Risk Of Noncardia Gastric Cancer Research Articles

Aspirin Use and the Risk of Gastric Cancer: A Meta-Analysis

Studies investigating the association between aspirin use and gastric cancer risk have reported conflicting results. The objective of this study was to quantitatively summarize the evidence for such a relationship. Two investigators independently searched the Medline, PubMed, Embase, and Academic Search Premier (EBSCO) databases. Fourteen studies with a total number of 5,640 gastric cancer cases were identified. Most of the study populations were Caucasian. The combined results based on all studies showed there was no statistically significant difference between aspirin use and gastric cancer risk (odds ratio (OR) = 0.80, 95% confidence intervals (CI) = 0.54-1.19). When stratifying by study designs and gender, results were similar except for cohort and randomized controlled trial (RCT) studies (OR = 0.72, 95% CI = 0.62-0.84). When stratifying by location and Helicobacter pylori (H. pylori) infection, we observed there were lower risks in noncardia gastric cancer (OR = 0.62, 95% CI = 0.55-0.69) and H. pylori-infected individuals (OR = 0.62, 95% CI = 0.42-0.90) for aspirin users. Among Caucasians, there were lower risks for noncardia gastric cancer (OR = 0.73, 95% CI = 0.62-0.87) and H. pylori-infected individuals (OR = 0.62, 95% CI = 0.42-0.90) also. This meta-analysis indicated that regular use of aspirin may be associated with reduced risk of noncardia gastric cancer, especially among Caucasians; for H. pylori-infected subjects the result was similar.

“Adjuvant” Therapy after Endoscopic Mucosal Resection of Early Gastric Cancer

“Adjuvant” Therapy after Endoscopic Mucosal Resection of Early Gastric Cancer

Genome sequence analysis of Helicobacter pylori strains associated with gastric ulceration and gastric cancer

BackgroundPersistent colonization of the human stomach by Helicobacter pylori is associated with asymptomatic gastric inflammation (gastritis) and an increased risk of duodenal ulceration, gastric ulceration, and non-cardia gastric cancer. In previous studies, the genome sequences of H. pylori strains from patients with gastritis or duodenal ulcer disease have been analyzed. In this study, we analyzed the genome sequences of an H. pylori strain (98-10) isolated from a patient with gastric cancer and an H. pylori strain (B128) isolated from a patient with gastric ulcer disease.ResultsBased on multilocus sequence typing, strain 98-10 was most closely related to H. pylori strains of East Asian origin and strain B128 was most closely related to strains of European origin. Strain 98-10 contained multiple features characteristic of East Asian strains, including a type s1c vacA allele and a cagA allele encoding an EPIYA-D tyrosine phosphorylation motif. A core genome of 1237 genes was present in all five strains for which genome sequences were available. Among the 1237 core genes, a subset of alleles was highly divergent in the East Asian strain 98-10, encoding proteins that exhibited <90% amino acid sequence identity compared to corresponding proteins in the other four strains. Unique strain-specific genes were identified in each of the newly sequenced strains, and a set of strain-specific genes was shared among H. pylori strains associated with gastric cancer or premalignant gastric lesions.ConclusionThese data provide insight into the diversity that exists among H. pylori strains from diverse clinical and geographic origins. Highly divergent alleles and strain-specific genes identified in this study may represent useful biomarkers for analyzing geographic partitioning of H. pylori and for identifying strains capable of inducing malignant or premalignant gastric lesions.

Cytokine gene polymorphisms and the risk of adenocarcinoma of the stomach in the European prospective investigation into cancer and nutrition (EPIC-EURGAST)

BackgroundThe relative contribution to gastric cancer (GC) risk of variants in genes that determine the inflammatory response remains mostly unknown and results from genotyping studies are inconsistent. Patients and methodsA nested case–control study within the prospective European Prospective Investigation into Cancer and Nutrition cohort was carried out, including 248 gastric adenocarcinomas and 770 matched controls. Twenty common polymorphisms at cytokine genes [interleukin (IL)1A, IL1B, IL1RN, IL4, IL4R, IL6, IL8, IL10, IL12A, IL12B, lymphotoxin α and tumor necrosis factor (TNF)] were analyzed. Antibodies against Helicobacter pylori (Hp) and CagA were measured. ResultsIL1RN 2R/2R genotype [odds ratio (OR) 2.43; 95% confidence interval (CI) 1.19–4.96] and allele IL1RN Ex5-35C were associated with an increased risk of Hp(+) non-cardia GC. IL8 -251AA genotype was associated with a decreased risk of Hp(+) non-cardia GC (OR 0.51; 95% CI 0.32–0.81), mainly of the intestinal type. These associations were not modified by CagA status. Carriers of IL1B -580C and TNF -487A alleles did not associate with an increased risk. A moderately increased risk of Hp(+) non-cardia GC for IL4R –29429T variant was observed (OR 1.74; 95% CI 1.15–2.63). ConclusionThis prospective study confirms the association of IL1RN polymorphisms with the risk of non-cardia GC and indicates that IL8 -251T>A may modify the risk for GC.

Body Mass and Physical Activity and Risk of Gastric Cancer in a Population-Based Cohort Study in Norway

There is a relation between excess body mass index and overall cancer incidence and mortality, but the relation to noncardia gastric cancer is inconsistent. A high physical activity level decreases the risk of several cancers, but few studies have focused on gastric cancer. We conducted a population-based, prospective cohort study in Nord-Trondelag county in Norway. During 1984 to 1986, all adult residents were invited to participate in a health survey, where body height and weight were measured, and frequency, duration, and intensity of recreational physical activity, together with potential confounding factors, were assessed by questionnaires. New gastric cancers occurring during follow-up in 1984 to 2002 were identified by linkage to the Cancer Registry of Norway. Cox proportional hazards regression models were used to calculate hazard ratios with 95% confidence intervals, adjusted for age, sex, occupation, salt intake, smoking, and alcohol drinking. Follow-up of 73,133 cohort members (88% of all inhabitants) revealed 313 gastric cancers, including 264 noncardia cancers. No statistically significant associations were revealed between different levels of body mass index and risk of noncardia gastric cancer. A statistically significant 50% risk reduction among persons reporting at least a moderate level of recreational physical activity, based on a summary score of physical activity (hazard ratio, 0.5; 95% confidence interval, 0.3-0.9), and a dose-response relation was indicated (P for trend = 0.01). It is concluded that recreational physical activity might have a protective effect against gastric cancer. The sedentary lifestyle gaining ground in western societies might counteract the ongoing decrease in incidence of gastric cancer.

Airborne exposures and risk of gastric cancer: A prospective cohort study

There is an unexplained male predominance among patients with gastric cancer, and many carcinogens are found in male-dominated dusty occupations. However, the relation between occupational exposures and risk of gastric cancer remains unclear. To investigate whether airborne occupational exposures might influence the risk of noncardia gastric cancer, we used a large, prospective cohort study of male Swedish construction workers. These workers were, during the period 1971-1993, regularly invited to health examinations by a nationwide occupational health service organization. Data on job titles and other variables were collected through self-administered questionnaires and forms completed by the health organization's staff. Industrial hygienists assessed 12 specific airborne occupational exposures for 200 job titles. Gastric cancer, death or emigration occurring during follow-up in 1971-2002 were identified by linkage to the Swedish registers of Cancer, Causes of Death and Total Population, respectively. Incidence rate ratios (IRR) and 95% confidence intervals (CI), adjusted for attained age, tobacco smoking, calendar period and body mass, were derived from Cox regression. Among 256,357 cohort members, contributing 5,378,012 person-years at risk, 948 noncardia gastric cancers were identified. Increased risk of this tumor was found among workers exposed to cement dust (IRR 1.5 [95% CI 1.1-2.1]), quartz dust (IRR 1.3 [95% CI 1.0-1.7]) and diesel exhaust (IRR 1.4 [95% CI 1.1-1.9]). Dose-response relations were observed for these exposures. No consistent positive associations were found regarding exposure to asbestos, asphalt fumes, concrete dust, epoxy resins, isocyanates, metal fumes, mineral fibers, organic solvents or wood dust. In conclusion, this study provides some support to the hypothesis that specific airborne exposures increase the risk of noncardia gastric cancer.

CagA+ Helicobacter pylori infection and gastric cancer risk in the EPIC‐EURGAST study

Helicobacter pylori (H. pylori), atrophic gastritis, dietary and life-style factors have been associated with gastric cancer (GC). These factors have been evaluated in a large case-control study nested in the European Prospective Investigation into Cancer and Nutrition carried out in 9 countries, including the Mediterranean area. Participants, enrolled in 1992-1998, provided life-style and dietary information and a blood sample (360,000; mean follow-up: 6.1 years). For 233 GC cases diagnosed after enrolment and their 910 controls individually-matched by center, gender, age and blood donation date H. pylori antibodies (antilysate and antiCagA) and plasma Pepsinogen A (PGA) were measured by ELISA methods. Severe chronic atrophic gastritis (SCAG) was defined as PGA circulating levels <22 microg/l. Overall, in a conditional logistic regression analysis adjusted for education, smoke, weight and consumption of total vegetables, fruit, red and preserved meat, H. pylori seropositivity was associated with GC risk. Subjects showing only antibodies anti-H. pylori lysate, however, were not at increased risk, while those with antiCagA antibodies had a 3.4-fold increased risk. Overall, the odds ratio associated with SCAG was 3.3 (95% CI 2.2-5.2). According to site, the risk of noncardia GC associated with CagA seropositivity showed a further increase (OR 6.5; 95% CI 3.3-12.6); on the other hand, a ten-fold increased risk of cardia GC was associated with SCAG (OR 11.0; 95% CI 3.0-40.9). These results support the causal relationship between H. pylori CagA+ strains infection, and GC in these European populations even after taking into account dietary habits. This association was limited to distal GC, while serologically defined SCAG was strongly associated with cardia GC, thus suggesting a divergent risk pattern for these 2 sites.

A Functional Polymorphism of Toll-Like Receptor 4 Gene Increases Risk of Gastric Carcinoma and Its Precursors

TLR4 is a cell-surface signaling receptor involved in the recognition and host response to Helicobacter pylori. The TLR4+896A>G polymorphism linked with impaired reactivity to bacterial lipopolysaccharide may play a role in gastric carcinogenesis. We assessed associations with premalignant gastric changes in 149 relatives of gastric cancer patients, including 45 with hypochlorhydria and gastric atrophy. We also genotyped 2 independent Caucasian population-based case-control studies of upper gastrointestinal tract cancer, initially in 312 noncardia gastric carcinoma cases and 419 controls and then in 184 noncardia gastric carcinomas, 123 cardia carcinomas, 159 esophageal cancers, and 211 frequency-matched controls. Odds ratios were computed from logistic models and adjusted for potential confounding factors. TLR4+896G carriers had an 11-fold (95% confidence interval [CI], 2.5-48) increased odds ratio (OR) for hypochlorhydria; the polymorphism was unassociated with gastric acid output in the absence of H pylori infection. Carriers also had significantly more severe gastric atrophy and inflammation. Seventeen percent of gastric carcinoma patients in the initial study and 15% of the noncardia gastric carcinoma patients in the replication study had 1 or 2 TLR4 variant alleles vs 8% of both control populations (combined OR = 2.3; 95% CI = 1.6-3.4). In contrast, prevalence of TLR4+896G was not significantly increased in esophageal squamous cell (2%, OR = 0.2) or adenocarcinoma (9%, OR = 1.4) or gastric cardia carcinoma (11%, OR = 1.4). Our data suggest that the TLR4+896A>G polymorphism is a risk factor for noncardia gastric carcinoma and its precursors. The findings underscore the role of the host innate immune response in outcome of H pylori infection.

Opposing Risks of Gastric Cardia and Noncardia Gastric Adenocarcinomas Associated With Helicobacter pylori Seropositivity

Colonization with Helicobacter pylori is a risk factor for gastric adenocarcinoma, but the magnitude of this association and its relationship to anatomic location of the cancer, duration of follow-up, age at diagnosis, histologic subtype, and H. pylori strain differences are less clear. We conducted a prospective nested case-control study of H. pylori serology to address these questions. Case and control subjects were selected from the 29,133 50- to 69-year-old males recruited into the Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study. At baseline, detailed demographic data and a serum sample were collected. From 1985 to 1999, 243 incident cases of gastric adenocarcinoma were diagnosed in cohort members. Serum samples from 234 case subjects (173 with noncardia gastric cancers and 61 with gastric cardia cancers) and 234 age-matched control subjects were assayed for antibodies against H. pylori whole-cell and CagA antigens. We fit conditional logistic regression models to estimate the unadjusted and adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association of H. pylori seropositivity, defined as seropositivity to either whole-cell or CagA antigens, with noncardia gastric and gastric cardia cancers. All statistical tests were two-sided. H. pylori seropositivity was strongly associated with the risk of noncardia gastric cancer (adjusted OR = 7.9, 95% CI = 3.0 to 20.9) but was inversely associated with the risk of gastric cardia cancer (adjusted OR = 0.31, 95% CI = 0.11 to 0.89). H. pylori seropositivity rates did not vary statistically significantly by length of follow-up, age at diagnosis, or histologic subtype. A calculation of rates showed that the absolute risks of noncardia gastric and cardia gastric adenocarcinomas in the H. pylori-positive participants of this cohort would be 63 and 12 per 100,000 person-years, respectively, whereas corresponding rates in H. pylori-negative participants would be 8 and 37 per 100,000 person-years, respectively. H. pylori is a strong risk factor for noncardia gastric cancer but is inversely associated with the risk of gastric cardia cancer. These findings bolster the hypothesis that decreasing H. pylori prevalence during the past century may have contributed to lower rates of noncardia cancer and higher rates of cardia cancer in Western countries.

Smoking and alcohol drinking in relation to risk of gastric cancer: A population‐based, prospective cohort study

The relations between tobacco, alcohol and risk of gastric cancer need to be established, and any gain from preventive measures should be estimated. We conducted a population-based, prospective cohort study in Nord-Trondelag county in Norway. During 1984-1986, adult residents were invited to a health survey and they answered questionnaires that assessed exposure to tobacco and alcohol, together with potential confounding factors. The exposure assessment regarding alcohol was limited to a 14-day period. New gastric cancers that occurred during follow-up (1984-2002) were identified by linkage to the Norwegian Cancer Registry. Cox proportion hazards regression models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CI), adjusted for sex, education and body mass index. Follow-up of 1,117,648 person-years at risk among 69,962 cohort members revealed 251 gastric cancers, including 224 noncardia cancers. The risk was almost twice as high in daily smokers (HR = 1.88 [CI 95% = 1.33-2.67]) as in never smokers. Independent dose-response relations were found with earlier age at initiation (p = 0.02), frequency (p = 0.00) and duration of smoking (p = 0.00). Attributable risk (AR) of gastric cancer among current smokers was 8.7/100,000 person-years and the corresponding population AR was 18.4%. No statistically significant associations between various degrees of exposure to alcohol and risk of gastric cancer was revealed, but combined high use of cigarettes (>20/day) and alcohol (>5 occasions/14 days) increased the risk of noncardia gastric cancer nearly 5-fold (HR = 4.90 [95% CI = 1.90-12.62]), compared to nonusers. It is concluded that smoking is a dose-dependent risk factor for gastric cancer. Combined high exposure to smoking and alcohol further increases the risk. Successful preventive measures could considerably reduce the incidence of gastric cancer.

Comparative Immunoproteomics of Identification and Characterization of Virulence Factors from Helicobacter pylori Related to Gastric Cancer

Helicobacter pylori is an important risk factor of gastric cancer (GC). Although many H. pylori virulence factors have been reported, the pathogenic mechanism by which H. pylori infection causes GC remains unclear. The aims of this study were to identify GC-related antigens from H. pylori and characterize their roles in the development of GC. As GC and duodenal ulcer (DU) are considered clinically divergent, we compared two-dimensional immunoblots of an acid-glycine extract of H. pylori probed with serum samples from 15 patients with GC and 15 with DU to find GC-related antigens, which were subsequently identified by mass spectrometry. Many protein spots were recognized by more than one serum, and 24 of these were better recognized by GC sera. The proteins showing higher frequency of recognition in GC group are threonine synthase, rod shape-determining protein, S-adenosylmethionine synthetase, peptide chain release factor 1, DNA-directed RNA polymerase alpha subunit, co-chaperonin GroES (monomeric and dimeric forms), response regulator OmpR, and membrane fusion protein. Of these proteins, GroES was identified as a dominant GC-related antigen with a much higher seropositivity of GC samples (64.2%, n = 95) compared with 30.9% for gastritis (n = 94) and 35.5% for DU (n = 124). GroES seropositivity was more commonly associated with antral GC than with non-antral GC (odds ratio = 2.7; 95% confidence interval, 1.1-6.7). In peripheral blood mononuclear cells, GroES stimulated production of interleukin (IL)-8, IL-6, granulocyte macrophage colony-stimulating factor, IL-1beta, tumor necrosis factor-alpha, cyclooxygenase-2, and prostaglandin E(2). Moreover when incubated with gastric epithelial cells, GroES induced expression of IL-8, cell proliferation, and up-regulation of c-jun, c-fos, and cyclin D1 but caused down-regulation of p27(Kip1). We conclude that GroES of H. pylori is a novel GC-associated virulence factor and may contribute to gastric carcinogenesis via induction of inflammation and promotion of cell proliferation.

No allelic variant associations of the IL‐1 and TNF gene polymorphisms in the susceptibility to duodenal ulcer disease

Recent studies have reported the association of a pro-inflammatory profile of genetic polymorphisms in IL-1B, IL-1RN, TNF-A, and IL-10 genes with an increased risk of non-cardia gastric cancer. Because gastric cancer and duodenal ulcer are mutually exclusive outcomes of Helicobacter pylori infection, we aimed to investigate possible allelic variant associations of several functional polymorphisms in the IL-1B, IL-1RN, TNFA, and LTA genes in the susceptibility to duodenal ulcer. Genomic DNA from 118 patients with duodenal ulcer and 97 healthy controls was typed for the IL-1B polymorphisms at positions -511, -31, and +3954, the VNTR polymorphism in intron 2 of the IL-1RN gene, the TNFA-308, TNFA -238, and the NcoI and BsI LTA polymorphisms by PCR, SSCP and TaqMan assays. H. pylori infection and non-steroidal anti-inflammatory drugs (NSAIDs) use was investigated in patients and controls. Logistic regression analysis identified H. pylori infection (OR: 12.86; 95%CI: 3.85-43), NSAID use (OR: 11.95; 95%CI: 4.19-34.05), and family history-ulcer (OR: 3.79; 95%CI: 1.68-8.54) as independent risk factors for duodenal ulcer. When the effect of the combinations of IL-1 and TNF genotypes was studied we found that the distribution of all possible combinations of these eight polymorphisms was similar in duodenal ulcer patients and controls. The simultaneous carriage of alleles IL-1RN*2/IL-1B -31T/IL-1B -511C/IL-IB +3954C/TNF-HaplotypeE negative (termed in some studies as 'low-producing' alleles) was increased in H. pylori-positive duodenal ulcer patients compared to H. pylori-infected healthy controls (10.5% vs. 5.9%) although the difference did not reach statistical significance (OR: 1.85; 95%CI: 0.57-5.99, P = 0.41). Moreover, no differences were found with respect to H. pylori status, NSAID use, age, gender, smoking habit, type of complication, recurrence of the ulcer, and need for surgical treatment. Our data show no association between allelic variants of IL-1 and TNF gene polymorphisms in the susceptibility to and final outcome of duodenal ulcer.

Mast Cells Are Critical Mediators of Vaccine-Induced Helicobacter Clearance in the Mouse Model

Despite the proven ability of immunization to prevent Helicobacter infection in mouse models, the precise mechanism of protection has remained elusive. We explored the cellular events associated with Helicobacter clearance from the stomach following vaccination by flow cytometry analysis and histological and molecular studies. Kinetic studies showed that the infection is undetectable in vaccinated mice at day 5 postbacterial challenge. Flow cytometry analysis showed that the percentages of mast cells (CD3 - CD117 + ) increased in the lymphoid cells isolated from the stomach at day 4 postchallenge in urease + cholera toxin (CT)-vaccinated mice in comparison with mice administered with CT alone (9.4% +/- 4.4% and 3.1% +/- 1%, respectively, for vaccinated and CT administered, n = 5; P < .01). Quantitative PCR analysis showed an increased messenger RNA (mRNA) expression of the mast cell proteases 1 and 2 at day 5 postchallenge in the stomach of vaccinated mice. In contrast to wild-type mice, mast cell-deficient mice (W/W v mice) were not protected from H felis colonization after vaccination. Indeed only 1 out of 12 vaccinated W/W v mice showed a negative urease test. Remarkably, vaccinated W/W v mice reconstituted with cultured bone marrow-derived mast cells recovered the ability to clear the infection after vaccination (8 out of 10 mast cell-reconstituted mice showed negative urease tests [ P < .006 as compared with wild-type mice]). These experiments show that mast cells are, unexpectedly, critical mediators of anti- Helicobacter vaccination.

Helicobacter pylori,Pepsinogen, and Gastric Adenocarcinoma in Hawaii

The objective was to investigate the association of Helicobacter pylori and serum pepsinogen (PG) levels with gastric adenocarcinoma. Serum obtained from 299 patients at the time of cancer diagnosis and from 336 population-based control subjects was tested for PG I, PG II, and antibodies to H. pylori and to CagA. Subjects with low PG I levels or low PG I/II ratios were at increased risk for cardia and noncardia gastric cancer, whereas those with H. pylori or CagA seropositivity had an elevated risk for noncardia cancer only. Subjects seropositive for either H. pylori or CagA who had low PG I levels had the highest odds ratio (OR) (9.21 [95% confidence interval {CI}, 4.95-17.13]) for noncardia cancer, compared with subjects with neither factor. Elevated risks were also found among subjects with only 1 factor (OR, 5.40 [95% CI, 2.61-11.20] for low PG I level only; OR, 4.86 [95% CI, 5.90-8.13] for H. pylori or CagA seropositivity only). This pattern persisted when PG I/II ratio replaced PG I level and when CagA seropositivity alone replaced H. pylori immunoglobulin G or CagA seropositivity. The results suggest that persons with both H. pylori or CagA seropositivity and a low PG I level or PG I/II ratio are highly susceptible to development of noncardia gastric cancer.

E-cadheringene C-160A promoter polymorphism and risk of non-cardia gastric cancer in a Chinese population

To test the hypothesis that E-cadherin gene (CDH1) C-160A promoter variant genotype is associated with an increased risk for developing gastric cancer. In this population-based case-control study of gastric cancer in Jiangsu Province, China, we performed polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) to genotype the C-160A polymorphism of CDH1 promoter in 206 non-cardia gastric cancer patients and 261 age- and sex-matched but unrelated cancer-free controls. The frequencies of genotypes CC, CA and AA were 57.8%, 36.4% and 5.8% in gastric cancer cases, respectively, and 58.2%, 34.9% and 6.9% in controls respectively. The distributions of CDH1 genotypes were not significantly different between gastric cancer cases and controls (P = 0.87 for genotype frequency and P = 0.92 for allele frequency). Compared with the CC genotype, the CA and AA genotypes were not associated with an increased risk for non-cardia gastric cancer (adjusted odds ratios (OR) = 1.15, and 95% confidence interval (95% CI) = 0.78-1.72 for CA genotype, and OR = 0.90 and 95% CI = 0.42-2.01 for AA genotype). E-cadherin gene C-160A promoter polymorphism may not play a major role in the etiology of non-cardia gastric cancer in Chinese population.

Non-steroidal anti-inflammatory drug use and the risk of gastric cancer: a systematic review and meta-analysis.

The relationship between the use of non-steroidal anti-inflammatory drugs (NSAIDs), including aspirin, and the risk of gastric cancer has not been well studied. We performed a systematic review and meta-analysis of published studies to evaluate the association between use of this class of drugs and the risk of gastric cancer. A fully recursive literature search to January 2003 was conducted in MEDLINE, PubMed, and CANCERLIT to identify potentially relevant case-control or cohort studies. Summary odds ratios (ORs) and 95% confidence intervals (CIs) were calculated under a random-effects model. Nine studies (eight case-control and one cohort) with a total of 2831 gastric cancer case patients were identified. NSAID use was associated with a reduced risk of gastric cancer, with a summary odds ratio of 0.78 (95% CI = 0.69 to 0.87). Users of aspirin (OR = 0.73, 95% CI = 0.63 to 0.86) and non-aspirin NSAIDs (OR = 0.74, 95% CI = 0.55 to 1.00) experienced similar magnitudes of risk reduction. Regular users of NSAIDs (OR = 0.57, 95% CI = 0.44 to 0.74) experienced a lower risk of gastric cancer relative to nonusers than did irregular users (OR = 0.76, 95% CI = 0.62 to 0.94; P =.09 versus regular users). A stratified analysis showed that NSAID use was associated with a statistically significant reduction in risk of noncardia gastric cancer (OR = 0.72, 95% CI = 0.58 to 0.89), but not of gastric cancer at the cardia (OR = 0.80, 95% CI = 0.53 to 1.20). There was no evidence that study design or type of control subject substantially influenced the estimate of effects. NSAID use was associated with a decreased risk of gastric cancer in a dose-dependent manner. This finding warrants proper clinical trials in populations with high risk of gastric cancer.

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

Background & Aims: Genetic variations in proinflammatory and anti-inflammatory cytokine genes influence individual response to carcinogenic exposures. Polymorphisms in interleukin (IL)-1β and its endogenous receptor antagonist are associated with risk of Helicobacter pylori-related gastric cancer. The aim of this study was to evaluate the role of proinflammatory cytokine gene polymorphisms in gastric and esophageal cancers defined by anatomic subsite. Methods: We assessed polymorphisms of the IL-1 gene cluster and 4 other cytokine genes in a population-based case-control study of upper gastrointestinal cancers, including gastric cardia (n = 126) and noncardia adenocarcinoma (n = 188), esophageal squamous cell carcinoma (n = 53), and adenocarcinoma (n = 108), and frequency-matched controls (n = 212). ORs for the different cancers were computed from logistic regression models adjusted for potential confounding factors. Results: Proinflammatory genotypes of tumor necrosis factor α and IL-10 were each associated with more than doubling of the risk of noncardia gastric cancer. Carriage of multiple proinflammatory polymorphisms of IL-1B o IL-1 receptor antagonist, tumor necrosis factor A, and IL-10 conferred greater risk, with ORs (and 95% confidence intervals) of 2.8 (1.6–5.1) for one, 5.4 (2.7–10.6) for 2, and 27.3 (7.4–99.8) for 3 or 4 high-risk genotypes. In contrast, these polymorphisms were not consistently related to the risks of esophageal or gastric cardia cancers. Polymorphisms in IL-4 and IL-6 were not associated with any of the cancers studied. Conclusions: A proinflammatory cytokine genetic profile increases the risk of noncardia gastric adenocarcinoma but not other upper gastrointestinal cancers, possibly by inducing a hypochlorhydric and atrophic response to gastric H. pylori infection.

Role of bacterial overgrowth in the stomach as an additional risk factor for gastritis.

Gastric bacteria can either be ingested or ascend from the distal bowel; however, their survival is usually limited by gastric acidity and motility. A reduction in gastric acid can result in bacterial overgrowth in the stomach and proximal small bowel, and the number of organisms rises as the intragastric pH rises. The increased risk of noncardia gastric cancer seen in patients with hypochlorhydria may be explained by an excess of nitrites and N-nitroso compounds (NOCs). These compounds are found in the diet of populations with a high gastric cancer risk, but can also be produced by the organisms that exist in the hypochlorhydria stomach. It has long been hypothesized that nitrites and NOCs act as one of the triggers in the atrophy-metaplasia-dysplasia-carcinoma path. However, although indirect data have linked the premalignant changes of metaplasia and dysplasia to NOCs, direct measurement of gastric nitrites and NOCs has not confirmed such a link. The role of Helicobacter pylori in bacterial overgrowth is mainly as a cause of hypochlorhydria resulting from atrophic gastritis, leading to a reduction in the parietal cell mass. Acid-suppressing drugs can result in bacterial overgrowth and increased nitrites and NOCs, although there is no current evidence for an increased risk of gastric cancer in patients taking them. One explanation is that the stomach appears to be colonized by different organisms than those in patients with hypochlorhydria for other reasons. There is some evidence that bacterial overgrowth per se can cause gastric inflammation in mice; however, although in humans the degree of gastric inflammation is greater when overgrowth is more prominent this may simply reflect the greater degree of hypochlorhydria in patients with a more severe H pylori-induced inflammation.

The evolving epidemiology of Helicobacter pylori infection and gastric cancer.

The relationship between Helicobacter pylori infection and the risk of gastric cancer has been well established in the last decade. Four meta-analyses have found that the infection increases the risk of noncardia gastric cancer by 2- to 6-fold compared with noninfected control populations. However, the role of cagA strains of H pylori in relation to gastric cancer has not been evaluated systematically. We undertook a meta-analysis of epidemiological studies examining the relationship between infection with cagA-positive strains of H pylori and the risk of gastric cancer, and found that patients who are seropositive for cagA strains of H pylori are at an increased risk for developing noncardia gastric cancer compared with those with H pylori infection alone. Therefore, searching for cagA-positive strains of H pylori may help identify populations at a greater risk for developing gastric cancer.

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms

Increased risk of noncardia gastric cancer associated with proinflammatory cytokine gene polymorphisms