The relationship between Helicobacter pylori and pancreatic cancer: a meta-analysis

Introduction

Pancreatic cancer is a type of tumor with highly malignant and invasive gastrointestinal. Most patients were diagnosed as advanced due to a lack of typical clinical manifestations. Because of concealment, low surgical rate, insensitivity to radiotherapy and chemotherapy, and it has resulted in unsatisfactory treatment effects and short survival time. It was reported that the 5-year overall survival rate of pancreatic cancer patients was only 9% (1). Therefore, the prevention of etiological factors become an important measure for the prevention and treatment of pancreatic cancer. The occurrence of pancreatic cancer was associated with various factors, among which smoking was the clearest risk factor. Chronic pancreatitis and long-term type 2 diabetes were also associated with increased risks of pancreatic cancer, but were not the main causes of this disease (2). The last several years have seen increased interest in the association between bacteria and pancreatic cancer. Carriage of certain bacteria in the oral cavity (e.g., Porphyromonas gingivalis, Aggregatibacter actinomycetemcomitans, Streptococcus sp.), gut [e.g., Helicobacter pylori (H. pylori, HP), Synergistetes, Proteobacteria], and pancreas (e.g., Fusobacterium sp., Enterobacteriaceae, Pseudomonadaceae) has been associated with an increased risk of developing pancreatic cancer (3). On this basis, several studies have proposed that H. pylori might be associated with the occurrence of pancreatic cancer (4-12). Some studies suggested that there was no obvious correlation between the two as a whole, but different subgroup of H. pylori infection might be significantly associated with the occurrence of pancreatic cancer (13-17). In addition, there remained some problems in the past seven meta-analyses. Due to the limited number of studies, although publication bias tests have been carried out, they were still not sure that there was no publication bias in their studies. The quality of cohort studies was regarded to be higher than the case-control studies, but only two studies have been included in the cohort study for analysis. This meta-analysis was necessary due to the relationship between the two was not clear so far. This article would include more research data to look for newer and stronger evidence to explore the relationship between H. pylori infection and pancreatic cancer further. We present the following article in accordance with the PRISMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-21-2803/rc).

Methods

Literature search

PubMed, Embase, and Cochrane databases were searched for all literature on H. pylori infection and the occurrence of pancreatic cancer from inception to October 2021, as well as references and abstracts of gastroenterology meetings. Here is an example of the retrieval strategy in PubMed: (“Pancreatic Neoplasms”[Mesh] OR “Neoplasm, Pancreatic”[Title/Abstract] OR “Pancreatic Neoplasm”[Title/Abstract] OR “Pancreas Neoplasms”[Title/Abstract] OR “Neoplasm, Pancreas”[Title/Abstract] OR “Neoplasms, Pancreas”[Title/Abstract] OR “Pancreas Neoplasm”[Title/Abstract] OR “Neoplasms, Pancreatic”[Title/Abstract] OR “Cancer of Pancreas”[Title/Abstract] OR “Pancreas Cancers”[Title/Abstract] OR “Pancreas Cancer”[Title/Abstract] OR “Cancer, Pancreas”[Title/Abstract] OR “Cancers, Pancreas”[Title/Abstract] OR “Pancreatic Cancer”[Title/Abstract] OR “Cancer, Pancreatic”[Title/Abstract] OR “Cancers, Pancreatic”[Title/Abstract] OR “Pancreatic Cancers”[Title/Abstract] OR “Cancer of the Pancreas”[Title/Abstract]) AND (“Helicobacter pylori”[Mesh] OR “Helicobacter nemestrinae”[Title/Abstract] OR “Campylobacter pylori”[Title/Abstract] OR “Campylobacter pylori subsp. Pylori”[Title/Abstract] OR “Campylobacter pyloridis”[Title/Abstract] OR “Gastritis, Atrophic”[Mesh] OR “Atrophic Gastritides”[Title/Abstract] OR “Atrophic Gastritis”[Title/Abstract] OR “Gastritides, Atrophic”[Title/Abstract]).

Inclusion criteria

(I) The content of the study was about the relationship between H. pylori and pancreatic cancer. (II) The type of study was a case-control study or cohort study. (III) NOS (Newcastle-Ottawa Scale) score >3 points. (IV) The diagnostic method of pancreatic cancer and H. pylori (such as serological test, breath test and gastroscopic biopsy) must be illustrated and the diagnosis must be clear. (V) The odds ratios (OR) and 95% confidence interval (CI) should be given in the study directly or could be calculated from the original data.

Exclusion criteria

(I) Study without a control group. (II) The study that could not extract data effectively. (III) The study only had abstracts without full text. (IV) Animal study and case report. (V) The study that did not explain the detection the method of H. pylori infection. (VI) The study whose sample size was too small.

Quality assessment and data extraction

Two investigators reviewed studies independently according to the above strategies, and strictly followed the inclusion and exclusion criteria to select eligible studies that met the retrieval conditions. For the divergent literature, it was decided whether to include it or not through discussion or consultation with the third researcher. For the lack of information in the literature, the original author was contacted as possible to supplement it. If the original author could not be contacted successfully, it would be decided whether or not to rule out according to the impact on the study. The NOS scoring criteria was used to evaluate the quality of the included studies. The information extracted from the studies includes: title, first author, time of publication, type of study, area, detection method of H. pylori, sample size, H. pylori infection rate, prevalence rate of pancreatic cancer, cytotoxin-associated gene A (CagA) positive rate and OR and 95% CI in observation group and control group. The data would be displayed in a tabular form.

Statistical methods

All data were analyzed with the R 4.1.0 meta package. The combined OR and 95% CI were calculated to compare the correlation between them. If OR >1, it was considered that HP infection promoted the occurrence of pancreatic cancer. If OR <1, it indicated that HP infection reduced the incidence of pancreatic cancer; 95% CI containing 1 equals P <0.05, which represented the result did not have statistical significance. Heterogeneity tests were used to assess the heterogeneity of studies, and the I² statistic represented the significant degree of heterogeneity. We stipulated that P<0.1 was statistically significant. When I²>50%, it was considered that there was significant heterogeneity between studies, and the random effect model would be used. When I²<50%, there was no obvious heterogeneity within studies, and the fixed effect model was adopted. The possible sources of heterogeneity were estimated by sensitivity-analysis, and the possible sources of heterogeneity were analyzed by subgroup-analysis. By carrying out the funnel plots and Egger test to examine whether publication bias existed. It indicated that the existence of publication bias was possible if P<0.05. In this study, all statistical tests were bilateral tests.

Results

Study retrieval results

Through extensive review and strict compliance with the inclusion criteria, a total of 17 articles met the inclusion criteria and were included in this study (Figure 1), including 8 case-control studies (3,790 subjects, 1,705 in the case group and 2,085 in the control group), 5 nested case-control studies (2,665 subjects, 1,113 in the case group and 1,552 in the control group) and 4 cohort studies (69,625 subjects, 29,346 in the case group and 40,279 in the control group). The basic information of each study was shown in Table 1, and the data extraction results were shown in Tables 2,3.

Figure 1 Flow diagram of literature screening. HP, Helicobacter pylori.

H. pylori infection and pancreatic cancer

An overall meta-analysis and three subgroup-analysis were carried out for the included studies. Meta-analysis results showed that H. pylori infection was generally associated with the occurrence of pancreatic cancer (OR =1.30; 95% CI: 1.02–1.64; P=0.03) (Figure 2). Heterogeneity test results indicated that the included studies had significant heterogeneity (I²=75%; P<0.01), so the random effect model should be selected. Subgroup-analysis was carried out to explore the source of heterogeneity due to the significant heterogeneity between studies, which could improve the credibility of this study.

Figure 2 Meta-analysis forest plot of the relationship between H. pylori infection and pancreatic cancer. Using random effects model (I²=75%). OR =1.30, 95% CI: 1.02–1.64. OR, odds ratio; CI, confidence interval.

Considering that there were great differences in the research methods and quality of each type of study, we divided this study into three groups according to the type of study (Figure 3). They were case-control group, nested case-control group and cohort study group. The results of the subgroup-analysis showed that there was significant heterogeneity in the case-control group (I²=83%; P<0.01), and the difference was statistically significant. H. pylori infection was not associated with pancreatic cancer in the case-control group (OR =1.40; 95% CI: 0.91–2.15). The nested case-control group also had heterogeneity (I²=51%; P=0.08), and the difference was statistically significant. H. pylori infection was not associated with pancreatic cancer in the nested case-control group (OR =1.01; 95% CI: 0.76–1.34). In the cohort study group, the heterogeneity was also significant (I²=65%; P=0.04). The difference was statistically significant. It showed that H. pylori infection had no connection with pancreatic cancer in the nested case-control group (OR =1.70; 95% CI: 1.00–2.91). To sum up, these three types of studies all suggested that H. pylori infection had no relation to the occurrence of pancreatic cancer. Since there was still high heterogeneity in these three subgroups, the research type was not the main source of heterogeneity.

Figure 3 Subgroup-analysis forest plot of the relationship between H. pylori infection and pancreatic cancer (study type). Type =1: case-control study. Using random effects model (I²=83%). OR =1.40, 95% CI: 0.91–2.15; Type =2: nested case-control study. Using random effects model (I²=51%). OR =1.01, 95% CI: 0.76–1.34; Type =3: cohort study. Using random effects model (I²=65%). OR =1.70, 95% CI: 1.00–2.91. OR, odds ratio; CI, confidence interval.

We believed that the infectivity and toxicity of H. pylori might be related to the economic level of the region (27), the subgroup analysis of the research data was carried out again according to the regional economic level (Figure 4). We regarded Europe, North America and parts of Asia (such as Japan, as well as Shanghai and Taiwan in China) as developed areas, and the rest as non-developed areas. The results of subgroup-analysis showed that there was a significant correlation between H. pylori infection and pancreatic cancer in economically undeveloped areas (OR =2.10; 95% CI: 1.44–3.05), while H. pylori infection was not associated with pancreatic cancer in developed areas (OR =1.17; 95% CI: 0.92–1.50). However, the developed areas group still had high intra-group heterogeneity.

Figure 4 Subgroup-analysis forest plot of the relationship between H. pylori infection and pancreatic cancer (economic level). Level =1: economically developed areas. Using random effects model (I²=73%). OR =1.17, 95% CI: 0.92–1.50; Level =2: economically underdeveloped areas. Using fixed effect model (I²=0%). OR =2.10, 95% CI: 1.44–3.05. OR, odds ratio; CI, confidence interval.

The living environment and habits of people in different regions were quite different, which could be the result of the significant heterogeneity in developed areas group. For this reason, we divided all the studies into three subgroups according to the continent the study came from. They were the Asian group, European group and North American group (Figure 5). The results of the subgroup-analysis showed that there existed heterogeneity in the North American group, and the difference was statistically significant (I²=63%; P=0.04). In this group, we did not observe the connection between H. pylori infection and pancreatic cancer (OR =1.04; 95% CI: 0.66–1.63). There was significant heterogeneity in the Asia group, and the difference was statistically significant (I²=89%; P<0.01). It didn’t show the relation between H. pylori infection and pancreatic cancer in the Asian group (OR =1.61; 95% CI: 0.90–2.90). The European group didn’t show significant heterogeneity (I²=36%; P=0.15). Similarly, this group indicated that H. pylori had nothing to do with pancreatic cancer (OR =1.15; 95% CI: 0.96–1.37). In a word, there was no association between H. pylori infection and the incidence of pancreatic cancer in the three regions, but the Asia group had significant heterogeneity (I²=89%), which might be the main source of overall heterogeneity. Therefore, this result was still not convincing due to the unexplained heterogeneity. Furthermore, after carrying out a sensitivity-analysis by the leave-one-out method, we found that Risch’s study was the main factor for the increase in heterogeneity (Figure 6). After being eliminated, the I² statistic was reduced to 58%. The overall results did not change significantly, while partial results of subgroup-analysis changed. When we carried out a subgroup-analysis according to the type of study, the I² statistic in the case-control group decreased to 22% (P=0.26), which indicated that there was no significant heterogeneity in the group. Case-control studies showed that H. pylori infection was related to pancreatic (OR =1.52; 95% CI: 1.24–1.88). When the subgroup-analysis is carried out according to the regional economic level, the result is stable. When the subgroup-analysis was carried out according to the continent, the results of the Asia group were reversed, which indicated that H. pylori infection could be significantly associated with pancreatic cancer in the Asian population (I²=63%; P=0.03; OR =1.95; 95% CI: 1.24–3.07).

Figure 5 Subgroup-analysis forest plot of the relationship between H. pylori infection and pancreatic cancer (region). USA = America. Using random effects model (I²=63%). OR =1.04, 95% CI: 0.66–1.63; AS = Asian region. Using random effects model (I²=89%). OR =1.61, 95% CI: 0.90–2.90; EU = European region. Using fixed effect model (I²=36%). OR =1.15, 95% CI: 0.96–1.37. OR, odds ratio; CI, confidence interval.

Figure 6 Sensitivity-analysis forest plot of the relationship between H. pylori infection and pancreatic cancer. For each study, the estimates of OR and 95% CI were plotted with a box and a horizontal line. Closed diamond indicates pooled OR and 95% CI. OR, odds ratio; CI, confidence interval.

CagA-positive H. pylori infection and pancreatic cancer

CagA antibody was detected in seven case-control studies, four nested case-control studies and 1 cohort study, with a total of 15,146 subjects. The result of the meta-analysis showed that there was no significant association between CagA-positive H. pylori infection and pancreatic cancer on the whole (I²=44%; OR =0.90; 95% CI: 0.80–1.01) (Figure 7).

Figure 7 Meta-analysis forest plot of the relationship between cytotoxin-associated gene A positive H. pylori infection and pancreatic cancer. Using fixed effect model (I²=44%). OR =0.90, 95% CI: 0.80–1.01. OR, odds ratio; CI, confidence interval.

VacA-positive H. pylori infection and pancreatic cancer

To further study the relationship between the subtype of H. pylori and pancreatic cancer, we explored whether VacA-positive H. pylori infection could promote the occurrence of pancreatic cancer. Two case-control studies and 1 nested case-control study were included, with a total of 1,086 subjects. We did not find the significant association between VacA-positive H. pylori infection and pancreatic cancer (I²=0%; OR =0.94; 95% CI: 0.71–1.25) (Figure 8).

Figure 8 Meta-analysis forest plot of the relationship between vacuolating cytotoxin gene A positive H. pylori infection and pancreatic cancer. Using fixed effect model (I²=0%). OR =0.94, 95% CI: 0.71–1.25. OR, odds ratio; CI, confidence interval.

Assessment of publication bias

A funnel plot was used to evaluate the publication bias of the included studies. The funnel plot was asymmetric on both sides, which indicated the existence of publication bias (Figures 9,10). Egger tests (P<0.05) also showed that there was a possibility of publication bias in this study. We used the trim and filling method to assess the impact of publication bias on this article. Seven additional studies were added to the trim and filling method and the results were consistent with this article. It was proved that although publication bias affected this study, the results were still robust.

Figure 9 Funnel plot of the relationship between H. pylori infection and pancreatic cancer.

Figure 10 Funnel plot of the relationship between cytotoxin-associated gene A positive H. pylori infection and pancreatic cancer.

Discussion

Since the discovery of H. pylori, researchers have devoted themselves to studying its pathological significance in humans. It is clear that H. pylori infection is associated with a variety of gastric diseases, such as gastric ulcers, chronic atrophic gastritis, gastric cancer, gastric lymphoma and so on (28). CagA and VacA are the critical virulence factors of H. pylori, which can regulate the host’s immune response to help H. pylor’s survival, and induce the formation of acidic vacuoles in the cytoplasm of gastric epithelial cells in vivo, as well as in permanent cell lines or primary epithelial cells (29,30). With further research, the researchers have found that H. pylori can colonize not only in gastric mucosa, but also in other digestive organs (31). Therefore, H. pylori infection might promote the occurrence of other non-gastric diseases, such as pancreatic cancer, colorectal cancer (32), liver cancer (33) and cholangiocarcinoma (34). In addition to digestive diseases, researchers have also found that H. pylori seropositive may be associated with some respiratory diseases, but there is no clear evidence to prove the reliability of this link due to the limited quality and quantity of research (35). Although many studies have been carried out, there is still no definite conclusion as to whether H. pylori is related to the occurrence of pancreatic cancer or not. There have been several meta-analyses of the relationship between H. pylori infection and pancreatic cancer previously (12-17,36), but the conclusions are controversial. To explore the correlation between the two fully, our study included more updated samples and various types of studies, such as case-control studies, nested case-control studies, prospective cohort studies and retrospective cohort studies.

Our meta-analysis confirmed that there was an overall association between H. pylori infection and pancreatic cancer, and this correlation would become more significant in underdeveloped areas. We have not confirmed that H. pylori infection was associated with pancreatic cancer in the Asian population. However, we observed that H. pylori infection significantly increased the possibility of pancreatic cancer in the Asian population after a sensitivity-analysis by the leave-one-out method. Therefore, the association between H. pylori infection and pancreatic cancer in the Asian population remained uncertain. In addition, although several studies have shown that CagA-seropositive H. pylori infection could promote the occurrence of pancreatic cancer, our studies indicated that CagA-positive H. pylori infection was not associated with the occurrence of pancreatic cancer. We further explored the relationship of the VacA- positive H. pylori infection and pancreatic cancer, but did not find a statistical significance between them. Due to the significant heterogeneity among the included studies, subgroup-analysis and sensitivity-analysis were carried out to find the source of heterogeneity. The results of the subgroup-analysis have shown that there existed heterogeneity among all subgroups. Sensitivity-analysis have found that Risch’s study led to the increase of heterogeneity in our study, but it was not the main factor for the increase of heterogeneity. Even if excluding Risch’s study, our study still had significant heterogeneity (I²=57%). After a review of all studies, we have found that there were two studies whose included population were smokers (10,20). Smokers tended to have a higher incidence of H. pylori infection (37,38) and a higher incidence of pancreatic cancer (39) compared with non-smokers, which made patients in this study have a higher incidence of pancreatic cancer than in other studies. In addition, two studies used various serological tests to detect H. pylori antibodies (18,20), and it was regarded as H. pylori infection only if more than 4 antibodies were seropositive. However, most of the studies detected IgG or IgM antibodies of H. pylori directly. It was considered as H. pylori infection when either of them was seropositive. As a result, the H. pylori infection rate in these two studies might be lower than that in other studies. The number of H. pylori seronegative but CagA-positive in Risch’s study was more than that in other studies. The main reason might be that different researchers have different methods of H. pylori typing. Some studies tested serum CagA in all patients, while others only tested CagA in H. pylori-positive patients, resulting in some H. pylori-negative but CagA-positive patients not counted as CagA-positive. In the study, Risch pointed out that the appreciable fraction of CagA-positive individuals H. pylori seronegative. Therefore, we believed that the significant heterogeneity might be caused by many factors, which may be related to the particularity of each study population (including race, living standard, smoking, etc.) and the differences between different studies (including testing methods, testing population, research quality, etc.). Although it did not affect the overall outcome, the relationship between H. pylori infection and pancreatic cancer in the Asian population needed to be treated with caution.

The mechanism by which H. pylori may cause pancreatic cancer is still unclear so far. A study showed that H. pylori could induce pancreatic cancer through ascending gastric infection or retrograde metastasis of the small intestine, based on the identification of peptide AIP1e7 in a small number of patients with pancreatic cancer, which was homologous to the amino acid sequence of PBP of H. pylori (40). Nilsson et al. (41) detected H. pylori DNA in pancreatic tumor and/or surrounding tissues of 60% of pancreatic cancer patients, and suggesting that H. pylori might cause pancreatic cancer by directly infecting pancreatic tissue. Takayama et al. (42) found that the secretion of interleukin-8 (IL-8) and vascular endothelial growth factor (VEGF) in pancreatic cells would increase after H. pylori infection, as well as the activities of proliferation factors (including NF-kappaB, AP-1 and SRE) related to pancreatic carcinogenesis increased, thus enhancing the malignant potential of pancreatic cells, which may be one of the important mechanisms of pancreatic cancer caused by H. pylori. Risch et al. (43) believed that smoking and food-derived N-nitrosamines were important factors leading to pancreatic cancer, and the colonization of H. pylori in the stomach could enhance this carcinogenic effect. In addition, ABO genotype/phenotypic status could affect the biological behavior of H. pylori and ultimately enhance the carcinogenicity of pancreatic cancer exposed to N-nitrosamines associated with diet and smoking, resulting in the risk of pancreatic cancer. A new study showed that there was a significant correlation between H. pylori infection and the expression of mucin family MUC4. MUC4 might be a potential action site in pancreatic cancer caused by H. pylori (44). To sum up, pancreatic cancer caused by H. pylori might be the result of the synergistic effect of multiple mechanisms, so a great number of studies are still needed to explore all possible carcinogenic mechanisms.

The limitations of our study were the existence of significant heterogeneity and publication bias. The reasons for publication bias were mostly due to the omission of included studies in meta-analysis, the bias of small sample studies, and the difficulty of publishing negative results. We believed that a possible source of publication bias in our study was due to the quality of previous retrospective analysis and meta-analysis follow-up studies, despite being more robust, might not be published due to repetition, while articles with negative results, might be more difficult to be published due to its contradictory narrative. Another source of publication bias in our study was the inclusion of studies that used small sample-size. Therefore, studies that draw similar results might be difficult to publish because of repeated conclusions, while articles with negative results were more likely to be inconsistent with the mainstream conclusions and thus get published opportunities. In addition, this study included more small sample studies, which may also lead to publication bias. Therefore, more high-quality cohort studies and case-control studies are needed to confirm the correctness of this conclusion. In addition, more and more in-depth basic studies should be carried out to clarify the specific mechanism of pancreatic cancer caused by H. pylori and to provide a stronger theoretical basis for the existence of this link from an etiological point of view.

Conclusions

Our study confirmed that H. pylori infection was generally associated with pancreatic cancer, and this correlation would become more significant in economically underdeveloped areas. Although have not confirmed that H. pylori infection was associated with pancreatic cancer in the Asian population, we observed that H. pylori infection significantly increased the possibility of pancreatic cancer in the Asian population after sensitivity-analysis, suggesting that the results were not stable. In addition, we did not observe the evidence which could prove the association between CagA/VacA-positive H. pylori infection and the occurrence of pancreatic cancer.

Acknowledgments

We would like to thank Arles Lesmana from Leiden University for his help in polishing our paper.

Funding: This study was supported by Science and Technology Plan of Suzhou City (No. SKY2021038), and Primary Research & Social Development Plan of Jiangsu Province (No. BE2018659).

Footnote

Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-21-2803/rc

Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-21-2803/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-21-2803/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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