The Presence of Human Papillomavirus and Epstein-Barr Virus Infection in Gastric Cancer: A Systematic Study

1  Background

Cancer is the leading cause of death in most developing and developed countries. Gastric cancer (GC) is the second leading cause of death and the most common malignant tumor globally [1]. GC is one of the multifactorial diseases whose main reason is the presence of infectious, genetic and environmental factors in individuals [2]. The prevalence of GC varies from the resulting mortality rate because the second phenomenon is more due to the late diagnosis of GC in the advanced phase of the disease [3]. Viruses cause many cancers, with about 15%–20% of human cancers associated with viruses [4]. Human Papillomavirus (HPV) is a DNA virus found in all human populations, and sometimes the infection it causes can lead to cancer [5,6]. The virus is divided into high-risk and low-risk types in terms of its potential to cause cancer [7]. HPV16 and HPV18 are among the most common subtypes involved in carcinogenesis [8]. Various studies have indicated the oncogenic properties of HPV, suggesting a role for the virus in the pathogenesis of cancer [9]. Integration of HPV DNA in the host genome is the main cause of carcinogenesis that causes the regulation of cellular oncogenes (mainly E6 and E7). The virus disrupts HPV E2 expression and causes overexpression of E6 and E7 oncoproteins [10]. Epstein-Barr virus (EBV) is a DNA virus in the herpes virus family. EBV is the first human virus responsible for approximately 1.8% of all human cancers, including Hodgkin’s lymphoma, Burkitt’s lymphoma, NK/T cell lymphoma, and Nasopharyngeal [11]. The first association between EBV and gastric epithelial lymphatic carcinoma was identified in 1990, indicating the first association between GC and EBV [12]. Subsequent studies have also shown an association between gastric adenocarcinoma and EBV, which may indicate an important role for EBV in pathogenesis [13]. Thus, these findings suggest that 10% of GCs worldwide are associated with EBV [13–15]. Considering that EBV can continuously infect a cell with monoclonal proliferation, EBV infection is effective in the early stages of GC [16–18]. Although various studies have investigated the mechanism of occurrence and development of GC and positive EBV, they found no association between EBV titer and GC risk [19]. Studies show that latent EBV infection and the expression of latent EBV genes as a co-factor increase carcinogenicity, which causes abnormalities in the host genome (such as aberrant DNA methylation), disruption of cell pathways, and immune cell function [20]. Nowadays, extensive research has reported the prevalence of HPV and EBV in GC. Therefore, the present study aimed to gain new insight into the prevalence of HPV and EBV in GC for a better understanding of carcinogenesis.

2  Methods

The present study was conducted by the indicators of preferred reporting items for systematic reviews and meta-analyses (PRISMA) [21].

2.1 Search Strategy

This study examined PubMed, Web of Science, Scopus, EMBASE and Google scholar databases to find studies on HPV, EBV and GC. Databases were searched from 2012 to 2022 with the keywords HPV, EBV and GC.

2.2 Study Selection

All findings from appropriate databases regarding subject matter, quality, and method were entered into the X9 version of EndNote (Thomson Reuters) software, and duplicate inputs were removed. Two researchers (AJS and BJ) performed screening of the obtained data independently. The full text of the remaining articles was then reviewed, and any disagreements were resolved through discussion by the third and fourth researchers (ASH and HBB).

2.3 Inclusion and Exclusion Criteria

The following eligible studies were included: (1) All research studies that report the prevalence of HPV and EBV infection in patients with GC; (2) Articles with free access; (3) Articles published in ten years in English in reputable journals. Studies with the following characteristics were excluded from the study: (1) Studies at intervals other than ten years, (2) Studies published in languages other than English, (3) Articles in the review process, letters to the editor and case report.

2.4 Extracting the Data

The following data were extracted from eligible studies: country, year, authors’ names, virus type, the total number of samples, positive samples, percentage of positive samples to total samples and source. The data obtained in this section were entered into a checklist and, after evaluation by the fifth researcher (BB), were entered in Table 1.

2.5 Statistical Analysis

The prevalence of HPV and EBV in the GC and the odds ratio of positive samples (ORs) with a 95% confidence interval (CIs) were used to assess the relationship between HPV and EBV and the occurrence of GC. In this study, SPSS software (version 16) was used for the statistical analysis of data.

3  Results

A total of 327 articles were searched. After screening, 60 articles were selected (Fig. 1) with the necessary standards to enter the study. A comparison of the prevalence of HPV and EBV viruses in GC is given in Table 1. The prevalence of HPV and EBV in 2249 GC samples was studied in 24 countries, and according to the results, the prevalence varied from 0% to 44.44%. The mean prevalence of HPV and EBV viruses in GC was 10.58% and 8.58%, respectively. Then, after classification based on the research area and calculating the average data of each country, it was found that the highest prevalence of HPV and EBV were 37.74% and 44.44% in Turkey and Iraq, respectively. However, the lowest prevalence of HPV and EBV were 0% and 0.69% in China and Japan, respectively. The total number of HPV and EBV samples in GC was analyzed based on continental segmentation (Table 2 and Fig. 2). By comparing the odds ratios for each continent, it was found that HPV in Asia, Europe, Africa and America was 17.54%, 14.6%, 6.67% and 3.51%, respectively. For the EBV in Africa, America, Europe and Asia, this ratio was 19.02%, 18.08%, 8.71% and 6.07%, respectively.

Figure 1: Flow-chart of the literature search and selection

Figure 2: Odds ratios for HPV and EBV positive GC on different continents

4  Discussion

GC is one of the most common malignancies associated with infection worldwide. Various studies have proven the carcinogenic mechanisms of Helicobacter pylori (H. pylori) and EBV virus [79–82]. However, comprehensive information on other carcinogenic viruses has not been obtained. Therefore, this systematic study was performed to determine this. The researchers’ findings indicate that HPV is one of the main infectious agents involved in prostate, cervical, anal, and colorectal cancer [83–87]. Most studies suggest that HPV can lead to cancer if it co-occurs with H. pylori, while other studies indicate that the prevalence of HPV is not associated with H. pylori [25,88]. HPV infection enters the esophagus through the mouth and eventually into the stomach, and the integration of HPV DNA into the host genome plays a key role in carcinogenesis [89]. Various studies in HPV-infected cells show that overexpression of E6 and E7 oncoprotein (caused by the integration of HPV in the host genome) in addition to tumorigenesis, can regulate the expression of multiple genes involved in cellular processes (such as proliferation, differentiation, apoptosis, adhesion, angiogenesis, transcription and protein translation), and induce genomic instability in normal human cells [90–96]. Yamato et al. and Jabbar et al. [97,98] have shown that the activity of E6 and E7 is necessary for the persistence of cancer caused by HPV because in the absence of the activity of these oncoproteins, cancer cells to senesce or undergo apoptosis. Our systematic study showed that the prevalence of HPV among GC patients from 24 countries was 10.58%. During a meta-analysis study, Zeng et al. concluded that out of the 1917 patients studied, 28% were HPV positive, which was more than the present study’s findings [89]. In their study, Bae showed that the proportion of HPV-positive cases in Chinese studies was 1.43 times higher than in non-Chinese studies [99]. In 2020, Wang et al. examined the presence of HPV in 901 patients with GC and found that 23.6% of the samples were HPV positive. Therefore, there is a significant relationship between HPV infection and the risk of gastric malignancy [100]. EBV is found in approximately 9% of GC [12,101]. Various studies have revealed the role of EBV infection in the progression of GC, which can be caused by EBV entering B lymphocytes in the oropharyngeal lymphoid tissues and then entering gastric epithelial cells, which can occur through cell-to-cell contact between B lymphocytes and gastric epithelial cells or direct entry into the gastric epithelium. This entry can be facilitated by mucosal damage [102,103]. The prevalence of EBV in the present study was 8.58%. Our findings are consistent with previous meta-analysis studies that reported the presence of EBV in GC from 6.9% to 8.8% [101,104–108]. Pyo et al. [109] estimated the presence of EBV in GC at 0.113%. Tavakoli et al. [110] reported an EBV prevalence of 8.77% in 20361 patients with GC. In addition, for the presence of EBV in GC, genome atlas research showed repeated PIK3CA mutations, severe DNA hypermethylation, amplification of JAK2, CD274, and PDCD1LG2 [111], which can enhance our understanding of the carcinogenic mechanism of EBV. This study contained the following limitations due to the data sources used in the systematic study. Age, sex, and H. pylori infection are important factors in the development of GC. However, the studies used were not mainly classified by age or sex, and there were no reports of an association between H. pylori infection and GC, so information on age, sex, and co-infection was not considered. There was also significant heterogeneity due to differences in sample size and geographical areas.

5  Conclusion

Overall, the present study’s findings indicated that the prevalence of HPV and EBV infections in GC was 10.58% and 8.58%, respectively. These findings suggest an association between HPV, EBV and GC infections. However, the evidence inferred in the present study is insufficient to conclude that HPV and EBV infection are associated with GC risk. In addition, the prevalence of HPV and EBV was found in 24 countries worldwide. Therefore, extensive studies in other countries are strongly recommended to obtain more reliable results.

Acknowledgement: This article was derived from Ph.D. degree thesis in the Islamic Azad University Kazerun branch. The authors acknowledge the Department of Microbiology, Kazerun Branch, Islamic Azad University, and the Research Deputy.

Authors’ Contributions: All authors contributed to the conception and the main idea of the work. AJS wrote the manuscript. ASH, HBB, BB, and BJ analyzed the data and edited the manuscript. All authors reviewed the results and approved the final version of the manuscript.

Ethics Approval and Informed Consent Statement: Not applicable.

Funding Statement: The authors received no specific funding for this study.

Conflicts of Interest: The authors declare that they have no conflicts of interest to report regarding the present study.

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