# Helicobacter pylori Pathogenicity Factors Related to Gastric Cancer

Authors: Kianoosh Dadashzadeh; Maikel P. Peppelenbosch; Akyala Ishaku Adamu
Journal: Canadian Journal of Gastroenterology and Hepatology
 (2017)

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## Abstract

Background. Although the causal relationship betweenHelicobacter pylori infection and the development of gastric cancer is firmly established, the exact nature of the pathogenicity factors ofH. pylori that predispose to gastric oncogenesis remains incompletely characterized. We investigated the association betweenH. pylorivirulence genotypes and disease in a well-characterized cohort consisting of 109H. pylori isolates from gastric biopsies originating from patients.Methods. The prevalence of genotype was assessed by PCR and related to clinical histopathological parameters.Results. The relation ofbabA2 andbabB negative andiceA1 positive genotype as a single genotype and the development of cases to GC was statistically significant (P<0.001). ThecagE,cagA, andiceA1were found more commonly in patients with GC as compared with the other groups. The relation of the presence oficeA1 and the development of cases to GC was statistically significant (P=0.008), butbabA2 andbabBalleles were not detected in these patients. These apparent negative associations were still statically significant (P=0  and 0.005).Conclusion. Our results show an elevated prevalence of infection withH. pylori strains carrying known virulence genotypes with high genetic diversity. This highlights the importance of identifying gene variants for an early detection of virulent genotypes.


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## Body

## 1. Introduction

Gastric cancer remains a prevalent disease worldwide with a poor prognosis.Helicobacter pylori plays a major role in gastric carcinogenesis. H. pylori colonization leads to chronic gastritis, which predisposes to atrophic gastritis, intestinal metaplasia, dysplasia, and eventually gastric cancer. Screening, treatment, and prevention ofH. pylori colonization can reduce the incidence of gastric cancer [1]. Other interventions that may yield a similar effect, although of smaller magnitude, include promotion of a healthy lifestyle including dietary measures, nonsmoking, low alcohol intake, and sufficient physical activity [2]. Furthermore, increasing evidence suggests that host factors, including genetic make-up, are also important determinants for carcinogenesis inH. pylori infection [3]. Colonization ofH. pylori has been associated with chronic gastritis because it can trigger fulminant inflammatory response which can lead to pathological conditions such as gastric carcinoma and peptic ulcer disease [4]. Consequently a clinical need exists to stratifyH. pylori-infected patients with respect to their propensity to developH. pylori-related pathology; especially for GC this is felt as a pressing concern. The importance ofH. pylori virulence factors is evident from the serious clinical outcome associated with bacteria positive for the vacillating cytotoxic (vacA) and the cytotoxin-associated gene A (cagA) antigen [5]. However, these two virulence factors are insufficient to explain the variety in clinical presentation of pathology associates withH. pylori infection [6, 7]. A potentialH. pylori virulence factor possibly important to explain this variance in clinical outcome is the cag pathogenicity island (cag-PAI). ThecagA gene is a marker for the presence of the cag-PAI of approximately 40 kb, whose presence is associated with the more severe clinical outcomes [8, 9]. A type IV secretion system translocatescagA protein into gastric epithelial cells, where it is phosphorylated. When this modification occurs,cagA affects various cellular processes and signal transduction pathways, such as disruption of tight and adherent junctions that lead to proinflammatory and mitogenic responses: effects [8, 10]. One of the six cag-PAI genes iscagE, located in the right half of the cag-PAI, that has been shown to induce secretion of interleukin- (IL-) 8, from infected host epithelial cells [11, 12].Another putative virulence factor isiceA, whose gene has two main allelic variants,iceA1 andiceA2. The expression of iceA1 is upregulated on contact ofH. pylori with human epithelial cells and may be linked with peptic ulcer disease [16, 17]. The blood group antigen binding adhesin (babA), a 78 KDa outer membrane protein encoded by the babA2 gene, binds to Lewis b antigens and ABO antigen [18, 19]. Although threebab alleles have been identified (babA1,babA2, andbabB), only thebabA2 gene product is functionally active [20]. Studies in Western populations have associated the presence of thebabA2 gene with gastric cancer [19, 21]. The aim of this study is to assess the genotype ofH. pylori strains infecting patients with chronic gastritis through the evaluation of the prevalence of several genes coding for virulence factors.


## 2. Materials and Methods

This research was approved by the regional Medical Research Ethics Committee of Azad University of Medical Science on 19 Jul 2016 (number 1311/28772) and all patients provided written informed consent for this research.This study protocol conforms to the ethical guidelines of the 1975 Declaration of Helsinki as reflected in a prior approval by the institution’s human research committee.


### 2.1. Patients, Bacterial Strains, and Cultivation

Our cohort consisted of 109 clinical isolates ofH. pylori;49 (45%) were from females and 60 from males (55%).From male patients (sex ratio F/M: 0.82), the average age of the patients from which the isolates were obtained was39±17 years.H. pylori was isolated employing gastric biopsies of patients presenting with gastritis, peptic ulcer, or gastric cancer. Patients were not exposed to antimicrobial agents at least one week before endoscopy was performed. Following collection, gastric biopsy samples were homogenized and cultured onto Brucella agar supplanted with 5% sheep blood and antibiotics (vancomycin, amphotericin B, and trimethoprim). Culture plates were incubated at microaerophilic condition, 37°C and high humidity for 5–7 days. Organisms were identified asH. pylori based on colony morphology, gram staining, and positive oxidase, catalase, and urease tests.


### 2.2. DNA Extraction from Culture

Genomic DNA of totalH. pylori isolates was extracted using the QiAamp DNA mini kit (QIAGEN, Hilden, Germany) according to manufacturer’s protocol and stored at −20°C until use.


### 2.3. Detection of Genes

In this study, PCR was used to detect theH. pylori specificureC gene for confirming that the cultures represented abona-fide H. pyloriisolate, and the same technique was employed to establish presence or absence ofcagE,cagA,iceA1,iceA2babA2, andbabB genes.All primer sets were selected from published literature (listed in Table1). PCR reactions were performed in a volume of 50 μL containing 10 mmol/L Tris-HCl, 1.5 mmol/L MgCl2, 0.2 mmol/L of each deoxynucleotide, 25 pmol of each primer, and 2.5 units of Taq polymerase (Geneone, Germany) [22, 23]. The thermal cycler program used consisted of the following steps: initial denaturation at 94°C for 3 min followed by 35 cycles of 30 seconds at 94°C (denaturation); 30 seconds at 58°C forcagA andglmM [24]; 30 seconds at 53°C forcagE; 48°C forbabA2; 49°C forbabB; 57°C foriceA1; and 48°C and foriceA2 all annealing steps, followed by 30 seconds at 72°C (extension step); and a final extension step was 3 min at 72°C [25].Table 1
Primer sequences for polymerase chain reaction.
Gene
Primer
Nucleotide sequence
Size (bp)
Reference
ure
C (glmM)
Hp-F
GGATAAGCTTTTAGGGGTGTTAGGGG
294
[13]
HP-R
GCTTACTTTCTAACACTAACGCGC
cag
E
cag
E-F
TTGAAAACTTCAAGGATAGGATAGAGC
508
[12]
cag
E-R
GCCTAGCGTAATATCACCATTACCC
bab
A2
bab
A2-F
CCAAACGAAACAAAAAGCGT
271
[6]
bab
A2-R
GCTTGTGTAAAAGCCGTCGT
bab
B
bab
B -F
ATGAAAAAAACCCTTTTAC
496
[14]
bab
B-R
CGAATTGCAAGTGATGGT
cag
A
cag
A-F
AGGGATAACAGGCAAGCTTTTGA
352
[15]
cag
A-R
CTGCAAAAGATTGTTTGGCAGA
ice
A1
ice
A1-F
GTGTTTTTAACCAAAGTATC
247
[13]
ice
A1-R
CTATAGCCASTYTCTTTGCA
ice
A2
ice
A2-F
GTTGGGTATATCACAATTTAT
229
[13]
ice
A2-R
TTRCCCTATTTTCTAGTAGGT


### 2.4. Statistics Analysis

Data were analyzed by SPSS version 16. Fisher’s exact test or the Chi-square test was used for analysis of categorical data. AP value of <0.05 was considered statistically significant.


## 2.1. Patients, Bacterial Strains, and Cultivation

Our cohort consisted of 109 clinical isolates ofH. pylori;49 (45%) were from females and 60 from males (55%).From male patients (sex ratio F/M: 0.82), the average age of the patients from which the isolates were obtained was39±17 years.H. pylori was isolated employing gastric biopsies of patients presenting with gastritis, peptic ulcer, or gastric cancer. Patients were not exposed to antimicrobial agents at least one week before endoscopy was performed. Following collection, gastric biopsy samples were homogenized and cultured onto Brucella agar supplanted with 5% sheep blood and antibiotics (vancomycin, amphotericin B, and trimethoprim). Culture plates were incubated at microaerophilic condition, 37°C and high humidity for 5–7 days. Organisms were identified asH. pylori based on colony morphology, gram staining, and positive oxidase, catalase, and urease tests.


## 2.2. DNA Extraction from Culture

Genomic DNA of totalH. pylori isolates was extracted using the QiAamp DNA mini kit (QIAGEN, Hilden, Germany) according to manufacturer’s protocol and stored at −20°C until use.


## 2.3. Detection of Genes

In this study, PCR was used to detect theH. pylori specificureC gene for confirming that the cultures represented abona-fide H. pyloriisolate, and the same technique was employed to establish presence or absence ofcagE,cagA,iceA1,iceA2babA2, andbabB genes.All primer sets were selected from published literature (listed in Table1). PCR reactions were performed in a volume of 50 μL containing 10 mmol/L Tris-HCl, 1.5 mmol/L MgCl2, 0.2 mmol/L of each deoxynucleotide, 25 pmol of each primer, and 2.5 units of Taq polymerase (Geneone, Germany) [22, 23]. The thermal cycler program used consisted of the following steps: initial denaturation at 94°C for 3 min followed by 35 cycles of 30 seconds at 94°C (denaturation); 30 seconds at 58°C forcagA andglmM [24]; 30 seconds at 53°C forcagE; 48°C forbabA2; 49°C forbabB; 57°C foriceA1; and 48°C and foriceA2 all annealing steps, followed by 30 seconds at 72°C (extension step); and a final extension step was 3 min at 72°C [25].Table 1
Primer sequences for polymerase chain reaction.
Gene
Primer
Nucleotide sequence
Size (bp)
Reference
ure
C (glmM)
Hp-F
GGATAAGCTTTTAGGGGTGTTAGGGG
294
[13]
HP-R
GCTTACTTTCTAACACTAACGCGC
cag
E
cag
E-F
TTGAAAACTTCAAGGATAGGATAGAGC
508
[12]
cag
E-R
GCCTAGCGTAATATCACCATTACCC
bab
A2
bab
A2-F
CCAAACGAAACAAAAAGCGT
271
[6]
bab
A2-R
GCTTGTGTAAAAGCCGTCGT
bab
B
bab
B -F
ATGAAAAAAACCCTTTTAC
496
[14]
bab
B-R
CGAATTGCAAGTGATGGT
cag
A
cag
A-F
AGGGATAACAGGCAAGCTTTTGA
352
[15]
cag
A-R
CTGCAAAAGATTGTTTGGCAGA
ice
A1
ice
A1-F
GTGTTTTTAACCAAAGTATC
247
[13]
ice
A1-R
CTATAGCCASTYTCTTTGCA
ice
A2
ice
A2-F
GTTGGGTATATCACAATTTAT
229
[13]
ice
A2-R
TTRCCCTATTTTCTAGTAGGT


## 2.4. Statistics Analysis

Data were analyzed by SPSS version 16. Fisher’s exact test or the Chi-square test was used for analysis of categorical data. AP value of <0.05 was considered statistically significant.


## 3. Results

### 3.1. Description of the Patient Cohort and Isolation of Study Samples

A total of 109H. pylori samples were isolated from an initial number of 359 biopsies included in this study (yielding an apparent infection rate of 30.4%), of which 60 (55%) were derived from male patients and 49 (45%) isolates came from female patients (sex ratio F/M: 0.82). The average patients’ age at the time of endoscopy was 39±17 years. From the 109 patients with establishedH. pylori infection, 81 patients had presented with a nonulcer dyspepsia, nineteen patients with a peptic ulcer dyspepsia, and nine patients with GC (Signet Ring Cell Carcinoma (SRCC)). There was no significant difference between the mean age and sex of patients with and without ulcers and cancer. We concluded that our cohort would enable analysis of the link betweenH. pylorivirulence factors and clinical presentation.


### 3.2. The Presence of Virulence Factors Is Common in the Clinical Cohort

The PCR-based amplification showed that thecagE,babA2, andbabB positive strains had a prevalence of, respectively, 55.9%, 71.7%, and 61.3% in our cohort, whereascagA,iceA1, andiceA2 were detected in, respectively, 70.6%, 42.2%, and 13.2% of the patients included in this study (Table 2). Thus, the virulence factors selected for this study are commonly detected in our patient cohort and allow statistical analysis as to their relation to disease manifestation.Table 2
Relationship between clinical outcome and status ofcagE, babA2, babB, iceA1, iceA2, and CagA.
Genotypes
Number (%) of isolates
Total(n=109)
P value
NUD(n=81)
PUD(n=19)
GC (n=9)
cag
E
40 (49.4%)
13 (68.4%)
8 (88.9%)
61 (55.9%)
0.198
bab
A2
60 (74%)
16 (84.2%)
0
76 (71.7%)
0.001
bab
B
53 (65.4%)
12 (63.1%)
0
65 (61.3%)
0.005
ice
A1
29 (35.8%)
8 (42.1%)
9 (100%)
46 (42.2%)
0.008
ice
A2
11 (13.6%)
3 (15.8%)
0
14 (13.2%)
0.779
cag
A
53 (65.4%)
15 (78.9%)
9 (100%)
77 (70.6%)
0.134
NUD: nonulcer dyspepsia; PUD: peptic ulcer disease; GC: gastric cancer;Pv: P value.


### 3.3. SpecificH. pylori Virulence Factors Show Trends of Being Positively or Negatively Associated with Patient’s Clinical Presentation

In our study the frequency ofcagE-positive isolates obtained from patients with nonulcer dyspepsia, peptic ulcer dyspepsia, or GC patients was 49.4%, 68.4%, and 88.9%, respectively, but this apparent positive association with more severe disease did not reach statistical significance (P=0.198). ThebabA2 genotype was detected in 74%, 84.2%, and 0% of isolates from NUD, PUD, and GC patients. The percentage ofbabA2− genotype within GC patients was significantly higher than that ofcagA+ genotype (P<0.001).Also the percentage ofbabB+ was 65.4% and 63.1% for NUD and PUD cases, respectively, but for isolates from patients with GC (0%), this apparent negative association was statistically significant (P=0.005). Conversely the prevalence of theiceA2 allele was observed in NUD patients (13.6%) and in PUD (15.8%) and in GC patients (0%), but no significant association was observed betweeniceA2 genotype and GC (P=0.779). Similarly, in this study the distribution oficeA1 and clinical outcome was analyzed statistically and it was observed that the frequency oficeA1-positive isolates in NUD, PUD, and GC patients was 35.8%, 42.1%, and 100%, respectively. The relation of the presence oficeA1 and the development of cases to gastric cancer was statistically significant (P=0.008).Although thecagA allele was observed in NUD (65.4%) cases and in PUD patients (78.9%) and in GC patients (100%), there was not statistically significant association betweencagA and the gastric outcomes (P=0.134). A full overview of all virulence factors studied and their linkage to specific clinical manifestations is provided through Table 2.It is apparent from our data thatcagE,cagA, andiceA1 are more common in patients with gastric cancer than in the other patient groups, whereasbabA2 andbabB alleles were absent in patients with GC.


### 3.4. Combining Different Virulence Factors Allows Stratification of the Patient Cohort with respect to Patient Stratification

We examined eight different combinations based on analysis ofbabA2,babB, andiceA1 genotypes (positive and negative) in patients as a single genotype (Table 3). We were able to identify an association between these genotypes and clinical outcome. The frequency distributions of the combination genotypes ofH. pylori showed the relation ofbabA2 andbabB negative andiceA1 positive genotype and the development of cases to gastric cancer was statistically significant (P<0.001) among the patient groups. But there was not statistically significant association between other genotype combinations and the gastric cancer (P≥0.113).Table 3
Combination ofbabA2, babB, and iceA1genotypes and clinical outcome.
bab
A2
bab
B
ice
A1
GC (n=9)
NUD(n=81)
PUD(n=19)
Total(n=109)
P value
Positive
Positive
Positive
0
19
6
25
0.113
Positive
Positive
Negative
0
15
3
18
0.121
Positive
Negative
Positive
0
12
2
14
0.136
Positive
Negative
Negative
0
9
4
13
0.196
Negative
Positive
Positive
3
7
1
11
0.216
Negative
Positive
Negative
0
11
2
13
0.157
Negative
Negative
Positive
6
3
1
10
0.001
Negative
Negative
Negative
0
5
0
5
0.253
Presence of a gene = positive; absence of a gene = negative;Pv: P value.The apparent absence ofbabA2 andbabBalleles in GC patients raises, however, hopes that larger studies may establish the usefulness of these alleles in guiding patient management.


## 3.1. Description of the Patient Cohort and Isolation of Study Samples

A total of 109H. pylori samples were isolated from an initial number of 359 biopsies included in this study (yielding an apparent infection rate of 30.4%), of which 60 (55%) were derived from male patients and 49 (45%) isolates came from female patients (sex ratio F/M: 0.82). The average patients’ age at the time of endoscopy was 39±17 years. From the 109 patients with establishedH. pylori infection, 81 patients had presented with a nonulcer dyspepsia, nineteen patients with a peptic ulcer dyspepsia, and nine patients with GC (Signet Ring Cell Carcinoma (SRCC)). There was no significant difference between the mean age and sex of patients with and without ulcers and cancer. We concluded that our cohort would enable analysis of the link betweenH. pylorivirulence factors and clinical presentation.


## 3.2. The Presence of Virulence Factors Is Common in the Clinical Cohort

The PCR-based amplification showed that thecagE,babA2, andbabB positive strains had a prevalence of, respectively, 55.9%, 71.7%, and 61.3% in our cohort, whereascagA,iceA1, andiceA2 were detected in, respectively, 70.6%, 42.2%, and 13.2% of the patients included in this study (Table 2). Thus, the virulence factors selected for this study are commonly detected in our patient cohort and allow statistical analysis as to their relation to disease manifestation.Table 2
Relationship between clinical outcome and status ofcagE, babA2, babB, iceA1, iceA2, and CagA.
Genotypes
Number (%) of isolates
Total(n=109)
P value
NUD(n=81)
PUD(n=19)
GC (n=9)
cag
E
40 (49.4%)
13 (68.4%)
8 (88.9%)
61 (55.9%)
0.198
bab
A2
60 (74%)
16 (84.2%)
0
76 (71.7%)
0.001
bab
B
53 (65.4%)
12 (63.1%)
0
65 (61.3%)
0.005
ice
A1
29 (35.8%)
8 (42.1%)
9 (100%)
46 (42.2%)
0.008
ice
A2
11 (13.6%)
3 (15.8%)
0
14 (13.2%)
0.779
cag
A
53 (65.4%)
15 (78.9%)
9 (100%)
77 (70.6%)
0.134
NUD: nonulcer dyspepsia; PUD: peptic ulcer disease; GC: gastric cancer;Pv: P value.


## 3.3. SpecificH. pylori Virulence Factors Show Trends of Being Positively or Negatively Associated with Patient’s Clinical Presentation

In our study the frequency ofcagE-positive isolates obtained from patients with nonulcer dyspepsia, peptic ulcer dyspepsia, or GC patients was 49.4%, 68.4%, and 88.9%, respectively, but this apparent positive association with more severe disease did not reach statistical significance (P=0.198). ThebabA2 genotype was detected in 74%, 84.2%, and 0% of isolates from NUD, PUD, and GC patients. The percentage ofbabA2− genotype within GC patients was significantly higher than that ofcagA+ genotype (P<0.001).Also the percentage ofbabB+ was 65.4% and 63.1% for NUD and PUD cases, respectively, but for isolates from patients with GC (0%), this apparent negative association was statistically significant (P=0.005). Conversely the prevalence of theiceA2 allele was observed in NUD patients (13.6%) and in PUD (15.8%) and in GC patients (0%), but no significant association was observed betweeniceA2 genotype and GC (P=0.779). Similarly, in this study the distribution oficeA1 and clinical outcome was analyzed statistically and it was observed that the frequency oficeA1-positive isolates in NUD, PUD, and GC patients was 35.8%, 42.1%, and 100%, respectively. The relation of the presence oficeA1 and the development of cases to gastric cancer was statistically significant (P=0.008).Although thecagA allele was observed in NUD (65.4%) cases and in PUD patients (78.9%) and in GC patients (100%), there was not statistically significant association betweencagA and the gastric outcomes (P=0.134). A full overview of all virulence factors studied and their linkage to specific clinical manifestations is provided through Table 2.It is apparent from our data thatcagE,cagA, andiceA1 are more common in patients with gastric cancer than in the other patient groups, whereasbabA2 andbabB alleles were absent in patients with GC.


## 3.4. Combining Different Virulence Factors Allows Stratification of the Patient Cohort with respect to Patient Stratification

We examined eight different combinations based on analysis ofbabA2,babB, andiceA1 genotypes (positive and negative) in patients as a single genotype (Table 3). We were able to identify an association between these genotypes and clinical outcome. The frequency distributions of the combination genotypes ofH. pylori showed the relation ofbabA2 andbabB negative andiceA1 positive genotype and the development of cases to gastric cancer was statistically significant (P<0.001) among the patient groups. But there was not statistically significant association between other genotype combinations and the gastric cancer (P≥0.113).Table 3
Combination ofbabA2, babB, and iceA1genotypes and clinical outcome.
bab
A2
bab
B
ice
A1
GC (n=9)
NUD(n=81)
PUD(n=19)
Total(n=109)
P value
Positive
Positive
Positive
0
19
6
25
0.113
Positive
Positive
Negative
0
15
3
18
0.121
Positive
Negative
Positive
0
12
2
14
0.136
Positive
Negative
Negative
0
9
4
13
0.196
Negative
Positive
Positive
3
7
1
11
0.216
Negative
Positive
Negative
0
11
2
13
0.157
Negative
Negative
Positive
6
3
1
10
0.001
Negative
Negative
Negative
0
5
0
5
0.253
Presence of a gene = positive; absence of a gene = negative;Pv: P value.The apparent absence ofbabA2 andbabBalleles in GC patients raises, however, hopes that larger studies may establish the usefulness of these alleles in guiding patient management.


## 4. Discussion

Various studies have observed substantial differences in incidence and/or severity of gastroduodenal pathologies related toH. pylori which may vary according to geographical regions [26]. Although many factors may contribute to these differences, an obvious contributing factor is the different distribution of pathogenic markers in circulating strains [27]. The clinical relevance of the putative virulence-associated genes ofH. pylori and geographical region remains controversial. Other factors that influence the risks for atrophy and cancer in the presence of infection may be related to the time when infection occurred, to other environmental factors, and to the host genetic variation [28]. In particular single nucleotide polymorphisms in genes that influence bacterial handling via pattern recognition receptors appear to be involved, further strengthening the link between host risk factors,H. pylori incidence, and cancer [29]. In the present study we exploited this situation to study the relationship between selected virulence genes ofH. pylori and the clinical status. Our results clearly support the notion that further studies aimed at establishing the negative predictive value of the presence ofbabA2 andbabBalleles for GC development are warranted.ThecagE is a pathogenicity biomarker ofH. pylori. A survey of previous studies suggested that thecagE prevalence is different around the world [30]. The general importance ofcagE is best illustrated by its high frequency in GC patients as demonstrated by studies performed in patient populations derived from India (100%), Turkey (81.8%), and Thailand (93.8%) [31]. However, the prevalence ofcagE gene in this study was only 55.9%, markedly different from the results obtained in the aforementioned countries [32]. In the present studycagE-positive isolates were slightly more detected in isolates from peptic ulcer dyspepsia (PUD) patients (68.4%), but the potential significance of this finding, if any, remains to be established. The prevalence ofcagA gene in our cohort is 70.6%, which resembles the situation in Western countries (Yamaoka et al., 2002), but is markedly lower than that observed in East Asian countries wherecagA is present in more than 90% of cases [32]. LikecagE,cagA-positive isolates were enriched in samples obtained from peptic ulcer dyspepsia patients, albeit not in a statistically significant manner. Nevertheless, our findings support previous studies [32] (Wu et al., 2003) and should prove interesting in including our data in a meta-analysis of virulence genes in this respect. Our results show that the prevalence oficeA1 andiceA2 genes in isolates was 42.2% and 13.2%, respectively. These results are in agreement with previous studies showing that theiceA1 gene is prevalent in Japanese, Korean, and Dutch patients [13] (Ito et al., 2000; Shiota et al., 2013); conversely theiceA2 allele was predominant in the United States and Colombia. In our cohort, the relation of the presence oficeA1 and the development of cases to gastric cancer was statistically significant (P=0.008). But our data showed that there was no significant association betweeniceA2and GC compared with PUD or NUD. However, several studies have reported different results, as theiceA2 gene was detected to be predominant genotype in these studies (Aghdam et al., 2014; Biernat et al., 2014).ThebabA is one of the mediators for the attachment to gastric cells byH. pylori [33]. More recent analysis ofbabA2 as a virulence marker has produced conflicting data on the usefulness ofbabA2 expression in predicting clinical outcome, which is most likely dependent on the geographic origin of theH. pylori strains. Survey of previous studies on Portuguese, Thai, and India populations showed thatbabA2 is not a marker for peptic ulcer disease or gastric cancer [12, 26, 34]. However, several studies have reported different results for strains isolated from Turkey or Germany [26, 35]. Our study suggests thatbabA2, “although quite prevalent,” is associated with reduced propensity to develop GC and is thus associated with less oncogenicH. pylori.Similar results were obtained concerningbabB.Our results showed the relation ofbabA2 andbabB negative andiceA1 positive genotype and the development of cases to gastric cancer was statistically significant. Further studies are required to determine the functions ofbabA2 andbabB and their relationship with disease outcome and whether the presence of these alleles indicates the presence of bacteria unlikely to confer progression towards GC.



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