International Journal of Infectious Diseases
Volume 14, Issue 7 , Pages e613-e617, July 2010

The relationship between Helicobacter pylori genes cagE and virB11 and gastric cancer

  • Valeska Portela Lima

      Affiliations

    • Department of Pathology and Forensic Medicine, Federal University of Ceará, Porangabussu Campus, Alexander Baraúna Street, 949, Fortaleza, Ceará 60183-630, Brazil
    • Corresponding Author InformationCorresponding author. Tel.: +55 85 8805 0432; fax: +55 85 3267 3840.
    • ,
  • Marcos Antonio Pereira de Lima

      Affiliations

    • Department of Pathology and Forensic Medicine, Federal University of Ceará, Porangabussu Campus, Alexander Baraúna Street, 949, Fortaleza, Ceará 60183-630, Brazil
    • ,
  • Márcia Valéria Pitombeira Ferreira

      Affiliations

    • Department of Pathology and Forensic Medicine, Federal University of Ceará, Porangabussu Campus, Alexander Baraúna Street, 949, Fortaleza, Ceará 60183-630, Brazil
    • ,
  • Marcos Aurélio Pessoa Barros

      Affiliations

    • Saint House of Mercy, Fortaleza, Brazil
    • ,
  • Sílvia Helena Barem Rabenhorst

      Affiliations

    • Department of Pathology and Forensic Medicine, Federal University of Ceará, Porangabussu Campus, Alexander Baraúna Street, 949, Fortaleza, Ceará 60183-630, Brazil

Received 17 February 2009; received in revised form 6 September 2009; accepted 8 September 2009. published online 27 January 2010.

Corresponding Editor: Sunit K. Singh, Hyderabad, India

Article Outline

Summary 

Background

The association between Helicobacter pylori gene diversity and gastric cancer has been poorly reported, although it is one of the important ways to explain the gastric pathogenesis. The aim of this study was to investigate the frequency of cagE and virB11 genes in H. pylori isolated from patients with gastric cancer and to analyze the histology profiles.

Materials and methods

The presence of H. pylori and subtypes (cagE and virB11) was detected by PCR from the genomic DNA of 101 patients who had been diagnosed with gastric cancer. The cases were grouped according to the presence/absence of the genes studied and were analyzed in relation to histopathological parameters.

Results

H. pylori infection was detected in 94 out of 101 (93.1%) gastric carcinomas. The cases were categorized into the following groups: cagE+/virB11+, cagE+/virB11−, cagE−/virB11+, and cagE−/virB11−. Frequencies were: 50% (47/94) cagE+/virB11+, 3.2% (3/94) cagE+/virB11−, 10.6% (10/94) cagE−/virB11+, and 36.2% (34/94) cagE−/virB11−. Tumors in the gastric antrum were predominant. An exception was the cagE−/virB11− group, in which tumors had a tendency to be located in the gastric cardia; the majority of the cardia tumors (56% (14/25)) were in this group. Intestinal histology type was the most frequent, but the cagE+/virB11− group only had diffuse tumors. H. pylori cagE+/virB11+ occurred most frequently (except at stage III), and was present at all gastric cancer stages.

Conclusions

This study is the first to include a relevant number of gastric cancer cases with H. pylori infection, reporting the frequency and relationship of cagE and virB11 genes and the genesis of this tumor. The presence of these cag pathogenicity island genes shows that they are important factors for the pathogenesis and malignancy of gastric cancer related to H. pylori.

Keywords: Gastric cancer, Helicobacter pylori, Genotype

 

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1. Introduction 

Helicobacter pylori is a Gram-negative bacterium that has been associated with diverse pathologies of varying severity, such as chronic gastritis, peptic ulcer, mucosa-associated lymphoid tissue (MALT) lymphoma, and gastric carcinoma.1 Although most infected persons remain asymptomatic, 15–20% of H. pylori-positive individuals will develop the associated diseases. This could be dependent on environmental factors, host genetic factors or specific properties of the microorganism.1

There is some evidence that the presence of certain virulence factors is important in the organism's ability to cause different diseases. Several bacterial virulence factors have been suggested, including the vacuolating cytotoxin (VacA) and the cytotoxin-associated gene A antigen (CagA). However, data supporting these findings are insufficient to explain the variety and severity of the related diseases. One important virulence factor of H. pylori is the cag pathogenicity island (cag-PAI). This contains 31 genes, including the cagA gene, but also codes for six proteins of a putative type IV secretion system, specialized in the transfer of a variety of protein complexes across the bacterial membrane to the extracellular space or into the host cells.2, 3 One of the cag-PAI genes is cagE, located in the right half of the cag-PAI.1, 4, 5, 6 Sozzi et al.6 and Ikenoue et al.7 have suggested that this gene is a more accurate marker of an intact cag-PAI than other cag genes. Another gene that codifies proteins of a type IV secretion system is virB11. This gene is located in the left half of the cag-PAI. The VirB11 protein has a ring-shaped structure composed of six monomeric units. It is important for the transportation of protein complexes and exhibits ATPase activity.8, 9 Several studies have described an association between H. pylori cagE and gastritis, duodenal ulcer, and peptic ulcer disease.10, 11, 12 Only a few studies have described an association with gastric cancer, but the number of cases included has been small and therefore the test results have often been combined with those of other diseases.13, 14, 15 In contrast to studies of cagE, those related to the gene virB11 are more frequently in vitro, with rare reports in vivo.6, 16 Therefore, the aim of this study was to investigate the frequency of cagE and virB11 genes in H. pylori isolates from patients with gastric cancer and to analyze the histology profiles.

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2. Materials and methods 

2.1. Clinical specimens 

This study was approved by the ethics committee of the Federal University of Ceará and all subjects signed an informed consent form before inclusion. Samples from 101 patients with gastric carcinoma who had undergone gastrectomy were collected from two hospitals in the state of Ceará, Brazil: Walter Cantídeo Hospital at the Federal University of Ceará and Saint House of Mercy in Fortaleza, both located in Fortaleza, the state capital. Histological classification was done according to the Lauren classification and the tumors were staged according to the TNM criteria (tumor, node, metastasis) by the study team of pathologists.

2.2. DNA extraction 

Genomic DNA was extracted from frozen tumor tissue using cetyltrimethyl ammonium bromide (CTAB), as per the method of Foster and Twell, with some modifications.17 DNA extraction was done only in fragments that presented more than 80% of tumor cells and the quality was analyzed by 1% agarose gel electrophoresis with ethidium bromide staining.

2.3. H. pylori and cagE and virB11 gene detection 

H. pylori infection was detected by amplification of the urease C (ureC) gene using oligonucleotide primers for PCR, as described by Lage et al.18 The presence of the cagE and virB11 genes was identified in the H. pylori-positive samples using the primers described by Sozzi et al.6 The PCR mixtures for amplification of both genes were prepared in a volume of 25μl using MasterMix (Taq DNA polymerase, dNTPs and MgCl2) according to the manufacturer's instructions (Promega), adding 0.8% of Tween 20, 0.4μM of each primer, and 1μl of the DNA sample. PCR products were analyzed by 1% agarose gel electrophoresis with ethidium bromide staining. The sample was considered H. pylori-positive when a ureC fragment of 294bp was amplified, while cagE and virB11 genes were considered positive when fragments of 509bp and 491bp, respectively, were detected. We used known DNA to be H. pylori-positive as a positive control. DNAse-free water was used as a negative control. DNA preservation was also confirmed by amplification of different genes using other approaches in our laboratory. Random samples were reanalyzed for confirmation of the results.

2.4. Statistical analysis 

Statistical analyses were carried out using Epi Info 6.04d (Centers for Disease Control and Prevention, Atlanta, GA, USA) and SPSS 12.0 (SPSS Inc., Chicago, IL, USA) programs. Statistically significant differences were evaluated by the Chi-square test. Results were considered statistically significant when the p-values were less than 0.05.

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3. Results 

Among the 101 cases analyzed, 68 (67.3%) were male and 33 (32.7%) female. The average age was 62.7 years, ranging from 23 to 90 years. The most frequent tumor site was the gastric non-cardia (76/101 (75.2%) vs. cardia 25/101 (24.8%)). Intestinal and diffuse types presented similar frequencies: 58 (57.4%) and 43 (42.6%), respectively.

3.1. Detection of H. pylori and presence of cagE and virB11 genes 

H. pylori infection was detected in 94 of the 101 (93.1%) gastric carcinomas. H. pylori-positive cases were more frequently male (64/94 (68.1%)). H. pylori infection was detected more frequently in non-cardia tumors (73.4% (69/94)) than in cardia tumors (26.6% (25/94)). Among these H. pylori-infected cases, the intestinal histology type was slightly more frequent (58.5% (55/94)). The cagE gene was found in 53.2% (50/94) and the virB11 gene in 60.6% (57/94) of the cases. Additionally, the cagE and virB11 genes had a significant positive correlation (r = 0.728, p = 0.000).

3.2. Relationship between H. pylori infection and cagE and virB11 genes with gastric cancer 

To investigate the relationship between the H. pylori infection and the presence of cagE and virB11 genes in gastric cancer, we divided the cases into four groups according to the presence of these genes: cagE+/virB11+, cagE+/virB11−, cagE−/virB11+, and cagE−/virB11−. The frequency of cases was 50% (47/94) in cagE+/virB11+, 3.2% (3/94) in cagE+/virB11−, 10.6% (10/94) in cagE−/virB11+, and 36.2% (34/94) in cagE−/virB11−.

Table 1 shows the distribution of the four groups according to gastric site. It is noteworthy that the cagE+/virB11+ group was predominant in non-cardia tumors (56.5%) and the cagE−/virB11− group was more frequent in tumors situated in the gastric cardia (56%).

Table 1. Correlation between gastric sites and the four determinate groups
CardiaNon-cardiap-Value
cagE+/virB11−0 (0%)3 (4.3%)0.422
cagE−/virB11+3 (12%)7 (10.2%)0.471
cagE+/virB11+8 (32%)39 (56.5%)0.032
cagE−/virB11−14 (56%)20 (29.0%)0.025

Fig. 1 shows the distribution of groups according to tumor stage. The cagE+/virB11+ group was present from stage IB, being the most frequent at stages IB, II and IV. Although the cagE−/virB11− group was present from stage IA, it was more frequent at stage III. Despite the small numbers in the cagE+/virB11− and cagE−/virB11+ groups, the former was restricted to the advanced stages (III and IV), while the latter was represented at almost all stages.

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  • Fig. 1. 

    Distribution of cases by tumor stage (IA, IB, II, III and IV) in the four defined groups: cagE+/virB11−, cagE−/virB11+, cagE+/virB11− and cagE−/virB11−.

Since the gastric cancer tumor grading included lymph node involvement and metastases as well as tumor size (TNM), we analyzed the data for tumor size alone to better verify whether H. pylori was present at the beginning of tumorigenesis (Fig. 2). In this distribution, it was possible to observe that the cagE+/virB11+ group was the most frequent at tumor sizes T2 and T3.

Fig. 3 shows the distribution of cases by lymph node involvement. The cagE+/virB11+ group was the most frequent in N0, N1 and N2 cases. The majority of the H. pylori-infected gastric cancers did not show metastasis (Fig. 4).

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  • Fig. 3. 

    Distribution of cases by lymph node involvement (N0, N1, N2, N3, Nx) in the four defined groups: cagE+/virB11−, cagE−/virB11+, cagE+/virB11− and cagE−/virB11−.

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  • Fig. 4. 

    Distribution of cases by presence/absence of metastasis (M0, M1, Mx) in the four defined groups: cagE+/virB11−, cagE−/virB11+, cagE+/virB11− and cagE−/virB11−.

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4. Discussion 

Several studies have reported the influence of particular virulence genes (mainly vacA and cagA) on the clinical outcome of H. pylori infection in different geographical regions. Nevertheless, the clinical relevance of these putative virulence-associated genes of H. pylori is still a matter of controversy. The cytotoxin-associated gene cagA, which codes for the outer membrane protein CagA, was initially considered an important virulence factor, due to its association with some gastrointestinal diseases.19, 20, 21 However, subsequent studies have provided more inconsistent results.22, 23 Miehlke et al.22 demonstrated that up to 80% of subjects without ulcer disease in Texas were infected with H. pylori strains that possessed cagA. In China and Japan, cagA-positive strains are nearly universally present and not associated with disease complications.24, 25 In children, infection with cagA-positive strains has not been consistently associated with peptic ulcer disease.26, 27, 28 These findings suggest that polymorphism of the cagA gene can be relevant,3, 9 but the presence of other possible H. pylori virulence genes may also be. The other virulence factor of H. pylori most studied is vacA, which presents genotype and geographic variation, with the genotype vacA s1m1 associated with more severe gastrointestinal diseases.29, 30 Even so, the presence of cagA and vacA has not been sufficient to explain diseases related to H. pylori infection.

Therefore, the pathogenicity of H. pylori strains could be related to the presence of other cag-PAI genes. Among these genes, cagE and virB11 stand out: these genes are located on different sides of the cag-PAI, so they can also be used as markers of the presence of this island, as proposed by some authors;1, 2, 4, 6 they also have pathogenic potential due to their critical functions.1, 8 Thus, we examined the frequency of H. pylori and the relationship between cagE and virB11 genes and the histological data.

The current study demonstrated the frequency of H. pylori infection to be 93.1% in gastric cancer cases. This frequency is similar to that reported in another study from Brazil by Thomazini et al.,31 which reported a frequency of 95%, and a study from Turkey by Saribasak et al.,32 which reported a frequency of 100%. Both of these studies used PCR to detect H. pylori infection in gastric cancers. In addition, Nomura et al.,33 found 94% prevalence of H. pylori infection in gastric cancer by serology, in a study conducted in Hawaii. On the other hand, these frequencies are higher than those found in the majority of previous studies, which have reported frequencies between 52% and 69%. However, most of these have used serology and histology to detect H. pylori infection.34, 35, 36

The cagE gene was found in 53.2% of H. pylori-positive gastric cancer cases. This is the first study to analyze the frequency of cagE in gastric cancer separately. Table 2 shows the frequency of the cagE gene found in studies of gastrointestinal diseases.11, 12, 13, 21, 37, 38, 39 These studies show that the frequency of the cagE gene is highest in more severe diseases, such as ulcer and gastric cancer, than in gastritis, suggesting that this gene may be important in the progression of these diseases. Likewise, the virB11 gene was found in a significant (60.6%) number of the gastric cancer cases analyzed. So far, there have been no studies linking the presence of gastric cancer to virB11. The only two studies found in the literature at the time of writing were those of Tomasini et al.16 and Sozzi et al.,6 both of which studied dyspeptic Italian patients with duodenal ulcer, non-atrophic gastritis and atrophic gastritis. These studies found the virB11 gene to be present in 90% and 94.7% of the cases, respectively, both higher than the frequency found in the present study.

Table 2. Frequencies of cagE found in the literature
Author, year [Ref.]Frequency (n/N)PopulationDisease
Lima et al., 2008 [present study]53.2% (50/94)BrazilianGastric cancer
Ali et al., 2005 [13]100% (14/14)IndiaGastric cancer
Erzin et al., 2006 [37]81.8% (27/33)TurkeyGastric cancer
Chomvarin et al., 2008 [12]93.8% (15/16)ThailandGastric cancer
Day et al., 2000 [11]92.3% (12/13)CanadaDuodenal ulcer
Erzin et al., 2006 [37]67.9% (19/28)TurkeyDuodenal ulcer
Chomvarin et al., 2008 [12]90% (18/20)ThailandGastric ulcer
Chomvarin et al., 2008 [12]85.7% (12/14)ThailandDuodenal ulcer
Audibert et al., 2001 [38]64.7% (99/153)FranceUlcer/gastritis
Lehours et al., 2004 [39]56.4% (22/39)FranceGastritis
Erzin et al., 2006 [37]26.7% (8/30)TurkeyDyspepsia
Chomvarin et al., 2008 [12]87.1% (54/62)ThailandNon-ulcer gastritis
Módena et al., 2007 [21]88.9% (72/81)BrazilianSome gastric duodenal diseases

The frequency of the cagE gene found in the present study was lower than in others (Table 2), but this could be due to the small number of gastric cancer cases analyzed in those studies. Also, the frequency of the virB11 gene was lower than that found in studies of other gastric diseases. Besides the significance of the number of cases studied, these differences may be related to regional variations in circulating H. pylori strains, since the bacterium is known to have great genomic variability.1

Together, these studies point to the importance of these genes in the progression and severity of gastric diseases. In fact, the VirB11 protein is strategically located in the type IV secretion system, associated with ATPase activity, and cagE is considered as contributing to the construction of the cag type IV secretion system and inducing the secretion of cytokines, such as interleukin-8, from infected host epithelial cells.

To verify the influence of cagE and virB11 genes of H. pylori on gastric cancer, we divided the cases into four groups based on the presence or absence of these genes. Although the gastric antrum was the most prevalent site of gastric cancer with H. pylori infection, the cagE−/virB11− group showed a slight increase in incidence of tumors located in the gastric cardia. Since this region is associated with the development of tumors without H. pylori infection,40, 41 the strains found in the cardia region may be less virulent.

Reports of the association of H. pylori with histological types of gastric cancer are controversial and there are no reports associating histological subtypes and H. pylori genotypes. The intestinal type was prevalent in the cagE−/virB11+, cagE+/virB11+, and cagE−/virB11− groups. However, in spite of the small number of cases, the cagE+/virB11− group was only found in the diffuse type. Some studies have shown an association between H. pylori and the intestinal type,33, 42 while others have observed a similar distribution between the two histological types.42, 43 Palestro et al.,44 reported that H. pylori infection may also be involved in the pathogenesis of diffuse gastric cancer. These variations could be due to the presence of strain factors that were not analyzed here, associated with host genetic predisposition, such as mutation in the E-cadherin gene.45, 46

There are only a few studies reporting the relationship between gastric cancer and H. pylori infection and tumor stage, such as that of Luo et al.47 They found a higher frequency of H. pylori infection at stage II. In the present study, we found the presence of H. pylori beginning at the early stages with cagE+/virB11+ and cagE−/virB11−. The presence of H. pylori cagE+/virB11+ from the earlier stages and the high frequency at all stages suggest that this strain can be more pathogenic than others and also that this strain can be important in gastric tumorigenesis. This aspect was confirmed by the presence of the H. pylori cagE+/virB11+ in tumors of a small size. Studies reporting high frequencies of these genes in more aggressive gastric diseases support this idea.6, 11, 12, 13, 16 On the other hand, the presence of the cagE−/virB11− group could be due to other virulence factors of H. pylori or even associated with other risk factors, such as particular foods, alcohol and smoking, which were not studied.

Finally, this study is the first to include a relevant number of gastric cancer cases with H. pylori infection, reporting the frequency and relationship of cagE and virB11 genes and also to analyze the presence of these genes focusing on histological aspects. The results presented here indicate that these genes, which are part of the cag-PAI, are important virulence factors of H. pylori in bacterial pathogenesis.

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Conflict of interest 

No conflict of interest to declare.

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PII: S1201-9712(09)00370-1

doi:10.1016/j.ijid.2009.09.006

International Journal of Infectious Diseases
Volume 14, Issue 7 , Pages e613-e617, July 2010

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