  Google Scholar 

  88. 88.

    Tsai CY, Liu YY, Liu KH, Hsu JT, Chen TC, Chiu CT, et al. Comprehensive profiling of virus microRNAs of Epstein–Barr virus-associated gastric carcinoma: highlighting the interactions of ebv-Bart9 and host tumor cells. J Gastroenterol Hepatol. 2017;32(1):82–91.

    CAS  PubMed  Article  Google Scholar 

  89. 89.

    Zhang Z-X, Guo D-L, Jin M, Zhang W, Huang L-H, Zhang J-B, et al. Invasion-related signal pathways in Epstein-Barr virus (EBV)-associated gastric carcinoma. Int J Clin Exp Med. 2016;9(2):3544–50.

    CAS  Google Scholar 

  90. 90.

    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(4):4903–14.

    PubMed  Article  Google Scholar 

  91. 91.

    Na SJ, Park HL, Lee SY, Song KY, Kim SH. Correlation between infection status of Epstein-Barr virus and 18F-Fluorodeoxyglucose uptake in patients with advanced gastric cancer. In Vivo. 2017;31(4):749–53.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  92. 92.

    Böger C, Krüger S, Behrens H, Bock S, Haag J, Kalthoff H, et al. Epstein–Barr virus-associated gastric cancer reveals intratumoral heterogeneity of PIK3CA mutations. Ann Oncol. 2017;28(5):1005–14.

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Kim JY, Bae BN, Kang G, Kim HJ, Park K. Cytokine expression associated with helicobacter pylori and Epstein-Barr virus infection in gastric carcinogenesis. APMIS. 2017;125(9):808–15.

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Nogueira C, Mota M, Gradiz R, Cipriano MA, Caramelo F, Cruz H, et al. Prevalence and characteristics of Epstein–Barr virus-associated gastric carcinomas in Portugal. Infect Agent Cancer. 2017;12(1):1–8.

    Article  CAS  Google Scholar 

  95. 95.

    de Souza CRT, Almeida MCA, Khayat AS, da Silva EL, Soares PC, Chaves LC, et al. Association between helicobacter pylori, Epstein-Barr virus, human papillomavirus and gastric adenocarcinomas. World J Gastroenterol. 2018;24(43):4928–38.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  96. 96.

    Wanvimonsuk S, Thitiwanichpiwong P, Keelawat S, Mutirangura A, Kitkumthorn N. Distribution of the Epstein-Barr virus in the normal stomach and gastric lesions in Thai population. J Med Virol. 2019;91(3):444–9.

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Martinez-Ciarpaglini C, Fleitas-Kanonnikoff T, Gambardella V, Llorca M, Mongort C, Mengual R, et al. Assessing molecular subtypes of gastric cancer: microsatellite unstable and Epstein-Barr virus subtypes. Methods for detection and clinical and pathological implications. ESMO Open. 2019;4(3):1–8.

    Article  Google Scholar 

  98. 98.

    Dunlap WP, Cortina JM, Vaslow JB, Burke MJ. Meta-analysis of experiments with matched groups or repeated measures designs. Psychol Methods. 1996;1(2):170–7.

    Article  Google Scholar 

  99. 99.

    Yue W, Zhu M, Zuo L, Xin S, Zhang J, Liu L, et al. Early pattern of Epstein-Barr virus infection in gastric epithelial cells by “cell-in-cell”. Virol Sin. 2019;34(3):253–61.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. 100.

    Ribeiro J, Oliveira C, Malta M, Sousa H. Epstein–Barr virus gene expression and latency pattern in gastric carcinomas: a systematic review. Future Oncol. 2017;13(6):567–79.

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Chang MS, Kim DH, Roh JK, Middeldorp JM, Kim YS, Kim S, et al. Epstein-Barr virus-encoded BARF1 promotes proliferation of gastric carcinoma cells through regulation of NF-κB. J Virol. 2013;87(19):10515–23.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  102. 102.

    Tahara T, Arisawa T. DNA methylation as a molecular biomarker in gastric cancer. Epigenomics. 2015;7(3):475–86.

    CAS  PubMed  Article  Google Scholar 

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A.T and M. F designed the study. M. F performed statistical analysis. A. T wrote, reviewed, and edited the manuscript. SH. M and SJ. K performed data interpretation. A. T, M. F, S. A, and F.S.M performed search strategy. All authors involved in the acquisition of data, read and approved the final draft.

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Correspondence to Mohammad Farahmand.

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Tavakoli, A., Monavari, S.H., Solaymani Mohammadi, F. et al. Association between Epstein-Barr virus infection and gastric cancer: a systematic review and meta-analysis. BMC Cancer 20, 493 (2020). https://doi.org/10.1186/s12885-020-07013-x

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Keywords

  • Epstein-Barr virus
  • EBV
  • Gastric cancer
  • Stomach cancer
  • Gastric carcinoma
  • Meta-analysis