Low-Positive Antibody Titer against Helicobacter pylori Cytotoxin-Associated Gene A (CagA) May Predict Future Gastric Cancer Better Than Simple Seropositivity against H. pylori CagA or against H. pylori

Department of Clinical Studies, Radiation Effects Research Foundation, Hiroshima, Japan.
Cancer Epidemiology Biomarkers & Prevention (Impact Factor: 4.13). 07/2007; 16(6):1224-8. DOI: 10.1158/1055-9965.EPI-06-1048
Source: PubMed


To investigate the IgG antibody titer against Helicobacter pylori CagA as a risk factor for future noncardia gastric cancer.
A nested case-control study was done in the longitudinal cohort of atomic bomb survivors using stored sera before diagnosis (mean, 2.3 years). Enrolled were 299 cancer cases and 3 controls per case selected from cohort members matched on age, gender, city, and time and type of serum storage and countermatched on radiation dose.
H. pylori IgG seropositive with CagA IgG low titer was the strongest risk factor for noncardia gastric cancer [relative risk (RR), 3.9; 95% confidence interval (95% CI), 2.1-7.0; P < 0.001], especially for intestinal-type tumor (RR, 9.9, 95% CI, 3.5-27.4; P < 0.001), compared with other risk factors, H. pylori IgG seropositive with CagA IgG negative (RR, 2.2; 95% CI, 1.3-3.9; P = 0.0052), H. pylori IgG seropositive with CagA IgG high titer (RR, 2.0; 95% CI, 1.3-3.2; P = 0.0022), chronic atrophic gastritis (RR, 2.4; 95% CI, 1.8-3.3; P < 0.001), current smoking (RR, 2.3; 95% CI, 1.4-3.5; P < 0.001), or radiation dose (RR, 2.1; 95% CI, 1.2-3.1; P = 0.00193). Current smoking showed significantly higher risk for diffuse-type than intestinal-type tumors (P = 0.0372). Radiation risk was significant only for nonsmokers, all noncardia, and diffuse-type gastric cancers.
A low CagA IgG titer is a useful biomarker to identify a high-risk group and it also provides a clue to understanding host-pathogen interaction.

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    • "Moreover, there also exists evidence that both age and the severity of the mucosal lesions negatively influence the performance of CagA as a serological marker for GC (Camorlinga-Ponce et al., 2008). An association between the presence of GC and a low titre of anti-CagA antibodies has also been reported (Nomura et al., 2002; Suzuki et al., 2007). These heterogeneous results make it difficult to use simple CagA-positive serology as a marker for malignancy. "
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    ABSTRACT: Infection with Helicobacter pylori cytotoxin-associated gene A (CagA) positive strains is associated with the development of gastric cancer. However, some reports have failed to demonstrate an increased frequency of CagA antibodies in gastric cancer patients. We evaluated the response of IgG antibody and subclasses IgG1 and IgG2 against both, CagA and H. pylori membrane antigens in patients with precancerous lesions and cases with gastric cancer. We selected 137 patients with a positive serum IgG response to H. pylori: 46 with intestinal metaplasia, 41 with gastric adenocarcinoma and 50 with non-atrophic gastritis considered as controls. The response of total-IgG, IgG1 and IgG2 was investigated by immunoblot and ELISA using an in-house recombinant CagA and membrane antigens from a local strain, and possible associations were estimated using a logistic regression model. Compared to NAG, gastric cancer patients showed a higher frequency of IgG2 CagA antibodies (55.2% vs 15.4%, p= 0.001), but a lower frequency (80.5% vs 96.0%, p= 0.021) and diminished levels of IgG2 H. pylori antibodies (12.5 EU vs 21.9 EU, p= 0.007). Gastric cancer patients also presented lower levels of CagA (32.6 EU vs 42.4 EU, p= 0.004) and H. pylori total-IgG (33.7 EU vs 38.7 EU, p= 0.029). Gastric cancer was associated with a positive IgG2 CagA response (OR = 3.74, 95% CI, 1.81 - 5.37) and with a low titer of total-IgG CagA antibodies (OR = 2.18, 95% CI, 1.35 - 2.69). Our results suggest that the IgG2 response to CagA might be used as a novel serologic marker to identify patients with H. pylori-associated gastric cancer.
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    ABSTRACT: Gastric colonization with Helicobacter pylori is a proposed protective factor against gastroesophageal reflux disease (GERD), but little population-based data exist and other data conflict. We conducted a case-control study within the membership of a large integrated health-care system that compared GERD-free subjects with two groups: subjects with a physician-assigned GERD diagnosis and randomly selected members with self-described weekly GERD symptoms. Subjects completed interviews, GERD questionnaires, and antibody testing for H. pylori and its cagA protein. Serologic data were available for 301 physician-assigned GERD patients, 81 general membership subjects with GERD symptoms, and 175 general membership subjects without GERD symptoms. Physician-assigned GERD patients were less likely to have H. pylori antibodies than GERD-free member controls (odds ratio (OR) = 0.27, 95% confidence interval (CI) 0.15-0.47); there was also an inverse association between H. pylori and GERD symptom severity (OR = 0.18, 95% CI 0.08-0.41; severe or very severe symptoms) and GERD frequency (OR = 0.18, 95% CI 0.09-0.38; for symptoms at least weekly). The association was stronger among persons with erosive GERD and was similar between H. pylori-positive subjects with and without cagA. There was no association among persons who were cagA positive, but H. pylori negative. Similar findings were found in analyses of the general membership with self-described GERD symptoms. H. pylori antibody status was inversely associated with a GERD diagnosis and GERD symptoms compared with a general membership population.
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