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1.  Accuracy and Cut-Off Values of Pepsinogens I, II and Gastrin 17 for Diagnosis of Gastric Fundic Atrophy: Influence of Gastritis 
PLoS ONE  2011;6(10):e26957.
Background
To establish optimal cutoff values for serologic diagnosis of fundic atrophy in a high-risk area for oesophageal squamous cell carcinoma and gastric cancer with high prevalence of Helicobacter pylori (H. pylori) in Northern Iran, we performed an endoscopy-room-based validation study.
Methods
We measured serum pepsinogens I (PGI) and II (PGII), gastrin 17 (G-17), and antibodies against whole H. pylori, or cytotoxin-associated gene A (CagA) antigen among 309 consecutive patients in two major endoscopy clinics in northeastern Iran. Updated Sydney System was used as histology gold standard. Areas under curves (AUCs), optimal cutoff and predictive values were calculated for serum biomarkers against the histology.
Results
309 persons were recruited (mean age: 63.5 years old, 59.5% female). 84.5% were H. pylori positive and 77.5% were CagA positive. 21 fundic atrophy and 101 nonatrophic pangastritis were diagnosed. The best cutoff values in fundic atrophy assessment were calculated at PGI<56 µg/l (sensitivity: 61.9%, specificity: 94.8%) and PGI/PGII ratio<5 (sensitivity: 75.0%, specificity: 91.0%). A serum G-17<2.6 pmol/l or G-17>40 pmol/l was 81% sensitive and 73.3% specific for diagnosing fundic atrophy. At cutoff concentration of 11.8 µg/l, PGII showed 84.2% sensitivity and 45.4% specificity to distinguish nonatrophic pangastritis. Exclusion of nonatrophic pangastritis enhanced diagnostic ability of PGI/PGII ratio (from AUC = 0.66 to 0.90) but did not affect AUC of PGI. After restricting study samples to those with PGII<11.8, the sensitivity of using PGI<56 to define fundic atrophy increased to 83.3% (95%CI 51.6–97.9) and its specificity decreased to 88.8% (95%CI 80.8–94.3).
Conclusions
Among endoscopy clinic patients, PGII is a sensitive marker for extension of nonatrophic gastritis toward the corpus. PGI is a stable biomarker in assessment of fundic atrophy and has similar accuracy to PGI/PGII ratio among populations with prevalent nonatrophic pangastritis.
doi:10.1371/journal.pone.0026957
PMCID: PMC3204997  PMID: 22066020
2.  Polymorphism in COX-2 modifies the inverse association between Helicobacter pylori seropositivity and esophageal squamous cell carcinoma risk in Taiwan: a case control study 
BMC Gastroenterology  2009;9:37.
Background
Overexpression of Cyclooxygenase-2 (COX-2) was observed in many types of cancers, including esophageal squamous cell carcinoma (ESCC). One functional SNP, COX-2 -1195G/A, has been reported to mediate susceptibility of ESCC in Chinese populations. In our previous study, the presence of Helicobacter pylori (H. pylori) was found to play a protective role in development of ESCC. The interaction of COX-2 and H. pylori in gastric cancer was well investigated. However, literature on their interaction in ESCC risk is scarce. The purpose of this study was to evaluate the association and interaction between COX-2 single nucleotide polymorphism (SNP), H. pylori infection and the risk of developing ESCC.
Methods
One hundred and eighty patients with ESCC and 194 controls were enrolled in this study. Personal data regarding related risk factors, including alcohol consumption, smoking habits and betel quid chewing, were collected via questionnaire. Genotypes of the COX-2 -1195 polymorphism were determined by PCR-based restriction fragment length polymorphism. H. pylori seropositivity was defined by immunochromatographic screening test. Data was analyzed by chi-squared tests and polytomous logistics regression.
Results
In analysis adjusting for the covariates and confounders, H. pylori seropositivity was found to be inversely association with the ESCC development (adjusted OR: 0.5, 95% CI: 0.3 – 0.9). COX-2 -1195 AA homozygous was associated with an increased risk of contracting ESCC in comparison with the non-AA group, especially among patients with H. pylori seronegative (adjusted OR ratio: 2.9, 95% CI: 1.2 – 7.3). The effect was strengthened among patients with lower third ESCC (adjusted OR ratio: 6.9, 95% CI 2.1 – 22.5). Besides, H. pylori seropositivity conveyed a notably inverse effect among patients with COX-2 AA polymorphism (AOR ratio: 0.3, 95% CI: 0.1 – 0.9), and the effect was observed to be enhanced for the lower third ESCC patients (AOR ratio: 0.09, 95% CI: 0.02 – 0.47, p for multiplicative interaction 0.008)
Conclusion
H. pylori seropositivity is inversely associated with the risk of ESCC in Taiwan, and COX-2 -1195 polymorphism plays a role in modifying the influence between H. pylori and ESCC, especially in lower third esophagus.
doi:10.1186/1471-230X-9-37
PMCID: PMC2693118  PMID: 19463183
3.  Serum pepsinogens and risk of esophageal squamous dysplasia 
Pepsinogens are a class of endopeptidases that are secreted by the gastric epithelium and released into the circulation. Low serum pepsinogen I (PGI) and low serum pepsinogen I / pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy, and have recently been shown to be associated with increased risk of esophageal squamous cell carcinoma (ESCC). We conducted the current study to test whether these markers are also associated with esophageal squamous dysplasia (ESD), the precursor lesion of ESCC.
We measured serum PGI and PGII, using enzyme-linked immunosorbent (ELISA) assays, in 125 case subjects (patients with moderate or severe ESD) and 250 sex-matched control subjects (no ESD) selected from an endoscopic screening study in Linxian, China. We used conditional logistic regression models adjusted for age, smoking, and place of residence to calculate odds ratios (ORs) and 95% confidence intervals (95% CIs).
Serum PGI showed no statistically significant association with ESD, whether analyzed as a dichotomous, ordinal (quartiles), or continuous variable. Lower serum PGI/II ratio, however, showed a dose-response association with increased risk of ESD, with an adjusted OR (95% CI) of 2.12 (1.08 − 4.18), comparing the lowest versus the highest quartile. The association between lower serum PGI/II ratio and log OR of ESD was nearly linear, and the p-value for the continuous association was 0.03.
Lower serum PGI/II ratio was linearly associated with higher risk of ESD. This result is consistent with recent findings that gastric atrophy may increase the risk of ESCC.
doi:10.1002/ijc.23918
PMCID: PMC2605159  PMID: 18844222
Esophageal cancer; Squamous dysplasia; Pepsinogen; China
4.  Relation of atrophic gastritis with Helicobacter pylori-CagA+ and interleukin-1 gene polymorphisms 
AIM: To determine the association of Helicobacter pylori (H pylori) CagA+ infection and pro-inflammatory polymorphisms of the genes interleukin (IL)-1RN and IL-1B with the risk of gastric atrophy and peptic ulcers in a dyspeptic population in Costa Rica, a country with high incidence and mortality of gastric cancer.
METHODS: Seven biopsy specimens, a fasting blood sample and a questionnaire concerning nutritional and sociodemographic factors were obtained from 501 consecutive patients who had undergone endoscopy for dyspeptic symptoms. A histopathological diagnosis was made. Pepsinogen concentrations were analyzed by enzyme linked immunosorbent assay (ELISA). Infection with H pylori CagA+ was determined by serology and polymerase chain reaction (PCR). IL-1B and IL-1RN polymorphisms genotyping was performed by PCR-restriction fragment length polymorphism (PCR-RFLP) and PCR respectively.
RESULTS: In this dyspeptic population, 86% were H pylori positive and of these, 67.8% were positive for CagA. Atrophic antral gastritis (AAG) was associated with CagA+ status [odd ratio (OR) = 4.1; P < 0.000] and fruit consumption (OR = 0.3; P < 0.00). Atrophic body gastritis (ABG) was associated with pepsinogen PGI/PGII < 3.4 (OR = 4.9; P < 0.04) and alcohol consumption (OR = 7.3; P < 0.02). Duodenal ulcer was associated with CagA+ (OR = 2.9; P < 0.04) and smoking (OR = 2.4; P < 0.04). PGI < 60 μg/L as well as PGI/PGII < 3.4 were associated with CagA+.
CONCLUSION: In a dyspeptic population in Costa Rica, H pylori CagA+ is not associated with ABG, but it is a risk factor for AAG. The pro-inflammatory cytokine polymorphisms IL-1B + 3945 and IL-1RN are not associated with the atrophic lesions of this dyspeptic population.
doi:10.3748/wjg.14.6481
PMCID: PMC2773333  PMID: 19030199
Atrophic gastritis; Pepsinogen; Peptic ulcers; Helicobacter pylori-CagA; Interleukins
5.  Serum pepsinogens and risk of gastric and esophageal cancers in the General Population Nutrition Intervention Trial cohort 
Gut  2009;58(5):636-642.
Objective
Low serum pepsinogen I (PGI) and low pepsinogen I/pepsinogen II ratio (PGI/II ratio) are markers of gastric fundic atrophy. We aimed to prospectively test the association between serum PGI/II ratio and risks of gastric noncardia adenocarcinoma, gastric cardia adenocarcinoma, and esophageal squamous cell carcinoma.
Design
Case-cohort study nested in a prospective cohort with over 15 years of follow-up.
Setting
Rural region of the People’s Republic of China.
Subjects
Men and women aged 40-69 at study baseline.
Main outcome measures
Adjusted hazard ratios and 95% confidence intervals for the association between serum PGI/II ratio and caner risk
Results
Compared to subjects with PGI/II ratio of > 4, those with ≤4 had HRs (95%CIs) of 2.72 (1.77-4.20) and 2.12 (1.42-3.16) for noncardia and cardia gastric cancers, respectively. Risk of both cancers were also increased when other cut points ranging from 3 to 6, or when we used quartile models, or nonlinear continuous models. Risk of ESCC was marginally increased in those with PGI/II ratio ≤4, with HR (95% CI) of 1.56 (0.99-2.47), but quartile models and continuous models showed no increased risk. The nonlinear continuous models suggested that any single cut point collapsed subjects with dissimilar gastric cancer risks, and that using cut points was not an efficient use of data in evaluating these associations.
Conclusion
In this prospective study, we found similar and significantly increased risks of noncardia and cardia gastric adenocarcinomas in subjects with low PGI/II ratio, but little evidence for an association with ESCC risk.
doi:10.1136/gut.2008.168641
PMCID: PMC2792746  PMID: 19136509
Gastric cancer; Esophageal cancer; Pepsinogen; Case-cohort
6.  Helicobacter pylori infection and esophageal cancer risk: An updated meta-analysis 
AIM: To clarify the association between Helicobacter pylori (H. pylori) infection and the risk of esophageal carcinoma through a meta-analysis of published data.
METHODS: Studies which reported the association between H. pylori infection and esophageal cancer published up to June 2013 were included. The odds ratios (ORs) and corresponding 95%CIs of H. pylori infection on esophageal cancer with respect to health control groups were evaluated. Data were extracted independently by two investigators and discrepancies were resolved by discussion with a third investigator. The statistical software, STATA (version 12.0), was applied to investigate heterogeneity among individual studies and to summarize the studies. A meta-analysis was performed using a fixed-effect or random-effect method, depending on the absence or presence of significant heterogeneity.
RESULTS: No significant association between H. pylori infection and esophageal squamous cell carcinoma (ESCC) risk was found in the pooled overall population (OR = 0.97, 95%CI: 0.76-1.24). However, significant associations between H. pylori infection and ESCC risk were found in Eastern subjects (OR = 0.66, 95%CI: 0.43-0.89). Similarly, cytotoxin-associated gene-A (CagA) positive strains of infection may decrease the risk of ESCC in Eastern subjects (OR = 0.77, 95%CI: 0.65-0.92), however, these associations were not statistically significant in Western subjects (OR = 1.26, 95%CI: 0.97-1.63). For esophageal adenocarcinoma (EAC) the summary OR for H. pylori infection and CagA positive strains of infection were 0.59 (95%CI: 0.51-0.68) and 0.56 (95%CI: 0.45-0.70), respectively.
CONCLUSION: H. pylori infection is associated with a decreased risk of ESCC in Eastern populations and a decreased risk of EAC in the overall population.
doi:10.3748/wjg.v19.i36.6098
PMCID: PMC3785633  PMID: 24106412
Helicobacter pylori; Esophageal carcinoma; Cancer risk; Meta-analysis
7.  Serum thyroglobulin, a biomarker for iodine deficiency, is not associated with increased risk of upper gastrointestinal cancers in a large Chinese cohort 
Iodine concentrates in gastric tissue and may act as an antioxidant for the stomach. We previously showed that self-reported goiter was associated with significantly increased risk of gastric noncardia adenocarcinoma (GNCA) and non-significantly increased risks of gastric cardia adenocarcinoma (GCA) and esophageal squamous cell carcinoma (ESCC) in a prospective case-cohort study in a high-risk population in China. Negatively correlated with iodine levels, serum thyroglobulin (Tg) is a more sensitive biomarker of iodine deficiency than goiter. This study aimed to determine whether baseline serum Tg was also associated with development of GNCA, GCA, and ESCC in the same cohort, the Linxian General Population Nutrition Intervention Trial. Sera from approximately 200 subjects of each case type and 400 non-cases were tested for serum Tg concentration using appropriate assays. Tg was modeled as sex- and assay-specific quartiles in Cox regression models adjusted for age, smoking, alcohol, Helicobacter pylori status, pepsinogens I/II ratio, family history, and commune of residence. In the final combined analysis, participants in the highest quartile of serum Tg, compared to those in the lowest quartile, had adjusted Hazard Ratios of 0.88 (95% confidence interval 0.50–1.52), 1.14 (0.63–2.05), and 0.78 (0.47–1.31) for GNCA, GCA, and ESCC, respectively. Using serum Tg, a sensitive biomarker of iodine deficiency, we found no association between serum Tg concentrations and risk of these upper gastrointestinal (UGI) cancers in the study population. Our results do not support the hypothesis that iodine deficiency, as assessed by serum Tg, is associated with an increased risk of UGI cancers.
doi:10.1002/ijc.25789
PMCID: PMC3075342  PMID: 21105043
iodine deficiency; esophageal cancer; gastric cancer; thyroglobulin; China
8.  Gastric atrophy and oesophageal squamous cell carcinoma: possible interaction with dental health and oral hygiene habit 
British Journal of Cancer  2012;107(5):888-894.
Background:
Gastric fundal atrophy has been hypothesised to increase the risk of oesophageal squamous cell carcinoma (OSCC), but studies have shown inconsistent results.
Methods:
We measured serum pepsinogen I (PGI) and pepsinogen II (PGII) among 293 incident cases and 524 matched neighbourhood controls in a high-risk area of Northern Iran. Conditional logistic regression model was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs).
Results:
After controlling for age, sex, residence area and other potential confounders, gastric atrophy (defined by a validated criterion, PGI <55 μg dl−1) was associated with a two-fold increased risk (OR=2.01, 95% CI: 1.18, 3.45) of OSCC in the absence of nonatrophic pangastritis (defined as PGII <11.8 μg dl−1). Stratification by PGII decreased the misclassification errors due to cancer-induced gastritis. Presence of both poor dental health, indicated by higher than median sum of decayed, missing, and filled teeth (DMFT score), and gastric atrophy further increased the risk of OSCC (OR=4.15, 95% CI: 2.04, 8.42) with relative excess risk due to interaction (RERI) of 1.47 (95% CI: −1.15, 4.1). Coexistence of poor oral hygiene habit with gastric atrophy elevated OSCC risk eight times (OR=8.65, 95% CI: 3.65, 20.46) and the additive interaction index was marginally statistically significant (RERI=4.34, 95% CI: −1.07, 9.76).
Conclusion:
Gastric atrophy is a risk factor for OSCC, and poor dental health and oral hygiene habit may act synergistically in increasing the risk.
doi:10.1038/bjc.2012.332
PMCID: PMC3425966  PMID: 22814581
atrophic gastritis; oesophageal neoplasm; relative risk; dental health; oral hygiene; pepsinogen
9.  Atrophic gastritis: Risk factor for esophageal squamous cell carcinoma in a Latin-American population 
AIM: To study the association between atrophic gastritis (AG) and esophageal squamous cell carcinoma (ESCC) in a Latin-America population.
METHODS: A case-control study was performed at two reference Brazilian hospitals including patients diagnosed with advanced ESCC and dyspeptic patients who had been subjected to upper gastrointestinal endoscopy, with biopsies of the gastric antrum and body. All cases with ESCC were reviewed by a single pathologist, who applied standard criteria for the diagnosis of mucosal atrophy, intestinal metaplasia, and dysplasia, all classified as AG. The data on the patients’ age, sex, smoking status, and alcohol consumption were collected from clinical records, and any missing information was completed by telephone interview. The association between AG and ESCC was assessed by means of univariate and multiple conditional logistic regressions.
RESULTS: Most patients were male, and the median age was 59 years (range: 37-79 years) in both the ESCC and control groups. Univariate analysis showed that an intake of ethanol greater than 32 g/d was an independent risk factor that increased the odds of ESCC 7.57 times (P = 0.014); upon multiple analysis, alcohol intake of ethanol greater than 32 g/d exhibited a risk of 4.54 (P = 0.081), as adjusted for AG and smoking. Smoking was shown to be an independent risk factor that increased the odds of ESCC 14.55 times (P = 0.011) for individuals who smoked 0 to 51 packs/year and 21.40 times (P = 0.006) for those who smoked more than 51 packs/year. Upon multiple analyses, those who smoked up to 51 packs/year exhibited a risk of 7.85 (P = 0.058), and those who smoked more than 51 packs/ year had a risk 11.57 times higher (P = 0.04), as adjusted for AG and alcohol consumption. AG proved to be a risk factor that increased the odds of ESCC 5.33 times (95%CI: 1.55-18.30, P = 0.008) according to the results of univariate conditional logistic regression.
CONCLUSION: There was an association by univariate conditional logistic regression between AG and ECSS in this sample of Latin-American population.
doi:10.3748/wjg.v19.i13.2060
PMCID: PMC3623983  PMID: 23599625
Atrophic gastritis; Esophagus; Squamous cell carcinoma; Risk factor; Alcohol; Tobacco
10.  Serum ghrelin is inversely associated with risk of subsequent oesophageal squamous cell carcinoma 
Gut  2011;61(11):1533-1537.
Background
Oesophageal cancers rank as the eighth most common cancer and the sixth most common cause of cancer death, worldwide. Gastric atrophy, as determined by a low serum pepsinogen I/II ratio, may be associated with an increased risk of oesophageal squamous cell carcinoma (OSCC). Ghrelin, a hormone which, like pepsinogen, is produced in the fundic glands of the stomach, may be a sensitive and specific marker of gastric atrophy, but its association with OSCC is not known.
Methods
To examine the relationship between baseline serum ghrelin concentration and subsequent risk of OSCC, we conducted a nested case-control study within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. 82 cases of OSCC were matched (1:1) by age and date of blood draw to controls from the ATBC study. Serum ghrelin was measured by radioimmunoassay. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using conditional logistic regression with adjustment for potential confounders.
Results
For those individuals in the lowest quartile of serum ghrelin, compared to those in the highest, the multivariate odds ratio of subsequent OSCC was 6.83 (95% CI: 1.46, 31.84). These associations were dose dependent (P for trend = 0.005 for both), and independent of the effects of low pepsinogen I/II ratio (a marker of gastric fundic atrophy) and Helicobacter pylori infection. The significance of these associations remained even for individuals developing OSCC up to 10 years after baseline ghrelin measurement, though they become attenuated after 10 years.
Conclusion
Lower baseline concentrations of serum ghrelin were associated with an increase in risk of OSCC. Further studies are needed to confirm this finding in other populations and to explore the role of ghrelin in the aetiology of OSCC.
doi:10.1136/gutjnl-2011-300653
PMCID: PMC3462270  PMID: 22180062
ghrelin; oesophageal squamous cell carcinoma; atrophy
11.  Associations of a PTPN11 G/A polymorphism at intron 3 with Helicobactor pylori seropositivity, gastric atrophy and gastric cancer in Japanese 
BMC Gastroenterology  2009;9:51.
Background
Previous studies have revealed the significance of Helicobacter pylori (H. pylori) infection as a risk factor of gastric cancer. Cytotoxin-associated gene A (cagA) positivity has been demonstrated to determine the clinical outcome of H. pylori infection in the presence of SHP-2 (src homology 2 domain-containing protein tyrosine phosphatase-2). This study aimed to examine the formerly reported association of G/A PTPN11 (protein-tyrosine phosphatase, nonreceptor-type 11) polymorphism (rs2301756) with gastric atrophy, as well as the association with gastric cancer in a Japanese population using a large sample size.
Methods
Study subjects were 583 histologically diagnosed patients with gastric cancer (429 males and 154 females) and age- and sex-frequency-matched 1,636 non-cancer outpatients (1,203 males and 433 females), who visited Aichi Cancer Center Hospital between 2001–2005. Serum anti-H. pylori IgG antibody and pepsinogens were measured to evaluate H. pylori infection and gastric atrophy, respectively. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by a logistic model.
Results
Among H. pylori seropositive non-cancer outpatients, the age- and sex-adjusted OR of gastric atrophy was 0.82 (95% CI 0.62–1.10, P = 0.194) for G/A, 0.84 (95% CI 0.39–1.81, P = 0.650) for A/A, and 0.83 (95% CI 0.62–1.09, P = 0.182) for G/A+A/A, relative to G/G genotype, and that of severe gastric atrophy was 0.70 (95% CI 0.47–1.04, P = 0.079), 0.56 (95% CI 0.17–1.91, P = 0.356), and 0.68 (95% CI 0.46–1.01, P = 0.057), respectively. Among H. pylori infected subjects (H. pylori seropositive subjects and seronegative subjects with gastric atrophy), the adjusted OR of severe gastric atrophy was further reduced; 0.62 (95% CI 0.42–0.90, P = 0.012) for G/A+A/A. The distribution of the genotype in patients with gastric cancer was not significantly different from that for H. pylori infected subjects without gastric atrophy.
Conclusion
Our study results revealed that those with the A/A genotype of PTPN11 rs2301756 polymorphism are at lower risk of severe gastric atrophy, but are not associated with a decreased risk of gastric cancer, which partially supported our previous finding that the polymorphism in the PTPN11 gene encoding SHP-2 was associated with the gastric atrophy risk in H. pylori infected Japanese. The biological roles of this PTPN11 polymorphism require further investigation.
doi:10.1186/1471-230X-9-51
PMCID: PMC2715419  PMID: 19589142
12.  Etiological study of esophageal squamous cell carcinoma in an endemic region: a population-based case control study in Huaian, China 
BMC Cancer  2006;6:287.
Background
Continuous exposure to various environmental carcinogens and genetic polymorphisms of xenobiotic-metabolizing enzymes (XME) are associated with many types of human cancers, including esophageal squamous cell carcinoma (ESCC). Huaian, China, is one of the endemic regions of ESCC, but fewer studies have been done in characterizing the risk factors of ESCC in this area. The aims of this study is to evaluate the etiological roles of demographic parameters, environmental and food-borne carcinogens exposure, and XME polymorphisms in formation of ESCC, and to investigate possible gene-gene and gene-environment interactions associated with ESCC in Huaian, China.
Methods
A population based case-control study was conducted in 107 ESCC newly diagnosed cases and 107 residency- age-, and sex-matched controls in 5 townships of Huaian. In addition to regular epidemiological and food frequency questionnaire analyses, genetic polymorphisms of phase I enzymes CYP1A1, CYP1B1, CYP2A6, and CYP2E1, and phase II enzymes GSTM1, GSTT1, GSTP1, and microsomal epoxide hydrolase (EPHX) were assessed from genomic DNA using PCR based techniques.
Results
Consuming acrid food, fatty meat, moldy food, salted and pickled vegetables, eating fast, introverted personality, passive smoking, a family history of cancer, esophageal lesion, and infection with Helicobacter pylori were significant risk factors for ESCC (P < 0.05). Regular clean up of food storage utensils, green tea consumption, and alcohol abstinence were protective factors for ESCC (P < 0.01). The frequency of the GSTT1 null genotype was higher in cases (59.4%) compared to controls (47.2%) with an odds ratio (OR) of 1.68 and 95% confidence interval (CI) from 0.96 to 2.97 (P = 0.07), especially in males (OR = 2.78; 95% CI = 1.22–6.25; P = 0.01). No associations were found between polymorphisms of CYP1A1, CYP1B1, CYP2A6, CYP2E1, GSTM1, GSTP1, and EPHX and ESCC (P > 0.05).
Conclusion
Our results demonstrated that dietary and environmental exposures, some demographic parameters and genetic polymorphism of GSTT1 may play important roles in the development of ESCC in Huaian area, China.
doi:10.1186/1471-2407-6-287
PMCID: PMC1774575  PMID: 17173682
13.  Serum pepsinogen II is a better diagnostic marker in gastric cancer 
AIM: To investigate screening makers for gastric cancer, we assessed the association between gastric cancer and serum pepsinogens (PGs).
METHODS: The subjects comprised 450 patients with gastric cancer, 111 individuals with gastric atrophy, and 961 healthy controls. Serum anti-Helicobacter pylori (H. pylori) immunoglobulin G (IgG), PGIand PG II were detected by enzyme-linked immunosorbent assay. Gastric atrophy and gastric cancer were diagnosed by endoscopy and histopathological examinations. Odds ratios and 95%CIs were calculated using multivariate logistic regression.
RESULTS: Rates of H. pylori infection remained high in Northeastern China. Rates of H. pylori IgG positivity were greater in the gastric cancer and gastric atrophy groups compared to the control group (69.1% and 75.7% vs 49.7%, P < 0.001). Higher levels of PG II (15.9 μg/L and 13.9 μg/L vs 11.5 μg/L, P < 0.001) and lower PGI/PG II ratio (5.4 and 4.6 vs 8.4, P < 0.001) were found in patients with gastric cancer or gastric atrophy compared to healthy controls, whereas no correlation was found between the plasma PGIconcentration and risk of gastric cancer (P = 0.537). In addition, multivariate logistic analysis indicated that H. pylori infection and atrophic gastritis were independent risk factors for gastric cancer. Lower plasma PGI/PG II ratio was associated with higher risks of atrophy and gastric cancer. Furthermore, plasma PG II level significantly correlated with H. pylori-infected gastric cancer.
CONCLUSION: Serum PG II concentration and PGI/PG II ratio are potential biomarkers for H. pylori-infected gastric disease. PG II is independently associated with risk of gastric cancer.
doi:10.3748/wjg.v18.i48.7357
PMCID: PMC3544042  PMID: 23326145
Gastric cancer; Pepsinogens; Helicobacter pylori; Gastric atrophy; Screening
14.  Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China 
BMC Cancer  2013;13:259.
Background
The role of tumor suppressor gene RASSF1A in the esophageal and gastric cardia carcinogenesis is still inconclusive. In this study, the polymorphism, promoter methylation and gene expression of RASSF1A were characterized in esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA).
Methods
We firstly analyzed the prevalence of RASSF1A A133S in a total of 228 cancer patients with ESCC (n=112) and GCA (n=116) and 235 normal controls by polymerase chain reaction (PCR) and restriction enzyme-digestion assay. Then, the promoter methylation status of the RASSF1A in ESCC (n=143), GCA (n=92) and corresponding adjacent normal tissues were further investigated using methylation-specific PCR (MSP) approach. Finally, the RASSF1A protein expression were determined in ESCC (n=27), GCA (n=24) and the matched adjacent normal tissues by immunohistochemical method.
Results
The frequency of 133Ala/Se and Ser/Ser genotype was significantly higher in GCA patients than in normal controls (19.0% vs. 10.2%, P=0.02). Compared with Ala/Ala genotype, Ala/Se and Ser/Ser genotype significantly increased susceptibility to GCA (OR=2.06, 95% CI=1.09–3.97). However, this polymorphism had no association with ESCC (P=0.69). The promoter methylation of RASSF1A gene was significantly increased the risk to both ESCC (OR=5.90, 95% CI=2.78–12.52) and GCA (OR=7.50, 95% CI= 2.78–20.23). Promoter methylation of RASSF1A gene in ESCC was also associated with age and cancer cell differentiation (for age: OR=3.11, 95% CI=1.10–8.73; for differentiation: OR=0.29, 95% CI=0.12–0.69). RASSF1A positive expression was significantly decreased the risk of GCA (OR=0.16, 95% CI=0.03–0.83). In contrast, there was no statistical significance between RASSF1A positive expression and ESCC. The expression of RASSF1A protein trend to be positively related with older GCA patients (OR=16.20, 95% CI=1.57–167.74).
Conclusions
The present findings suggest that alterations of RASSF1A may play an important role in gastric cardia carcinogenesis in terms of polymorphism, promoter hypermethylation and protein expression. Whereas, RASSF1A hypermethylation may probably also be involved in esophageal squamous cell carcinogenesis.
doi:10.1186/1471-2407-13-259
PMCID: PMC3668992  PMID: 23705663
Esophageal squamous cell carcinoma; Gastric cardia adenocarcinoma; A133S in RASSF1A; Polymorphism; Methylation; Protein expression
15.  Predominant mucosal IL-8 mRNA expression in non-cagA Thais is risk for gastric cancer 
AIM: To study gastric mucosal interleukine-8 (IL-8) mRNA expression, the cytotoxin-associated gene A (cagA) mutation, and serum pepsinogen (PG) I/II ratio related risk in Thai gastric cancer.
METHODS: There were consent 134 Thai non-cancer volunteers who underwent endoscopic narrow band imaging examination, and 86 Thais advance gastric cancer patients who underwent endoscopic mucosal biopsies and gastric surgery. Tissue samples were taken by endoscopy with 3 points biopsies. The serum PG I, II, and Helicobacter pylori (H. pylori) immunoglobulin G (IgG) antibody for H. pylori were tested by enzyme-linked immunosorbent assay technique. The histopathology description of gastric cancer and non-cancer with H. pylori detection was defined with modified Sydney Score System. Gastric mucosal tissue H. pylori DNA was extracted and genotyped for cagA mutation. Tissue IL-8 and cyclooxygenase-2 (COX-2) mRNA expression were conducted by real time relative quantitation polymerase chain reaction. From 17 Japanese advance gastric cancer and 12 benign gastric tissue samples, all were tested for genetic expression with same methods as well as Thai gastric mucosal tissue samples. The multivariate analysis was used for the risk study. Correlation and standardized t-test were done for quantitative data, P value < 0.05 was considered as a statistically significant.
RESULTS: There is a high non cagA gene of 86.8 per cent in Thai gastric cancer although there are high yields of the East Asian type in the positive cagA. The H. pylori infection prevalence in this study is reported by combined histopathology and H. pylori IgG antibody test with 77.1% and 97.4% of sensitivity and specificity, respectively. The serum PG I/II ratio in gastric cancer is significantly lower than in the non-cancer group, P = 0.045. The serum PG I/II ratio of less than 3.0 and IL-8 mRNA expression ≥ 100 or log10 ≥ 2 are significant cut off risk differences between Thai cancer and non-cancer, P = 0.03 and P < 0.001, respectively. There is a significantly lower PGI/II ratio in Japanese than that in Thai gastric cancer, P = 0.026. Serum PG I/II ratio at cut off less than 3.0 and IL-8 mRNA expression Raw RQ > 100 or log10 > 2 are significantly difference between Thai cancer group when compared to non-cancer group, P = 0.013 and P < 0.001, respectively. In the correlation study, low PG I/II ratio does not associate with chronic atrophic gastritis severity score in Thais non-cancer cases. However, there is a trend, but not significant convert correlation between IL-8 mRNA expression level and low PG I/II ratio in Thai positive H. pylori infection. The high expression of IL-8 gene demonstrates a poorer prognosis by stage and histology.
CONCLUSION:Predominant gastric mucosal IL-8 mRNA expression level, H. pylori infection, and low PG I/II ratio are relative risks for Thai gastric cancer without correlation with cagA mutation.
doi:10.3748/wjg.v19.i19.2941
PMCID: PMC3660819  PMID: 23704827
Gastric cancer; CagA mutation; Interleukine-8 mRNA expression; Helicobacter pylori; Pepsinogen I/II ratio
16.  Early-Life Family Structure and Microbially Induced Cancer Risk 
PLoS Medicine  2007;4(1):e7.
Background
Cancer may follow exposure to an environmental agent after many decades. The bacterium Helicobacter pylori, known to be acquired early in life, increases risk for gastric adenocarcinoma, but other factors are also important. In this study, we considered whether early-life family structure affects the risk of later developing gastric cancer among H. pylori+ men.
Methods and Findings
We examined a long-term cohort of Japanese-American men followed for 28 y, and performed a nested case-control study among those carrying H. pylori or the subset carrying the most virulent cagA+ H. pylori strains to address whether family structure predicted cancer development. We found that among the men who were H. pylori+ and/or cagA+ (it is possible to be cagA+ and H. pylori− if the H. pylori test is falsely negative), belonging to a large sibship or higher birth order was associated with a significantly increased risk of developing gastric adenocarcinoma late in life. For those with cagA+ strains, the risk of developing gastric cancer was more than twice as high (odds ratio 2.2; 95% confidence interval 1.2–4.0) among those in a sibship of seven or more individuals than in a sibship of between one and three persons.
Conclusions
These results provide evidence that early-life social environment plays a significant role in risk of microbially induced malignancies expressing five to eight decades later, and these findings lead to new models to explain these interactions.
This study suggests that early-life social environment has a significant role in risk of microbially induced malignancies such as gastric adenocarcinoma occuring five to eight decades later.
Editors' Summary
Background.
Although the theory that certain cancers might be caused by infectious agents (such as bacteria and viruses) has been around for some time, concrete evidence linking specific cancers and infections is only recently beginning to emerge. There is now very good evidence that stomach cancer, once one of the frequent types worldwide but now less common, is strongly associated with a particular infection of the stomach lining. This specific bacterium colonizing the stomach, Helicobacter pylori (or H. pylori), often infects people early in childhood through close contact with other people, and tends to stay in the body throughout life. However, most people do not suffer any symptoms as a result of being colonized with H. pylori. Researchers are interested in the relationship between stomach cancer and aspects of someone's upbringing, for example whether an individual has a large number of sisters and brothers and whether they are the youngest or oldest in a large group of siblings. One reason for being interested in this topic is that if H. pylori is mainly spread from one child to another in the home, we might expect children from large sibling groups, and the youngest children in a group, to be at greater risk of being infected, and then more likely to get stomach cancer later in life. Furthermore—and this was the primary reason for the study—the researchers wished to determine whether, among H. pylori+ people, the structure of the family affects the risk of developing stomach cancer much later in life. With all study participants being H. pylori+, the essential comparison was between people of high and low birth order.
Why Was This Study Done?
This group of researchers had already done a previous study that had shown that people who carry H. pylori in their stomachs are more likely to get stomach cancer, and also that younger children in a sibling group are more likely to get stomach cancer. In the period following that study, the examined population has become older and more of the people concerned have developed stomach cancer. This meant that the researchers could go back and extend their previous work to see, more reliably, whether stomach cancer was linked to family structure. It also meant that the researchers could look at the effects of each factor not only in isolation, but also the combined effect of all the different factors. The researchers also stratified for the most virulent strains (those that were cagA+).
What Did the Researchers Do and Find?
In this study, the researchers started out with a pool of 7,429 Japanese-American men living in Hawaii, USA, who had donated blood samples between 1967 and 1975. Of these men, 261 eventually developed stomach cancer. Each of the 261 men was then matched with a similarly aged man from the original pool of 7,429 men who did not have stomach cancer. The researchers then went back to the original blood samples taken many years before and tested the samples to see if the men were infected with H. pylori at the time the sample was taken and, if so, whether a particular strain of the bacterium, cagA, was present. The researchers then looked at whether the risk of getting stomach cancer was associated with the number of siblings a man had and whether he was older or younger than the other siblings.
Similar to the prior study, they found that men who had stomach cancer were three times more likely to carry H. pylori compared to men who did not develop stomach cancer. In men who had H. pylori, those with large numbers of siblings were more likely to get stomach cancer, and this was especially true for men who had the cagA strain of H. pylori. In the whole group of men with cancer, the order of birth (whether a man was older or younger in his sibling group) did not seem to be particularly linked to development of stomach cancer. However, in men who had the cagA strain of H. pylori, those from the largest sibships were at highest risk of developing gastric cancer; in this group, one particular type of cancer (the most common type—intestinal-type gastric cancer) was also associated with later birth order.
What Do These Findings Mean?
The researchers initially thought that men with H. pylori would be at a higher risk of getting stomach cancer if they had a large number of sisters and brothers, and especially if they were a younger sibling in a large group. This idea was supported by their data. These findings support the idea that people often get H. pylori from their older sisters and brothers, but there is not conclusive proof of this. There might be some other factor that explains the association between large family size and stomach cancer, for example that people from large families might be poorer and more at risk from stomach cancer for some other reason. Currently, most doctors do not recommend routinely testing people without any symptoms to see if they have H. pylori, but people with pain or discomfort in the upper abdomen would generally be screened for H. pylori and then treated to eliminate the infection if it is found. The main novel idea is that those people who are born in a large sibship, and/or are of higher birth order, are more likely to acquire their H. pylori from a genetically related person (a sibling) than from an unrelated person (friend/classmate). This “family-structure effect” could be the explanation as to why there is a higher risk of stomach cancer developing later—the strain from a genetically related person already is “preadapted” to the new host, and has a “head-start” on immunity, compared to a strain from an unrelated person. The researchers hypothesize that it is the nature of that initial interaction with the host that sets the stage for the kind of events that lead to cancers decades later.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040007.
A Perspective article by Dimitrios Trichopoulos and Pagona Lagiou discusses these findings further
MedLine Plus encyclopedia entry on stomach cancer
Wikipedia entry on Helicobacter pylori (Wikipedia is an internet encyclopedia that anyone can edit)
The US National Cancer Institute publishes information about stomach cancer
doi:10.1371/journal.pmed.0040007
PMCID: PMC1769414  PMID: 17227131
17.  Helicobacter pylori and Esophageal Cancer Risk -- A Meta-Analysis 
We conducted this meta-analysis to examine the association between H. pylori and esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC).
We searched the PubMed database, the ISI database, and the references of the selected articles. Case-control or nested case-control studies were selected if they used serology or endoscopic methods to detect H. pylori in the stomach and if control subjects were not restricted to upper gastrointestinal tract cancer or peptic ulcer disease patients. A total of 19 studies were used for this analysis. Summary odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using the DerSimonian-Laird method. Q-statistics and I2 statistics were calculated to examine heterogeneity. Subgroup analyses were conducted by CagA status.
For EAC, the summary OR (95% CI) was 0.56 (0.46 – 0.68). There was little heterogeneity among studies (I2 = 15%). Further analysis showed that colonization with CagA-positive strains was inversely associated with EAC risk (OR (95%CI) 0.41 (0.28–0.62)) but colonization with CagA-negative strains was not (OR (95%CI) 1.08 (0.76–1.53)). For ESCC, the summary OR (95% CI) was 1.10 (0.78 – 1.55). However, there was substantial heterogeneity among studies (I2 = 73%), with statistically significant associations in both directions.
Our results suggest an inverse association between CagA-positive H. pylori colonization and risk of EAC. The prominent decline of H. pylori colonization in the past few decades may be partly responsible for the recent increase in EAC incidence in Western countries.
doi:10.1158/1940-6207.CAPR-08-0109
PMCID: PMC3501739  PMID: 19138977
Helicobacter pylori; CagA; esophageal cancer; adenocarcinoma; squamous cell carcinoma; colonization
18.  The Role of Serum Pepsinogen in the Detection of Gastric Cancer 
Gut and Liver  2010;4(3):307-319.
The incidence of gastric cancer is very high in Japan, Korea, and China. Reducing the morbidity and mortality associated with gastric cancer requires early diagnosis, which can be facilitated by applying gastroscopy more frequently in high-risk groups. A strategy of population screening for gastric cancer is currently being adopted in Korea, Japan, and the Matsu region of Taiwan, but using different screening methods. In addition, the history of pepsinogen (PG) in research as a gastric cancer biomarker has varied, in that the use of serum levels of PGI and PGII and the PGI/PGII ratio as gastric cancer screening tools was introduced in Japan before 1990, but in Korea the first research results were only reported in 2008. This review first evaluates the physiology of PG, followed by the usefulness or limitations of serum PG testing with regard to the detection of gastric cancer. Finally, the factors affecting the efficacy of PG tests as a gastric cancer biomarker (i.e., Helicobacter pylori infection status, gender, histopathologic features, and cancer location and depth) are evaluated. It was found that the strategies used to increase the efficacy of PG tests should be individualized in each country according to the seroprevalence of H. pylori.
doi:10.5009/gnl.2010.4.3.307
PMCID: PMC2956341  PMID: 20981206
Pepsinogen; Gastric cancer; Atrophic gastritis; Helicobacter pylori
19.  Higher number of Helicobacter pylori CagA EPIYA C phosphorylation sites increases the risk of gastric cancer, but not duodenal ulcer 
BMC Microbiology  2011;11:61.
Background
Helicobacter pylori infection is one of the most common infections worldwide and is associated with gastric cancer and peptic ulcer. Bacterial virulence factors such as CagA have been shown to increase the risk of both diseases. Studies have suggested a causal role for CagA EPIYA polymorphisms in gastric carcinogenesis, and it has been shown to be geographically diverse. We studied associations between H. pylori CagA EPIYA patterns and gastric cancer and duodenal ulcer, in an ethnically admixed Western population from Brazil. CagA EPIYA was determined by PCR and confirmed by sequencing. A total of 436 patients were included, being 188 with gastric cancer, 112 with duodenal ulcer and 136 with gastritis.
Results
The number of EPIYA C segments was significantly associated with the increased risk of gastric carcinoma (OR = 3.08, 95% CI = 1.74 to 5.45, p < 10-3) even after adjustment for age and gender. Higher number of EPIYA C segments was also associated with gastric atrophy (p = 0.04) and intestinal metaplasia (p = 0.007). Furthermore, patients infected by cagA strains possessing more than one EPIYA C segment showed decreased serum levels of pepsinogen I in comparison with those infected by strains containing one or less EPIYA C repeat. Otherwise, the number of EPIYA C segments did not associate with duodenal ulcer.
Conclusions
Our results demonstrate that infection with H. pylori strains harbouring more than one CagA EPIYA C motif was clearly associated with gastric cancer, but not with duodenal ulcer.
Higher number of EPIYA C segments was also associated with gastric precancerous lesions as demonstrated by histological gastric atrophic and metaplastic changes and decreased serum levels of pepsinogen I.
doi:10.1186/1471-2180-11-61
PMCID: PMC3073878  PMID: 21435255
20.  cagA positive and negative Helicobacter pylori strains are simultaneously present in the stomach of most patients with non-ulcer dyspepsia: relevance to histological damage 
Gut  1998;42(6):772-778.
Background/Aims—Infection with Helicobacter pylori strains harbouring the cagA gene (cagA+) is associated with an increased risk of developing peptic ulcer and gastric cancer. The aim of this study was to assess whether H pylori isolates with different cagA status were present in patients with non-ulcer dyspepsia, and whether a variable cagA status is relevant to histological gastric mucosal damage and glandular cell proliferation. 
Methods—Well separated H pylori colonies (between 2 and 25) from primary plates, per gastric area, for each of 19 patients with non-ulcer dyspepsia were examined for cagA by hybridisation. Western blotting was used to examine both representative colonies for CagA expression and the patients' sera for antibody response to CagA. Glandular gastric cell proliferation was assessed immunohistochemically. 
Results—Of the 747 colonies examined, 45.3% were cagA+. All colonies from four patients were cagA+, and all colonies from two patients were cagA−. In 13 patients (68%) both cagA+ and cagA− colonies were found. CagA expression of isolates corresponded to their cagA status. H pylori strains with different CagA molecular masses were present in three patients. Results based on all 19patients studied showed that the prevalence of cagA+ colonies in areas with mucosal atrophy associated or not with intestinal metaplasia (67.9%) was significantly higher than in normal mucosa (44.7%) and mucosa from patients with chronic gastritis (44.0%) (p< 0.001). High levels of cell proliferation were associated with histological atrophy with or without intestinal metaplasia, but not with the possession of cagA by organisms colonising the same mucosal sites. 
Conclusions—Most patients with non-ulcer dyspepsia are infected by both cagA+ and cagA−H pylori colonies. The cagA status of infecting organisms may play a role in the development of atrophy and intestinal metaplasia. 


Keywords: gastritis; Helicobacter pylori infection; cagA; mucosal atrophy; cell proliferation
PMCID: PMC1727148  PMID: 9691913
21.  Association of polymorphism of PTPN 11 encoding SHP-2 with gastric atrophy but not gastric cancer in Helicobacter pylori seropositive Chinese population 
BMC Gastroenterology  2012;12:89.
Background
The interaction between Src homology 2 domain-containing protein tyrosine phosphatase (SHP-2) of gastric epithelial cells and cagA from H. pylori plays a crucial role in developments of gastric atrophy and gastric cancer. This study aimed to investigate the association of haplotype tagging SNPs (htSNPs) in the PTPN11 gene encoding SHP-2 with gastric atrophy and gastric cancer in Chinese population.
Methods
The subjects comprised 414 patients with gastric cancer, 109 individuals with gastric atrophy and 923 healthy controls. Blood was collected from October 2008 to October 2010. Five htSNPs rs2301756, rs12423190, rs12229892, rs7958372 and rs4767860 from the PTPN11 gene were selected and genotyped by Taqman assay. Serum Ig G antibodies to H. pylori were detected by ELISA. Gastric atrophy was screened by the levels of serum pepsinogenIandII, and confirmed by endoscopy and histopatholgical examinations. Odds ratio (ORs) and 95% confidence intervals (CIs) were calculated by a multivariate logistic regression.
Results
Among H. pylori seropositive subjects, age and gender-adjusted OR of gastric atrophy was 2.47 (95%CI 1.13-4.55, P = 0.02) for CC genotype compared with CT/TT genotypes, suggesting a recessive model of genetic risk for rs12423190. The prevalence of H. pylori seropositivity were significantly higher in groups of gastric cancer and gastric atrophy compared to the control group (70.3% vs. 75.2% vs. 49.7%, P <0.001). However, the distributions of genotypes and haplotypes in patients with gastric cancer were not significantly different from healthy controls.
Conclusions
Our study provides the first evidence that rs12423190 polymorphism of the PTPN11 gene is significantly associated with an increased risk of gastric atrophy in H. pylori infected Chinese Han population, suggesting that rs12423190 polymorphism could be used as a useful marker of genetic susceptibility to gastric atrophy among H. pylori infected subjects. The biological roles of this polymorphism require a further investigation.
doi:10.1186/1471-230X-12-89
PMCID: PMC3509400  PMID: 22788847
22.  Risk for gastric cancer in people with CagA positive or CagA negative Helicobacter pylori infection. 
Gut  1997;40(3):297-301.
BACKGROUND AND AIMS: It is not known why some people with Helicobacter pylori infection develop gastric cancer whereas others do not. Whether the CagA phenotype of H pylori infection affected risk for cancer independently of other posited risk factors was evaluated. SUBJECTS: 242 persons who participated in a previous nested case-control study of gastric cancer. 179 (90 cases and 89 controls) were infected with H pylori as determined by enzyme linked immunosorbent assay (ELISA) in serum and 63 (13 cases and 50 controls) were uninfected. METHODS: Serum samples from cases and controls, obtained a mean of 14.2 years before diagnosis of cancer in the cases, were tested by ELISA for IgG antibodies against the CagA gene product of H pylori. They had previously been tested for pepsinogen I. Using logistic regression analysis, risk for cancer was compared among infected persons with CagA antibodies, infected persons without CagA antibodies, and uninfected persons. RESULTS: Subjects infected with H pylori who had CagA antibodies were 5.8-fold more likely than uninfected subjects to develop gastric cancer (95% confidence interval (95% CI) = 2.6-13.0). This was true for both intestinal (odds ratio (OR) 5.1, 95% CI = 2.1-12.2) and diffuse type (OR 10.1, 95% CI = 2.2-47.4) cancers. By contrast, H pylori infected subjects without CagA antibodies were only slightly, and not significantly, at increased risk for cancer (OR 2.2, 95% CI = 0.9-5.4) and any possible association was restricted to diffuse type carcinoma (OR 9.0, 95% CI = 1.2-65.8). Pepsinogen 1 < 50 ng/ml significantly increased risk for both cancer types in H pylori infected persons and lessened the magnitude of association between CagA and cancer. Educational attainment, cigarette smoking, and ABO blood group were not associated with malignancy. CONCLUSIONS: When compared with uninfected subjects, persons infected with CagA positive H pylori are at considerably increased risk of gastric cancer. CagA negative H pylori are less strongly linked to malignancy and may only be associated with diffuse type disease.
PMCID: PMC1027076  PMID: 9135515
23.  Predicting the development of gastric cancer from combining Helicobacter pylori antibodies and serum pepsinogen status: a prospective endoscopic cohort study 
Gut  2005;54(6):764-768.
Background and aim: Helicobacter pylori infection and gastric atrophy are both risk factors for gastric cancer. We aimed to elucidate the natural history of gastric cancer development according to H pylori infection and gastric atrophy status.
Subjects and methods: A total of 9293 participants in a mass health appraisal programme were candidates for inclusion in the present prospective cohort study: 6983 subjects revisited the follow up programme. Subjects were classified into four groups according to serological status at initial endoscopy. Group A (n = 3324) had “normal” pepsinogen and were negative for H pylori antibody; group B (n = 2134) had “normal” pepsinogen and were positive for H pylori antibody; group C (n = 1082) had “atrophic” pepsinogen and were positive for H pylori antibody; and group D (n = 443) had “atrophic” pepsinogen and were negative for H pylori antibody. Incidence of gastric cancer was determined by annual endoscopic examination.
Results: Mean duration of follow up was 4.7 years and the average number of endoscopic examinations was 5.1. The annual incidence of gastric cancer was 0.04% (95% confidence interval (CI) 0.02–0.09), 0.06% (0.03–0.13), 0.35% (0.23–0.57), and 0.60% (0.34–1.05) in groups A, B, C, and D, respectively. Hazard ratios compared with group A were 1.1 (95% CI 0.4–3.4), 6.0 (2.4–14.5), and 8.2 (3.2–21.5) in groups B, C, and D, respectively. Age, sex, and “group” significantly served as independent valuables by multivariate analysis.
Conclusions: The combination of serum pepsinogen and anti-H pylori antibody provides a good predictive marker for the development of gastric cancer.
doi:10.1136/gut.2004.055400
PMCID: PMC1774550  PMID: 15888780
gastric cancer; Helicobacter pylori; pepsinogen; endoscopy; screening
24.  Helicobacter pylori Seropositivity and Risk of Lung Cancer 
PLoS ONE  2012;7(2):e32106.
Lung cancer is the leading cause of cancer mortality worldwide. Helicobacter pylori (H. pylori) is a risk factor for distal stomach cancer, and a few small studies have suggested that H. pylori may be a potential risk factor for lung cancer. To test this hypothesis, we conducted a study of 350 lung adenocarcinoma cases, 350 squamous cell carcinoma cases, and 700 controls nested within the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC) cohort of male Finnish smokers. Controls were one-to-one matched by age and date of baseline serum draw. Using enzyme-linked immunosorbent assays to detect immunoglobulin G antibodies against H. pylori whole-cell and cytotoxin-associated gene (CagA) antigens, we calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) for associations between H. pylori seropositivity and lung cancer risk using conditional logistic regression. H. pylori seropositivity was detected in 79.7% of cases and 78.5% of controls. After adjusting for pack-years and cigarettes smoked per day, H. pylori seropositivity was not associated with either adenocarcinoma (OR: 1.1, 95% CI: 0.75–1.6) or squamous cell carcinoma (OR: 1.1, 95% CI: 0.77–1.7). Results were similar for CagA-negative and CagA-positive H. pylori seropositivity. Despite earlier small studies suggesting that H. pylori may contribute to lung carcinogenesis, H. pylori seropositivity does not appear to be associated with lung cancer.
doi:10.1371/journal.pone.0032106
PMCID: PMC3286451  PMID: 22384154
25.  Inverse background of Helicobacter pylori antibody and pepsinogen in reflux oesophagitis compared with gastric cancer: analysis of 5732 Japanese subjects 
Gut  2001;49(3):335-340.
BACKGROUND—The relationship between Helicobacter pylori and reflux oesophagitis remains controversial.
AIMS—To evaluate the relationship between H pylori and reflux oesophagitis in a large number of Japanese subjects.
SUBJECTS—A total of 5732 consecutive Japanese subjects during a health screening were enrolled.
METHODS—Gastrointestinal endoscopy was performed on all subjects. We simultaneously measured serum anti-H pylori antibody and pepsinogen as markers of H pylori infection together with gastric atrophy. The risk of reflux oesophagitis was evaluated in relation to these markers, and the results were compared with those of gastric cancer.
RESULTS—Reflux oesophagitis was found in 108 subjects. Both positivity for H pylori antibody (adjusted odds ratio (OR) 0.67 (95% confidence interval 0.45-1.0)) and "low" pepsinogen indicating gastric atrophy (OR 0.35 (0.18-0.68)) were negatively associated with reflux oesophagitis. After subjects were classified into four groups based on positivity or negativity for H pylori antibody and "low" pepsinogen, the prevalence of reflux oesophagitis showed a decreasing trend as H pylori induced gastric atrophy became more severe. The risk of gastric cancer showed an increasing trend, exactly the opposite to that of reflux oesophagitis.
CONCLUSIONS—Analysis of a large series of Japanese subjects revealed a decreasing prevalence of reflux oesophagitis in conjunction with progress of gastric atrophy induced by H pylori infection. This pattern was completely opposite to that of gastric cancer cases. A protective role of H pylori for reflux oesophagitis through the development of gastric atrophy has been suggested.


Keywords: Helicobacter pylori; oesophagitis; gastro-oesophageal reflux disease; atrophic gastritis; gastric cancer
doi:10.1136/gut.49.3.335
PMCID: PMC1728449  PMID: 11511553

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