Helicobacter pylori cagA Status and Gastric Mucosa-associated Lymphoid Tissue Lymphoma: a Systematic Review and Meta-analysis

DOI: https://doi.org/10.21203/rs.3.rs-289927/v1

Abstract

Background: Recent studies have investigated the role of Helicobacter pylori infection in the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. It is estimated that approximately 0.1% of people infected with H. pylori develop gastric MALT. However, the role of the CagA antigen, the highest causative agent of H. pylori, in increasing the risk of gastric MALT remains unclear and controversial. A systematic review and meta-analysis were conducted to evaluate the effect of cagA status on the development of gastric MALT.

Methods: All articles evaluating the status of the cagA gene in the development of gastric MALT were collected using systematic searches in online databases, including PubMed, Scopus, Embase, and Google Scholar, regardless of publication date. The association between cagA and gastric MALT was assessed using the odds ratio (OR) summary. In addition, a random-effects model was used in cases with significant heterogeneity.

Results: A total of 10 studies met our inclusion criteria, among which 1,860 patients participated. We observed a meaningful association between cagA status and gastric MALT, especially in Western countries (OR: 1.30; 0.90–1.87 with 95% CIs). However, the heterogeneity was significant; therefore, the results should be interpreted with caution. Surprisingly, a strong positive association was observed between cagA status and high-grade lymphomas (OR: 6.43; 2.45–16.84 with 95% CIs). In addition, no study has evaluated the correlation between cagA and vacA, but we observed an inverse association between vacA and gastric MALT risk (OR: 0.92; 0.57–1.50 with 95% CIs).

Conclusion: CagA may not play a significant role in the early stages of gastric MALT, but it can be translocated to B cells and affect the development of high-grade lymphomas.

Introduction

Helicobacter pylori (H. pylori) is one of the most unique human pathogenic bacteria, and because of its exceptional ability to tolerate harsh stomach conditions, it colonizes the stomachs of about 4–4.5 billion people worldwide[1, 2]. Depending on environmental, socioeconomic, and health conditions, the prevalence of H. pylori infection varies in different geographical areas, with values of about 34% in Western countries and close to 100% in developing countries[3, 4]. Bacterial strains enter the gastric submucosa and cause chronic gastritis by evading the immune system response. However, 15–20% of people infected with H. pylori experience severe clinical outcomes, especially peptic ulcer disease (gastric ulcer or duodenal ulcer), chronic atrophy gastritis, and gastric adenocarcinoma, e.g., gastric cancer or mucosa-associated lymphoid tissue (MALT) lymphoma[5, 6].

It is currently unknown why most people infected with H. pylori are asymptomatic carriers, and severe clinical outcomes are seen only in a small part of the human population. The genomic content of H. pylori is specific to the strain, and evaluating the role of strain virulence factors is critical[7, 8]. The cytotoxin-associated gene A (CagA) is one of the major virulence factors in this bacterium, which is encoded by the cag pathogenicity islands (PAIs) and is classified into four different classes based on the flanking nucleotide sequence of EPIYA motifs. The CagA pattern in the East Asian population is usually ABD, while strains containing patterns such as ABC, ABCC, and ABCCC are isolated from Western countries[9, 10]. According to previous studies, cagA-positive strains are significantly present in the population with gastric ulcers and precancerous lesions[11]. Although the role of CagA in tumorigenesis remains unclear, according to the first hypothesis, phosphorylated CagA can phosphorylate intracellular eukaryotic proteins, particularly SHP-2 and Src kinase, and induce the hummingbird phenotype and oncogenesis by altering the normal cell signaling pathway[12]. The affinity of EPIYA-D for the binding and effect of SHP2 tyrosine phosphatase is much higher than that of EPIYA-C, so the differences are reported to be related to the fact that the prevalence of gastric cancer in East Asia is higher than that in Western countries[11, 13].

According to the second hypothesis, CagA is an immunogenic protein that stimulates the ‎production of interleukin (IL)-8 and leads to the infiltration of neutrophils in the inflamed area, the production of free ‎radicals, and DNA damage[14–16]. Accordingly, infection with this bacterium appears to increase the risk of two cancers of the digestive system, including gastric cancer and gastric MALT[17].

MALT lymphoma was first identified by Isaacson and Wright in 1983 and accounts for more than 50% of gastric lymphoma, a B-cell lymphoma derived from MALT during chronic inflammation[17, 18]. Carlson et al. (1996) showed that H. pylori gastritis can lead to gastric MALT by causing polyclonal lymphatic hyperplasia[19]. Recently, it has been shown that there is a positive association between H. pylori infection and the development of gastric MALT, with more than 90% of patients with gastric MALT lymphoma being infected with H. pylori[20]. In a study by Asenjo et al., the global prevalence of H. pylori infection in high-grade and low-grade lymphomas was estimated to be about 60% and 79%, respectively[21]. Interestingly, the eradication of H. pylori infection is very effective in the regression of gastric MALT; therefore, antibiotic therapy is considered the first line of treatment for gastric MALT[22]. According to in vitro experiments, the immune response in low-grade lymphomas is formed as a result of T cell-mediated immunity[23, 24]. Studies have shown that the CagA antigen can be translocated to B-cell lymphocytes following the destruction of gastric mucosa during chronic gastritis[25, 26]. In B cells, this antigen prevents apoptosis through extracellular signal-regulated kinase, which in turn leads to the proliferation and immortalization of B cells and eventually MALT lymphoma[26–28].

In general, despite limited information and conflicting results in some studies, events such as chronic inflammation, production of reactive oxygen species (ROS), B-cell proliferation, and genetic instability can lead to susceptibility to gastric MALT lymphoma[29–31]. In the present meta-analysis, we investigated the association between CagA and MALT to evaluate the role of CagA in the development of gastric MALT lymphoma.

Materials And Methods

Literature search

We conducted a comprehensive electronic search using the following online databases: PubMed, Scopus, Embase, and Google Scholar to retrieve all relevant documents printed in English up until December 2020. The search for terms was performed based on the MeSH library using words such as “Helicobacter pylori,” “H. pylori,” "MALT,” “mucosa-associated lymphoid tissue,” “CagA,” and “cytotoxin-associated gene A.” The literature search was performed independently by two authors (MK1 and MK2) without publication date restrictions.

Study selection

In the first stage, after initial evaluations, duplicate articles were excluded from the study, and then a reference list of each article was evaluated to avoid losing additional documents. The inclusion criteria were as follows: 1) all original, cross-sectional, case-control, and longitudinal articles related to our purpose, 2) studies on the association between cagA gene status and gastric MALT lymphoma; 3) studies based on standard diagnostic methods such as polymerase chain reaction (PCR), ELISA, and conventional microbiology tests; and 4) studies published in English. Exclusion criteria were as follows: (i) congress abstracts, case series, review articles, and letters to the editor; II) articles without full text available; III) articles published in non-English language; IV) animal studies or in vitro studies; and V) studies with vague results and insufficient data.

Quality assessment and data extraction

The Newcastle-Ottawa Scale checklist was used to assess the quality of the studies. The required data, including the first author, country, population sample size, number of H. pylori strains, diagnostic method, and frequency of cagA-positive strains, are listed in Table 1. All participants were divided into case (gastric MALT lymphoma) and control (gastritis or non-ulcer dyspepsia) groups.

Table 1

Characteristics of included studies

First author

Year

Country

Population size

H. pylori strains

Diagnostic method

cagA positive H. pylori strains

Gastritis or NUD

MALT

Jong et al.

1996

Netherlands

89

89

Culture-PCR

26

7

Peng et al.

1998

United kingdom

123

123

PCR

17

37

Lamarque et al.

1999

France

598

182

ELISA

20

10

Doorn et al.

1999

Netherlands

36

36

Culture-PCR

16

5

Schmaußer et al.

2000

Germany

30

30

ELISA

14

12

Delchier et al.

2001

France

598

162

ELISA

22

29

Koehler et al.

2003

Germany

121

91

Multiplex-PCR

27

15

Lehours et al.

2009

France

79

79

PCR

22

21

Talebi et al.

2013

Iran

134

128

Culture-PCR

63

5

Hashinaga et al.

2016

Japan

52

52

Culture-PCR

4

12

 

Statistical analysis

All statistical analyses were performed using Comprehensive Meta-Analysis software (Ver 2.2; Biostat, Englewood, NJ). The colonization rate of cagA-positive strains in both groups was reported as event rate (EER) with 95% confidence intervals (CIs). The impact of cagA gene status on the development of gastric MALT was also measured using the odds ratio (OR) at 95% CIs. The heterogeneity between studies was assessed with the I2 > 50 test and Cochran’s Q Statistic p value > 0.05. High levels of heterogeneity were evaluated according to the random-effects model with the DerSimonian and Laird method. In contrast, the fixed-effects model, based on the Mantel-Haenszel method, was used for low levels of heterogeneity. Furthermore, publication bias was assessed using asymmetry of funnel plots, Begg’s test p value, and Egger’s test p value.

Reults

Characteristics of selected studies

A total of 153 articles were collected in the initial search, and finally 10 eligible articles met our criteria and were included in the current analysis[32–41]. A flowchart of the article search strategy and study selection is presented in Fig. 1.

All eligible studies were conducted from 1996–2016, and data from 1860 patients were reviewed in these studies. Two studies were performed on the Asian population, and eight studies were conducted in Western countries. No significant relationship was observed between cagA status and age/sex distribution in any of the studies. In two studies, the association between the cagA genotype and the development of gastric MALT lymphoma was controversial[33, 40]. Unfortunately, the association between CagA EPIYA motifs and gastric MALT lymphoma was not evaluated in all studies, so we could not investigate this association. However, in three studies, the association between cagA status and both low-grade and high-grade forms of gastric MALT lymphoma was investigated[33, 36, 37]. In addition, the association between vacA status and gastric MALT was assessed in six studies[33–36, 39, 41].

Association between CagA status and susceptibility to gastric MALT

In this study, patients were divided into cases (gastric MALT lymphoma: 280 patients) and control (gastritis/non-ulcer dyspepsia (NUD): 414 patients). The prevalence of CagA-expressing strains in patients with MALT lymphoma and gastritis/NUD patients was estimated to be 54.6% (44–64.7 with 95% CIs) and 56.4% (41.5–70.3 with 95% CIs), respectively. However, according to the subgroup analysis by different geographical regions, we found that the frequency of cagA-positive strains in patients with gastritis/NUD in Western countries was higher than that in Asian countries (57.6% vs. 36%). The results showed that the cagA genotype was not significantly different between Western and Asian patients with gastric MALT lymphoma.

Based on the results of statistical analysis, we observed a weak correlation between cagA status and gastric MALT lymphoma (OR: 1.01; 0.71–1.42 with 95% CIs; I2: 83.52; Q-Value: 54.61; p value: 0.01; Egger’s p value: 0.36; Begg’s p value: 0.28). In the subgrouping, we found that there was an inverse significant association between cagA genotype and gastric MALT lymphoma in the Asian population (OR: 0.10; 0.03–0.31 with 95% CIs; I2: 95.6; Q-Value: 23.08; p value: 0.08), while there was a marginal association between cagA and the development of gastric MALT lymphoma in Western countries (OR: 1.30; 0.90–1.87 with 95% CIs; I2: 45.83; Q-Value: 12.92; p value: 0.58). Surprisingly, we observed a strong positive significant association between cagA status and the development of high-grade gastric MALT lymphoma (OR: 6.43; 2.45–16.84 with 95% CIs; I2: 0.00; Q-Value: 0.6; p value: 0.73; Egger’s p value: 0.21; Begg’s p value: 0.21).

Unfortunately, no studies have yet examined the relationship between CagA and VacA in the ‎development of MALT lymphoma, but VacA induces apoptosis by forming a vacuole ‎and release of cytochrome c from mitochondria and appears to inhibit the development of ‎MALT lymphoma[42, 43]. We found that there was a significant inverse association between infection with VacA-expressing H. pylori strains and gastric MALT lymphoma (OR: 0.92; 0.57–1.50 with 95% CI; I2: 32.3; Q-Value: 7.39; p value: 0.1; Egger’s p value: 0.79; Begg’s p value: 0.45). Therefore, despite the small sample size and significant heterogeneity between the studies, the results of the present study showed that cagA status has a marginal association with the risk of gastric MALT lymphoma, especially in Western countries. We also observed a strong association between CagA status and the development of high-grade MALT, indicating the importance of this virulence factor in the immune-pathogenesis of gastric MALT lymphoma. However, further investigation is required to confirm the results of this study.

Publication bias analysis

In the present study, the presence of bias in publication was evaluated using Begg’s p value and Egger’s p value. We did not observe any significant publication bias in the present study, although the funnel plot showed a slight publication bias in the eligible studies.

Discussion

MALT lymphoma refers to a group of low-grade B-cell lymphomas that involve the extranodal region of the mucosal and non-mucosal organs. Surprisingly, these organs normally lack lymphocytes, and infiltration of B-cell lymphocytes occurs as a result of chronic inflammation or autoimmune diseases (particularly Hashimoto’s thyroiditis). Gastric MALT lymphoma is the most common marginal zone lymphoma[44, 45]. Although almost 80% of low-grade MALT lymphomas are associated with H. pylori infection, disorders such as trisomy 3, trisomy 18, deletion in p16, and specific chromosomal translocations, such as t(1; 14)(p22; q32) and t(11; 18)(q21; q21) also increase the risk of gastric MALT lymphoma in H. pylori-negative individuals[46]. Today, the role of H. pylori infection in the development of gastric MALT lymphoma has been well-described, and recent studies have shown that eradication infection in low-grade lymphomas can lead to lymphoma regression in 60–90% of cases[47]. The most likely hypothesis is that persistent infection with H. pylori can lead to inflammation and infiltration of lymphocytes into the stomach with persistent stimulation of the immune response, and active proliferation of B cells leads to the formation of lymph follicles and the onset of gastric MALT lymphoma[48]. To date, several studies have attempted to investigate the association between cagA status and the development of gastric MALT lymphoma, but the results are unclear[31–33]. In addition, no comprehensive meta-analysis was performed in this area; therefore, using the available evidence, we performed the present meta-analysis to evaluate the exact role of the CagA antigen in the development of gastric MALT lymphoma.

Our results showed that there is a marginal association between cagA status and gastric MALT lymphoma. In the subgroup analysis, we observed a weak association between CagA and MALT lymphoma in Western countries. Interestingly, the present analysis showed an inverse association between cagA status and gastric MALT lymphoma risk in the Asian population (OR: 0.10; 0.03–0.31 with 95% CIs).

Previous studies indicated that early lymphomagenesis in lymphomas is a process related to CD4 + T cells stimulated by H. pylori antigens, and the proliferation of B-cell gastric lymphoma is dependent on CD40-mediated signaling, Th2 activities, co-stimulatory CD80, and CD86[24, 49–52]. Hussel et al. (1993) in their studies showed that the reduction of infiltrating T cells can significantly disrupt the effect of H. pylori infection on tumor B-cell proliferation[53]. Umehara et al. found that CagA could inhibit B-lymphoid cell proliferation by IL-3-dependent signaling by targeting the JAK-STAT pathway[26]. Furthermore, recent studies have shown an association between t(11; 18)(q21; q21) and infection with cagA-positive H. pylori strains in gastric MALT lymphoma; the anti-CagA titer is significantly higher in people with t(11; 18)(q21; q21)[46]. Liu et al. (2001) showed that the API2–MALT1 chimeric transcript was observed in all cases of H. pylori-infected gastric MALT lymphoma[54]. However, there is no correlation between H. pylori infection and the presence of API2–MALT1[55]. Thus, the formation of gastric MALT lymphoma appears to be more dependent on H. pylori antigen stimulation and T cell-mediated response. H. pylori cagA-positive strains with risk factors such as t(11; 18)(q21; q21) or API2–MALT1 chimeric translocation, and suppression of p53 accumulation as a cofactor, can effectively contribute to progression of stomach MALT lymphoma[26, 56].

Ohnishi et al. (2008) demonstrated the major role of CagA in the development of gastric and hematologic neoplasms[57]. After transfer to B-cell lymphocytes via the type 4 secretory system (T4SS), CagA, through the formation of phosphorylated CagA-SHP-2 complex by affecting ERK1, ERK2, p38MAPKs, ‎BCL2, and NF-κB, as well as accumulation of p53 or inhibition of the JAK-STAT signaling pathway, promotes lymphogenesis and immortalization of B-cell lymphocytes‎[26, 48, 58]. Gastric MALT lymphoma is classified into two subclasses based on the percentage of blast cells, including low-grade and high-grade lymphomas. Evaluation of cagA status in patients with low-grade and high-grade gastric lymphomas showed that this gene significantly increases the risk of developing high-grade lymphoma (OR: 6.43; 2.45–16.84 with 95% CIs). Based on previous studies, the presence of cagA-positive H. pylori strains in patients with high-grade lymphomas is significantly higher than that in patients with low-grade lymphomas[31]. The role of VacA in gastric MALT lymphoma is also controversial, and in one study, Miehlke et al. (1998) showed that the level of the vacA s1m1 genotype in gastric MALT lymphoma patients is high; however, ‎Doorn et al. (1999) rejected this hypothesis‎[35, 59]. Although we could not assess the correlation between cagA and vacA, we observed an inverse association between the vacA genotype and gastric MALT lymphoma (OR: 0.92; 0.57–1.50 with 95% CIs). Although vacA is a potent immune gene, given the fact that this protein causes apoptosis, it does not appear to play a significant role in the development of gastric MALT lymphoma[60, 61]. In general, the most likely hypothesis to describe the role of H. pylori in the development of ‎gastric MALT lymphoma is that this bacterium (CagA-dependent or independent) causes ‎chronic gastritis, resulting in the production of IL-8 and other molecules associated with neutrophil chemotaxis. Neutrophil activation leads to destruction of the gastric mucosa and close contact of CD4 + T cells with H. pylori, where the activity of DC and CD4 + T cells causes B cells to mature. Continuous stimulation and proliferation of B-cell lymphocytes leads to the formation of lymph follicles, in which case the patient develops low-grade lymphomas. In addition, no H. pylori eradication, particularly of cagA-positive strains, leads to the translocation of CagA into B cells. Intracellular CagA causes DNA and microRNA damage by reactive oxygen and nitrogen species, inhibition of p53, and chromosomal translocation, and ultimately the development of high-grade lymphomas (Fig. 2).

Our study had several limitations including: I) low sample size, II) evaluation of only studies published in English, III) high heterogeneity in some cases, IV) inaccessibility to the raw data for finding EPIYA motifs, correlation of CagA and VacA. The results of the study are unstable under the influence of significant heterogeneity, and further research is needed for confirmation.

Conclusion

In the present study, we performed a large pooled analysis to evaluate the role of CagA in gastric MALT lymphoma. Based on the available findings, the role of CagA was marginal in the initiation of low-grade lymphomas, especially in Asian countries, where we observed an inverse association between CagA and low-grade gastric MALT lymphoma. However, CagA can stimulate lymphogenesis and lead to the contentious proliferation and immortalization of B cells; therefore, it plays an important role in the development of high-grade gastric MALT lymphoma.

Abbreviations

H. pylori: Helicobacter pylori

MALT: mucosa-associated lymphoid tissue lymphoma

CagA: cytotoxin-associated gene A

PCR: Polymerase Chain Reaction

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Availability of data and materials

Not applicable.

Competing interests

The authors declare that they have no competing interests.

Funding

Not applicable.

Authors' Contributions

MK1 and AS equally contributed to the conception and design of the study; MK1 and MK2 performed the literature review and analysis. All authors equally contributed to drafting, critical revision, editing, and final approval.

Acknowledgements

Not applicable.

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