Background and Aim: Gastric cancer (GC) is one of the most common infection-related malignancies worldwide. Human Papillomavirus (HPV) and Epstein-Barr virus (EBV) are among the most important viruses affecting many people worldwide. The potential role of these viruses in gastric tissue may explain the possibility of GC, as seen in Helicobacter pylori (H. pylori). This study aimed to systematically investigate the presence of HPV and EBV in GC. Methods: According to the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines, this study is a systematic review based on reported cases. The keywords HPV, EBV and GC, were searched in PubMed, Web of Science, Scopus, EMBASE and Google scholar databases from 2012 to 2022. Articles were selected and evaluated by five researchers independently. The odds ratio of HPV and EBV viruses in GC was estimated. Data analysis was performed by SPSS (Version 20) software. Results: Sixty studies with 14949 patients were included in the study after obtaining the inclusion criteria. The mean prevalence of HPV and EBV viruses in GC was 10.58% and 8.58%, respectively. The highest prevalence of HPV and EBV were 37.74% and 44.44% in Turkey and Iraq, respectively. The highest odds of HPV and EBV in GC were observed in Asia (17.54%) and Africa (19.02%), respectively. Conclusion: The findings indicate the presence of HPV and EBV in GC in the study areas. However, the present study’s results are insufficient for a more accurate conclusion. Therefore, further studies are necessary for the conclusion in this regard.
Human PapillomavirusEpstein-Barr virusgastric cancersystematic studyBackground
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.
Methods
The present study was conducted by the indicators of preferred reporting items for systematic reviews and meta-analyses (PRISMA) [21].
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.
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).
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.
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.
Comparison of HPV and EBV infection in GC classified based on the publication calendar period, region, Virus type, and odds ratio
Country
Year
Author
Method
Virus type
Number of case
Positive case
P/N %
Ref.
Brazil
2012
Lima et al.
In situ hybridization and PCR
EBV
160
11
6.88
[22]
China
2013
Wang et al.
PCR
HPV
92
20
21.73
[23]
China
2013
Yuan et al.
PCR
HPV
24
0
0
[24]
Brazil
2013
Cândido et al.
PCR
HPV
40
4
10
[25]
Tunisia
2014
Ksiaa et al.
In situ hybridization and PCR
EBV
43
4
9.3
[26]
Poland
2015
Snietura et al.
Real-time PCR
HPV
84
0
0
[9]
China
2015
Su et al.
PCR
HPV
15
1
6.67
[27]
Sudan
2016
Elemam et al.
Immunohistochemistry
HPV
30
2
6.67
[28]
Iran
2016
Fakhraei et al.
PCR
HPV
100
5
5
[29]
Algeria
2016
Aslane et al.
In situ hybridization and Immunohistochemistry
EBV
97
22
22.68
[30]
China
2016
Zhang et al.
In situ hybridization and Immunohistochemistry
EBV
600
30
5
[31]
China
2016
Liu et al.
In situ hybridization and PCR
EBV
206
15
7.28
[32]
Germany
2016
Böger et al.
Immunohistochemistry
EBV
451
20
4.43
[33]
China
2016
Dong et al.
Immunohistochemistry
EBV
855
59
6.9
[34]
China
2016
Li et al.
In situ hybridization and Immunohistochemistry
EBV
137
30
21.9
[35]
USA
2016
Ma et al.
Immunohistochemistry
EBV
44
7
15.91
[36]
Iran
2016
Leila et al.
PCR
EBV
90
10
11.11
[37]
Taiwan
2016
Tsai et al.
In situ hybridization and qPCR
EBV
1039
52
5
[38]
South Korea
2017
Na et al.
In situ hybridization
EBV
205
15
7.32
[39]
Germany
2017
Boger et al.
In situ hybridization
EBV
484
22
4.55
[40]
South Korea
2017
Kim et al.
Immunohistochemistry
EBV
207
13
6.28
[41]
Japan
2017
Kawazoe et al.
In situ hybridization
EBV
487
25
5.13
[42]
Korea
2017
Kwon et al.
In situ hybridization and Immunohistochemistry
EBV
394
26
6.6
[43]
Japan
2017
Saito et al.
In situ hybridization and Immunohistochemistry
EBV
232
96
41.38
[44]
USA
2017
Thompson et al.
In situ hybridization and Immunohistochemistry
EBV
34
2
5.88
[45]
Portugal
2017
Nogueira et al.
In situ hybridization and PCR
EBV
82
9
10.98
[46]
Portugal
2017
Ribeiro et al.
In situ hybridization and Immunohistochemistry
EBV
179
15
8.38
[11]
Brazil
2018
de Souza et al.
PCR
HPV
302
8
2.65
[47]
Brazil
2018
de Souza et al.
PCR
EBV
302
62
20.53
[47]
Korea
2018
Chang et al.
Quantitative image analysis
EBV
241
40
16.6
[48]
Italy
2018
de Rosa et al.
Immunohistochemistry
EBV
169
33
19.53
[49]
USA
2018
Hissong et al.
In situ hybridization and Immunohistochemistry
EBV
31
7
22.58
[50]
Brazil
2018
Pereira et al.
In situ hybridization and Immunohistochemistry
EBV
287
30
10.45
[51]
Thailand
2019
Wanvimonsuk et al.
In situ hybridization and PCR
EBV
33
4
12.12
[52]
Turkey
2019
Bozdayi et al.
PCR
HPV
53
20
37.74
[53]
Spain
2019
Martinez-Ciarpaglini et al.
In situ hybridization
EBV
209
13
6.22
[54]
Portugal
2019
Gullo et al.
In situ hybridization
EBV
78
19
24.36
[55]
Italy
2019
Valentini et al.
Immunohistochemistry
EBV
70
2
2.86
[56]
Japan
2019
Kawazoe et al.
In situ hybridization
EBV
2025
14
0.69
[57]
China
2019
Sun et al.
In situ hybridization and Immunohistochemistry
EBV
165
2
1.21
[58]
Japan
2019
Mishima et al.
In situ hybridization
EBV
80
4
5
[59]
Germany
2020
Moore et al.
qPCR
EBV
74
17
22.97
[60]
Taiwan
2020
Fang et al.
In situ hybridization
EBV
460
43
9.35
[61]
Korea
2020
Choi et al.
In situ hybridization
EBV
514
32
6.23
[62]
Korea
2020
Kim et al.
In situ hybridization and Immunohistochemistry
EBV
286
17
5.94
[63]
USA
2020
Martinson et al.
In situ hybridization and Immunohistochemistry
EBV
85
19
22.35
[64]
Italy
2020
di Pinto et al.
In situ hybridization and Immunohistochemistry
EBV
70
2
2.86
[65]
Korea
2020
Liu et al.
In situ hybridization
EBV
300
18
6
[66]
Irish
2021
Weadick et al.
In situ hybridization
EBV
103
8
7.77
[67]
Brazil
2021
Moreira-Nunes et al.
In situ hybridization
EBV
1000
190
19
[68]
Morocco
2021
Nshizirungu et al.
In situ hybridization
EBV
97
6
6.19
[69]
Congo
2021
Mambouene et al.
PCR
EBV
52
2
3.85
[70]
Turkey
2021
Gareayaghi et al.
ELISA and qPCR
EBV
34
12
35.29
[71]
China
2021
Yang et al.
In situ hybridization
EBV
226
11
4.87
[72]
Morocco
2021
Rihane et al.
PCR
EBV
100
40
40
[73]
Japan
2021
Suzuki et al.
In situ hybridization
EBV
618
12
1.94
[74]
Iraq
2022
Mallakh et al.
In situ hybridization and Immunohistochemistry
HPV
54
24
44.44
[75]
Peru
2022
Castañeda et al.
In situ hybridization and qPCR
EBV
98
41
41.84
[76]
Russia
2022
Danilova et al.
In situ hybridization
EBV
282
27
9.57
[77]
China
2022
Ye et al.
PCR
EBV
40
5
12.5
[78]
Total
HPV
794
84
10.58%
EBV
14155
1215
8.58%
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.
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.
Flow-chart of the literature search and selection
Comparison of HPV and EBV infection in GC classified by continental type
Continent
Virus type
Total number of cases
Positive cases
America
HPV
342
12
EBV
2041
369
Europe
HPV
137
20
EBV
2285
199
Africa
HPV
30
2
EBV
389
74
Asia
HPV
285
50
EBV
9440
573
Odds ratios for HPV and EBV positive GC on different continents
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.
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.
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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