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Polymorphism in the CagA EPIYA motif impacts development of gastric cancer.

ABSTRACT: Helicobacter pylori causes diseases ranging from gastritis to peptic ulcer disease to gastric cancer. Geographically, areas with high incidences of H. pylori infection often overlap with areas with high incidences of gastric cancer, which remains one of the leading causes of cancer-related deaths worldwide. Strains of H. pylori that carry the virulence factor cytotoxin-associated gene A (cagA) are much more likely to be associated with the development of gastric cancer. Moreover, particular C-terminal polymorphisms in CagA vary by geography and have been suggested to influence disease development. We conducted a large-scale molecular epidemiologic analysis of South Korean strains and herein report a statistical link between the East Asian CagA EPIYA-ABD genotype and the development of gastric cancer. Characterization of a subset of the Korean isolates showed that all strains from cancer patients expressed and delivered phosphorylatable CagA to host cells, whereas the presence of the cagA gene did not strictly correlate to expression and delivery of CagA in all noncancer strains.

SUBMITTER: Jones KR

PROVIDER: S-EPMC2668329 | biostudies-literature | 2009 Apr

REPOSITORIES: biostudies-literature

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Polymorphism in the CagA EPIYA motif impacts development of gastric cancer.

Jones Kathleen R KR Joo Young Min YM Jang Sungil S Yoo Yun-Jung YJ Lee Hak Sung HS Chung In-Sik IS Olsen Cara H CH Whitmire Jeannette M JM Merrell D Scott DS Cha Jeong-Heon JH

Journal of clinical microbiology 20090121 4

Helicobacter pylori causes diseases ranging from gastritis to peptic ulcer disease to gastric cancer. Geographically, areas with high incidences of H. pylori infection often overlap with areas with high incidences of gastric cancer, which remains one of the leading causes of cancer-related deaths worldwide. Strains of H. pylori that carry the virulence factor cytotoxin-associated gene A (cagA) are much more likely to be associated with the development of gastric cancer. Moreover, particular C-te ...[more]

PMID: 19158258

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Project description:BackgroundHelicobacter pylori chronic infection is associated with chronic gastritis, peptic ulcer, and gastric cancer. Cytotoxin-associated gene A (cagA)-positive H. pylori strains increase the risk of gastric pathology. The carcinogenic potential of CagA is linked to its polymorphic EPIYA motif variants. The goals of this study were to investigate the frequency of cagA-positive Helicobacter pylori in Mexican patients with gastric pathologies and to assess the association of cagA EPIYA motif patterns with peptic ulcer and gastric cancer.MethodsA total of 499 patients were studied; of these, 402 had chronic gastritis, 77 had peptic ulcer, and 20 had gastric cancer. H. pylori DNA, cagA, and the EPIYA motifs were detected in total DNA from gastric biopsies by PCR. The type and number of EPIYA segments were determined by the electrophoretic patterns. To confirm the PCR results, 20 amplicons of the cagA 3' variable region were sequenced, and analyzed in silico, and the amino acid sequence was predicted with MEGA software, version 5. The odds ratio (OR) was calculated to determine the associations between the EPIYA motif type and gastric pathology and between the number of EPIYA-C segments and peptic ulcers and gastric cancer.ResultsH. pylori DNA was found in 287 (57.5%) of the 499 patients, and 214 (74%) of these patients were cagA-positive. The frequency of cagA-positive H. pylori was 74.6% (164/220) in chronic gastritis patients, 73.6% (39/53) in peptic ulcer patients, and 78.6% (11/14) in gastric cancer patients. The EPIYA-ABC pattern was more frequently observed in chronic gastritis patients (79.3%, 130/164), while the EPIYA-ABCC sequence was more frequently observed in peptic ulcer (64.1%, 25/39) and gastric cancer patients (54.5%, 6/11). However, the risks of peptic ulcer (OR = 7.0, 95% CI = 3.3-15.1; p < 0.001) and gastric cancer (OR = 5.9, 95% CI = 1.5-22.1) were significantly increased in individuals who harbored the EPIYA-ABCC cagA gene pattern.ConclusionscagA-positive H. pylori is highly prevalent in southern Mexico, and all CagA variants were of the western type. The cagA alleles that code for EPIYA-ABCC motif patterns are associated with peptic ulcers and gastric cancer.

Project description:BackgroundIncreasingly, studies have focused on the relationship between Helicobacter pylori (H pylori) cytotoxin associated gene A protein (CagA) Glu-Pro-Ile-Tyr-Ala (EPIYA)-D motifs or multiple EPIYA-C phosphorylation sites and peptic ulcer disease (PUD) or gastric cancer (GC) risk. However, the conclusions have been inconsistent. The aim of this meta-analysis was to evaluate whether 1 CagA EPIYA-D motif or multiple EPIYA-C phosphorylation sites were associated with PUD or GC risk.Materials and methodsA literature search was performed in PubMed, Web of Science, Wanfang Data, Excerpt Medica Database, and the Chinese National Knowledge Infrastructure database to identify eligible research. We analyzed the odds ratios (OR) and 95% confidence intervals (CI) to assess the strength of association.ResultsCompared with 1 EPIYA-C motif in Asian populations, 1 EPIYA-D site was associated with an increased GC risk (OR=1.91, 95% CI=1.19-3.07, P = .008). However, 1 EPIYA-D motif was not significantly associated with PUD (OR = 0.90, 95% CI = 0.46-1.76, P = .764), gastric ulcer (GU) (OR = 0.85, 95% CI = 0.27-2.63, P = .771), or duodenal ulcer (DU) (OR = 0.89, 95% CI = 0.25-3.16, P = .859) risk. Compared with no more than 1 EPIYA-C motif, multiple motifs were associated with increased PUD (OR = 2.33, 95% CI = 1.29-4.20, P = .005) and DU (OR = 2.32, 95% CI = 1.08-5.00, P = .031) risk in Asia and GC risk in the United States and Europe (OR = 3.28, 95% CI = 2.32-4.64, P < .001). Multiple EPIYA-C sites were not associated with GU risk (OR = 4.54, 95% CI = 0.95-21.83, P = .059). There was no publication bias identified in these comparisons.ConclusionsIn Asia, 1 EPIYA-D motif was significantly associated with increased GC risk. Multiple EPIYA-C motifs were associated with increased PUD and DU risk, particularly in Asia. In the United States and Europe, multiple EPIYA-C motifs were associated with increased GC risk. Therefore, detection of polymorphic CagA EPIYA motifs may improve clinical prediction of disease risk.

Dataset Information

Polymorphism in the CagA EPIYA motif impacts development of gastric cancer.

Publications

Polymorphism in the CagA EPIYA motif impacts development of gastric cancer.

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