Development Of Stomach Cancer Research Articles

Gastric-and-intestinal mixed-type intestinal metaplasia: aberrant expression of transcription factors and stem cell intestinalization

Helicobacter pylori plays a causative role in the development of chronic atrophic gastritis, intestinal metaplasia (IM), and stomach cancer. Although IM has long attracted attention as a putative preneoplastic lesion for stomach cancers, its clinicopathologic significance has yet to be clarified in detail. Using gastric and intestinal epithelial cell markers, IM was here divided into two major types: a gastric-and-intestinal (GI) mixed type and a solely intestinal (I) type. In the former, gastric and intestinal phenotypic markers appeared not only at the glandular but also at the cellular level. Furthermore, neuroendocrine cells also showed intestinalization along with their exocrine counterparts. In animal models, GI-type IM was found to appear first, followed by the solely I type. Summarizing these data, it was suggested that IM might be caused by the gradual intestinalization of stem cells from the GI to the I type. The molecular mechanisms of IM include the ectopic expression of CDX1, CDX2, OCT-1, and members of the Erk pathway. Suppression of the expression of gastric transcription factors such as SOX2, genes that are involved in the Sonic hedgehog pathway, and RUNX3, a tumor suppressor gene, could be additional relevant alterations. The expression of PDX1 may also be associated with pseudopyloric gland metaplasia and IM. Detailed analysis of gene regulation may shed light on the molecular bases of gastric lesions, leading to strategies for chemoprevention.

Gastric and intestinal phenotypes and histogenesis of advanced glandular stomach cancers in carcinogen‐treated, Helicobacter pylori‐infected Mongolian gerbils

The Helicobacter pylori-infected Mongolian gerbil (MG) has been established as an appropriate animal model for studies of stomach cancer development. However, there have hitherto been no data on the phenotypic classification of glandular stomach cancers in H. pylori-infected and non-infected MG. We therefore examined the phenotypes of 50 and six advanced glandular stomach cancers in H. pylori-infected and non-infected MG, respectively, as well as adjacent non-neoplastic mucosa, using several gastrointestinal epithelial phenotypic markers. The lesions were divided phenotypically into 21 gastric, 24 gastric-and-intestinal mixed, four intestinal and one null types, with 90.0% of the lesions harboring gastric elements and 56.0% demonstrating intestinal phenotypic expression in H. pylori-infected MG. All six lesions were classified as gastric type in non-infected MG. There was no clear correlation with the presence of intestinal metaplasia in surrounding mucosa. In conclusion, our data suggest that most advanced adenocarcinomas retain a gastric cellular phenotype in the glandular MG stomach. Thus, it might be proposed that intestinal metaplasia is a paracancerous phenomenon rather than a premalignant condition. H. pylori infection may trigger intestinalization of both stomach cancers and non-neoplastic mucosa.

Critical Evaluation of the Cancer Risk of Dibromochloropropane (DBCP)

Dibromochloropropane (1,2-dibromo-3-chloropropane, DBCP), a pesticide used widely for over 20 years to control nematodes on crops, turf and in nurseries, was banned by the United States Environmental Protection Agency (US EPA) in 1977 because of evidence of infertility in men and induction of a variety of tumors in laboratory animals. Despite the ban on the use of DBCP, this pesticide remains persistent in soil and continues to be detected as a groundwater contaminant in areas of past high use, in particular California's Central Valley. In this review, we present a critical evaluation of the available scientific literature on the potential for DBCP to affect cancer risk, including the results of animal cancer bioassays, human epidemiological studies and in vitro and in vivo genotoxicity studies. In addition, we provide updated information on DBCP chemistry and metabolism, production and past use, current regulations, its environmental fate, potential for human exposure and current remediation efforts. Results from long-term cancer bioassays in rodents show a statistically significant increase in the incidence of malignant and benign mammary gland tumors in female rats treated orally with DBCP compared to controls and some evidence of increased incidence of mammary fibroadenomas in DBCP low-dose treated female rats exposed by inhalation. Significantly increased incidence of tumors of the forestomach occurred in both sexes of rats and mice treated orally. Rats exposed to DBCP by inhalation showed significant increases in tumors of the tunica vaginalis in males; tumors of the pharynx and adrenal gland in females; and tumors of the tongue, nasal turbinate and nasal cavity in both sexes compared to controls. Male and female mice exposed to DBCP by inhalation experienced increased tumor incidence in the lungs and nasal cavity compared to controls. Significant increases in tumors of the lung and forestomach have also been reported in female mice treated by a dermal route. Although high mortality rates in both rat and mouse bioassays limited the ability to detect tumors late in life, the induction of a variety of tumors by multiple routes of exposure in two rodent species provides clear evidence of a DBCP tumorigenic response. In vitro, in vivo and human genotoxicity studies indicate that DBCP is capable of acting as a mutagen and clastogen. Few studies have been conducted to assess whether DBCP workplace or drinking water exposures affect cancer risk in humans. While case-control, cohort and ecological epidemiology studies have not found significant, positive associations between DBCP exposure and cancer in exposed populations, these studies have numerous limitations including small numbers of participants, a lack of control for confounding factors, lack of exposure information on DBCP and other chemicals and short follow-up times. Given the persistent nature of DBCP contamination in areas of past use, efforts should be made to continue remediation efforts and follow previously exposed populations for development of certain human cancers, including breast, ovarian, stomach, respiratory, oral and nasal cancers, among others.

CD44v6

Objective Intestinal metaplasia is a well-established risk factor in the development of stomach cancer. However, since the specificity is low it would be of great practical value to find a marker to separate cases of intestinal metaplasia into low and high risk for progression to dysplasia/carcinoma. So far this has not been achieved. CD44 is a cell surface molecule involved in cell–cell and cell–matrix interactions, and the spliced variant 6 has been shown to play a role in the progression of gastric carcinoma. The aim of this study was therefore to evaluate CD44v6 as a marker of increased cancer risk in intestinal metaplasia. Methods The current study investigated immunohistochemical CD44v6 expression in biopsies of normal gastric mucosa (n = 154) and gastric mucosa with intestinal metaplasia (n = 127). A third group consisted of cancer gastrectomies (n = 117) in which both tumour and uninvolved mucosa was studied. Proximal (cardia) and distal (corpus/antrum) locations were noted in all cases. Results There was a significant sequential increase in CD44v6 expression from normal mucosa and mucosa showing intestinal metaplasia to uninvolved mucosa adjacent to cancers without and with intestinal metaplasia to tumour. The most striking increase was from ‘normal’ to intestinal metaplastic mucosa adjacent to cancers. There were no differences between proximal and distal cases in any group. Conclusion These findings strongly suggest that CD44v6 expression is a late phenomenon in the transformation of intestinal metaplasia to dysplasia/cancer. It may therefore be a useful marker of cancer risk in patients with intestinal metaplasia.

CD44v6: a potential marker of malignant transformation in intestinal metaplasia of the stomach? An immunohistochemical study using tissue microarrays.

Intestinal metaplasia is a well-established risk factor in the development of stomach cancer. However, since the specificity is low it would be of great practical value to find a marker to separate cases of intestinal metaplasia into low and high risk for progression to dysplasia/carcinoma. So far this has not been achieved. CD44 is a cell surface molecule involved in cell-cell and cell-matrix interactions, and the spliced variant 6 has been shown to play a role in the progression of gastric carcinoma. The aim of this study was therefore to evaluate CD44v6 as a marker of increased cancer risk in intestinal metaplasia. The current study investigated immunohistochemical CD44v6 expression in biopsies of normal gastric mucosa (n = 154) and gastric mucosa with intestinal metaplasia (n = 127). A third group consisted of cancer gastrectomies (n = 117) in which both tumour and uninvolved mucosa was studied. Proximal (cardia) and distal (corpus/antrum) locations were noted in all cases. There was a significant sequential increase in CD44v6 expression from normal mucosa and mucosa showing intestinal metaplasia to uninvolved mucosa adjacent to cancers without and with intestinal metaplasia to tumour. The most striking increase was from 'normal' to intestinal metaplastic mucosa adjacent to cancers. There were no differences between proximal and distal cases in any group. These findings strongly suggest that CD44v6 expression is a late phenomenon in the transformation of intestinal metaplasia to dysplasia/cancer. It may therefore be a useful marker of cancer risk in patients with intestinal metaplasia.

Immunohistochemical analysis of Omi/HtrA2 expression in stomach cancer.

The serine protease Omi/HtrA2 is released from mitochondria into the cytosol after apoptosis stimuli, inducing apoptosis in a caspase-independent manner through its protease activity and in a caspase-dependent manner by neutralizing the inhibition of inhibitor of apoptosis proteins (IAPs) on caspases. Alteration of apoptosis is essential for cancer development, and cancer cell death by radiation and chemotherapy is largely dependent upon apoptosis. Thus, analysis of the expression status of Omi/HtrA2, a regulator of apoptosis, in cancer tissues is needed for an understanding of cancer development. In the current study, we analyzed the expression of Omi/HtrA2 in 60 advanced gastric adenocarcinomas by immunohistochemistry using a tissue microarray approach. Immunopositivity (defined as >/=30%) was observed for Omi/HtrA2 in 43 (72%) of the 60 cancers. By contrast, the surface mucous cells and mucous neck cells in the normal gastric mucosa showed no or weak expression of Omi/HtrA2. Taken together, these results suggest that stomach cancer cells in vivo may need Omi/HtrA2 expression for apoptosis, and that Omi/HtrA2 expression might be involved in stomach cancer development.

Work, salt intake and the development of stomach cancer

An excess of stomach cancer among workers has been observed and it could be argued that men whose occupation involves heavy work eat more and are consequently exposed to a greater quantity of carcinogens in their food. Working under conditions of heat stress greatly increases a worker’s salt excretion by as much as 0.1–15.0 g through sweating during one shift of work. Workers exposed to heat stress had consumed daily as much as from 13.0 to 38.0 g of salt, which is much higher than the safe level of 6 g/person/day recommended by the WHO, to keep a balance of salt in the body. Because salt strongly enhances and promotes chemical gastric carcinogenesis and Helicobacter pylori infection in both humans and animals, there is an association between work, salt intake, and the development of stomach cancer among workers in particular and in humans in general.

Complex analysis of lung cancer and stomach cancer risk factors

BACKGROUND: We conducted a multifactorial cancer epidemiology case-control study to assess effects of a complex of factors on high cancer morbidity of population of an industrial town in the central part of Russia. The study was carried out in the town of Tula, one of the oldest industrial centers of Russia with a high occupational and industrial load on the population and a high cancer incidence rate exceeding the Russian average rates by 38.4% in men and 89.9% in women. METHODS: We examined 200 lung cancer cases, 206 stomach cancer cases, and 213 controls, all residents of Tula. On each of the 619 study participants we collected personal data, which allowed characterization of cases and controls by a complex of 29 features reflecting well-known lung and stomach cancer risk factors. Mathematical processing was performed using the technique of multifactorial analysis based on mathematical pattern recognition methods. All tasks were solved in the package of applied programs of pattern recognition KVAZAR. RESULTS: The results of the multifactorial analysis of epidemiological data collected showed that the contribution of smoking in the development of stomach cancer in Tula was 7%, alcohol abuse 4%, occupational exposure to carcinogens 12% a complex of individual biological factors 28%, environmental factors 22% radiation factors 5%, nutrition habits 10%, and other factors 12%. The contribution of smoking in lung cancer mortality was 27%, alcohol abuse 4% occupational exposure to carcinogens 14%, a complex of individual biological factors 32%, environmental factors 9%, radiation factors 7%, and other factors 7%. CONCLUSION: The results of the epidemiological study carried out on the basis of methods of a multifactorial analysis in the city of Tula Russia, showed the effectiveness of such an approach to solving complicated epidemiological tasks. The suggested method allows one to assess a complex effect of different factors on oncologic morbidity in an industrial town and the prediction of effectiveness of various cancer preventive measures facilitates the choice of the most effective complex of preventive actions on the certain territory and at low cost.

Expression of COX-2 in Stomach Cancers and Its Relation to Their Biological Features

Background/Aim: Cyclooxygenase-2 (COX-2) is one of the key isoenzymes in the production of prostaglandins, and is believed to be involved in carcinogenesis. This study was conducted to examine the role of COX-2 in the development and biological behavior of stomach cancer. Methods: Expression of COX-2 at the mRNA and protein levels was analyzed using RT-PCR and immunoblotting assay in 50 cancerous and corresponding non-cancerous tissue specimens. Also, COX-2 expression was detected by an immunohistochemical method in 55 paraffin-embedded gastric adenocarcinoma tissues. Results: Of the 50 carcinoma tissue samples analyzed, 38 (76.0%) had overexpression of COX-2 as compared to the paired non-cancerous specimens. The overexpression of COX-2 (91.7%) was more prevalent in tumors with sizes of >5 cm than those (61.5%) of ≤5 cm (p < 0.05). COX-2 overexpression was higher in tumors with >6 metastatic nodes compared to those with ≤6 metastatic nodes (100.0 vs. 61.3%, p < 0.01). The rate of COX-2 overexpression in non-signet ring cell carcinoma was significantly higher compared with signet ring cell carcinoma (84.1 vs. 16.7%, p < 0.05). The rate of COX-2 overexpression (86.8 or 90.9%) in patients with a cancer invasion depth of pT3 + pT4 or with stage III + IV was significantly higher than that (41.7 or 47.1%) in patients with pT1 + pT2 or with stage I + II (both p < 0.01). Furthermore, consistent with the results at the protein and mRNA levels, immunohistochemical stain indicated that COX-2 protein was overexpressed in 39 of 55 (70.9%) carcinomas, and the 5-year survival rate (25.6%) for patients with COX-2 overexpression seemed better than that (50.0%) of patients without overexpression, though the difference was not significant (p < 0.05). Conclusion: Our results indicate that COX-2 may play a role in the development of gastric cancer and its overexpression is associated with lymphatic metastasis, tumor invasion and differentiation of gastric carcinoma.

Comparative Classification and Grading of Helicobacter pylori Gastritis in Patients with Gastric Cancer and Patients with Functional Dyspepsia

Background: It has previously been shown that corpus-dominant grade and activity of Helicobacter pylori gastritis in combination with intestinal metaplasia in the antrum or corpus are risk markers for the development of stomach cancer. If one point is scored for each of these three parameters, a gastric cancer risk index is obtained that permits prediction of the risk of gastric cancer developing on the soil of H. pylori gastritis. The aim of the present study was to evaluate the accuracy of the gastric cancer risk index based on a large number of patients compared with dyspeptic controls. Methods: In 415 biopsied patients with gastric carcinoma, biopsy specimens taken from the antrum and corpus were investigated retrospectively. From this group of patients, 244 patients positive for H. pylori were compared with 244 sex- and age-matched H. pylori -infected patients with functional dyspepsia. Results: H. pylori gastritis was detected in 395 carcinoma patients (95.2%). The 244 sex- and age-matched patients significantly more frequently had corpus-dominant H. pylori gastritis (compared with NUD controls). The incidence of intestinal metaplasia was also significantly increased. For a gastric cancer risk index score of 3 points (i.e. corpus pronounced grade and activity of gastritis, and intestinal metaplasia in antrum or corpus), a sensitivity of 93% and a specificity of 85% for the presence of gastric carcinoma can be calculated. Conclusion: Using the proposed risk index, the topographic grading of H. pylori gastritis in the antrum and corpus enables the diagnosis of a 'risk gastritis' to be made.

Synergistic promoting effects of Helicobacter pylori infection and high-salt diet on gastric carcinogenesis in Mongolian gerbils.

Helicobacter pylori (Hp) infection and high‐salt diet administration are both considered to be important factors in gastric carcinogenesis in man. To investigate the interaction of these two factors on gastric carcinogenesis, an experimental study of the carcinogenesis model was performed. Mongolian gerbils were treated with 20 ppm of N‐methyl‐N‐nitrosourea (MNU) in their drinking water for alternate weeks for a total of 5 weeks' exposure (groups 1, 2, 3 and 4) or were maintained as controls (groups 5, 6, 7 and 8). At week 11, the animals were inoculated with Hp (groups 1, 2, 5 and 6) or the vehicle alone (groups 3, 4, 7 and 8), and after week 12, animals were fed a 10% high salt diet (groups 1, 3, 5 and 7) or the control diet (groups 2, 4, 6 and 8). At week 50, the incidence of adenocarcinomas in group 1 (32.1%, 6 well‐differentiated, 2 poorly‐differentiated adenocarcinomas, and one signet‐ring cell carcinoma) was significantly higher than in groups 3 (0%) (P<0.005) and 4 (0%) (P<0.01). The incidence of adenocarcinomas in group 2 (11.8%, one well‐differentiated adenocarcinoma, and one signet‐ring cell carcinoma) was also higher than in groups 3 and 4. A high‐salt diet enhanced the effects of Hp infection on gastric carcinogenesis, and these two factors acted synergistically to promote the development of stomach cancers. Moreover, Hp infection promoted gastric carcinomas more than the high‐salt diet.

Suppressive effects of garlic extract on Helicobacter pylori-induced gastritis in Mongolian gerbils

Helicobacter pylori infection is intimately involved in stomach cancer development and recent epidemiological studies have indicated that the consumption of allium vegetables reduces the risk of gastric neoplasia. Therefore, in the present study, we investigated the effect of a garlic extract on H. pylori-induced gastritis in Mongolian gerbils. Garlic extract was fed to animals at doses of 1, 2 and 4% in the diet from 4 h after H. pylori inoculation until the end of the experiment, at week 6. With the administration of garlic extract, H. pylori-induced gastritis in animals was decreased in a dose-dependent manner, and significantly so at 4%. The numbers of hemorrhagic spots in the glandular stomach and the microscopic score for gastritis were significantly reduced from 19.2±15.6 and 5.9±0.8 in control gerbils to 8.1±11.2 and 4.2±1.5, respectively, by 4% garlic extract treatment. The stomach wet weight (1.04±0.22 g) of control gerbils was also reduced by 4% garlic extract (0.86±0.18 g). However, the number of viable H. pylori was not changed by the garlic extract treatment. The above observations indicated that garlic extract might be useful as an agent for prevention of H. pylori-induced gastritis, leading to reduction in the risk of gastric cancer.

Dendritic cell appearance and differentiation during early and late stages of rat stomach carcinogenesis.

Dendritic cell appearance and differentiation during early and late stages of rat stomach carcinogenesis were studied in the pyloric mucosa. Young male rats were given drinking water with or without N‐methyl‐N′‐nitro‐N‐nitrosoguanidine (MNNG; 100 nig/liter) for 14 days. Use of competitive RT‐PCR and northern blotting showed that MNNG exposure induced 3‐to 4–fold greater expression of the genes for integrin β7 and integrin αE2 (identical with antigen OX–62, a dendritic cell marker), as well as three cytokines, IL–4, GM‐CSF and TNFα, in the stomach pyloric mucosa of resistant Buffalo rats compared to sensitive ACI rats. These genes were minimally expressed in control animals. The results confirm the appearance of dendritic cells in the target pyloric mucosa and suggest the possibility that dendritic cell differentiation and maturation are induced by various cytokines, at least in Buffalo rats. Competitive RT‐PCR showed expression of integrin αE2 and β7, MHC class II‐associated invariant chain (Ii), MHC class II, B7–1, CD28, GM‐CSF and TNFα genes in all 12 examined stomach adenocarcinomas and adenomas induced in male Lewis and WKY rats with 30 weeks' MNNG exposure, suggesting the presence of dendritic cells in tumors. OX–62 staining and western blotting for OX–62 also confirmed the presence of dendritic cells in tumors. However, the population of dendritic cells in tumors was less than that in the pyloric mucosa after 14 days' MNNG exposure. The present results suggest that immune defense involving dendritic cells is marshaled from the very early initiation stage during rat stomach cancer development, but is downgraded in developed tumors.

HOGG1 Ser(326)Cys polymorphism and modification by environmental factors of stomach cancer risk in Chinese.

Oxidative stress is involved in many types of DNA damage, e.g., resulting in 8-hydroxyguanine adducts. Since a human counterpart exists for the yeast gene OGG1 (hOGG1) encoding an enzyme that repairs 8-hydroxyguanine, its polymorphism, Ser(326)Cys, might have potential as a genetic marker for cancer susceptibility. To investigate its association with stomach cancer risk and possible interactions with environmental factors, we conducted a case-control study of 101 stomach cancer cases and 198 controls using PCR-single-strand conformation polymorphism and a questionnaire approach. The proportional distribution of the Cys/Cys alleles did not differ between stomach cancer cases and controls, but subgroup analyses revealed that a frequent drinking habit elevated the odds ratio (OR) for stomach cancer in Cys/Cys compared to Ser/Ser and Ser/Cys carriers. The ORs with frequent consumption of pickled vegetables and meat tended to be higher in Cys/Cys than in Ser/Ser and Ser/Cys carriers, these interactions being on the borderline of statistical significance. Our findings suggest that the hOGG1 Ser(326)Cys polymorphism may alter the impact of some environmental factors on stomach cancer development. For confirmation, an additional study with a larger number of subjects is now required.

Glutathione- S-transferases M1 (GSTM1) and GSTT1 genotype, smoking, consumption of alcohol and tea and risk of esophageal and stomach cancers: a case-control study of a high-incidence area in Jiangsu Province, China

To evaluate interactions between lifestyle factors and glutathione- S-transferases M1 (GSTM1) and GSTT1 genotypes with reference to development of esophageal and stomach cancers, we conducted a case-control study of 141 cases of esophageal cancer, 153 cases of stomach cancer and 223 population-based controls in Huaian City of Jiangsu Province, China. GSTM1 and GSTT1 genotypes were identified by multiplex polymerase chain reaction. The GSTM1 null genotype was associated with an increased odds ratio for esophageal cancer (2.17, 95% confidence interval=1.35–3.50), but not for stomach cancer. A combined effect was also observed between smoking and the GSTM1 null genotype with regard to esophageal risk. Tea drinking was a protective factor for both cancers, its effect being independent of the GSTT1 and GSTM1 genotypes. These findings suggest the GSTM1 polymorphism is involved in the susceptibility to esophageal cancer development, and tea consumption reduces the risk of esophageal and stomach cancers.

Active and passive smoking and the risk of stomach cancer, by subsite, in Canada

This study assessed the influence of active and passive smoking on the risk of stomach cancer by subsite. Mailed questionnaires were used to obtain information on 1171 newly diagnosed histologically confirmed stomach cancer cases and 2207 population controls between 1994 and 1997 in eight Canadian provinces. Data were collected on socio-economic status, lifestyle and passive smoking status. Odds ratios (OR) and 95% confidence intervals (95% CI) were derived by logistic regression. Compared with those who had never smoked, there was strongly increased risk for ex- and current smokers among subjects with cardial stomach cancer. For men with cardial cancer, the adjusted ORs were 1.9 (95% CI 1.2-3.0) and 2.6 (95% CI 1.6-4.3) for ex-smokers and current smokers, respectively, with a similar pattern among women. Among men, the adjusted ORs were lower for subsites of stomach cancer other than cardia. These findings suggest that active and passive smoking may play an important role in the development of cardial stomach cancer.

Seventh Japanese–German workshop on molecular and cellular aspects of carcinogenesis

Seventh Japanese–German workshop on molecular and cellular aspects of carcinogenesis

The gastrointestinal tract: A major site of antioxidant action?

Diets rich in fruits and vegetables delay the onset of many age-related diseases, and contain a complex mixture of antioxidants (including ascorbate, carotenoids, vitamin E and other phenolics such as the flavonoids). However, diet also contains pro-oxidants, including iron, copper, H2O2, haem, lipid peroxides and aldehydes. Nitrite is frequently present in diet, leading to generation of reactive nitrogen species in the stomach. In considering the biological importance of dietary antioxidants, attention has usually focussed on those that are absorbed through the gastrointestinal tract into the rest of the body. In the present paper we develop the argument that the high levels of antioxidants present in certain foods (fruits, vegetables, grains) and beverages (e.g. green tea) play an important role in protecting the gastrointestinal tract itself from oxidative damage, and in delaying the development of stomach, colon and rectal cancer. Indeed, carotenoids and flavonoids do not seem to be as well absorbed as vitamins C and E. Hence their concentrations can be much higher in the lumen of the GI tract than are ever achieved in plasma or other body tissues, making an antioxidant action in the GI tract more likely. Additional protective mechanisms of these dietary constituents (e.g. effects on intercellular communication, apoptosis, cyclooxygenases and telomerase) may also be important.

Seventh Japanese-German workshop on molecular and cellular aspects of carcinogenesis

Seventh Japanese-German workshop on molecular and cellular aspects of carcinogenesis

Helicobacter pylori infection on the risk of stomach cancer and chronic atrophic gastritis.

Helicobacter pylori infection is associated with gastric adenocarcinoma. However, the mechanisms of this interaction are still unclear. This study was conducted to explore the effects of H. pylori infection on early and late stage gastric carcinogenesis. This study included 134 patients with adenocarcinoma of the stomach (ACS), 67 patients with chronic atrophic gastritis (CAG), and 65 normal controls recruited at Memorial Sloan-Kettering Cancer Center (MSKCC) from November 1, 1992 to November 1, 1994. Epidemiologic data were collected by a modified National Cancer Institute Health Habits History Questionnaire. H. pylori infection was diagnosed by pathological evaluation. Risk factors were analyzed using logistic regression. The odds ratio (OR) associated with H. pylori infection was 10.4 [95% confidence interval (CI): 2.6-41.6] for CAG and 11.2 (95% CI: 2.5-50.3) for gastric cancer in comparison with normal controls, with adjustment for pack-years of smoking, alcohol drinking, body mass index, total caloric intake, dietary fat and fiber intake, and Barrett's esophagus. But H. pylori infection was not associated with risk of stomach cancer when patients with stomach cancer were compared with patients with CAG (OR = 0.6, 95% CI: 0.3-1.3) after controlling for potential confounding variables. This association was persistent when only patients with both gastric cancer and chronic gastritis were considered as cases and patients with CAG were considered as controls (OR = 0.7, 95% CI: 0.3-2.0) in the multivariate analysis. Our results suggest that H. pylori infection may be involved in the early stage of development of CAG, but not in the development of stomach cancer from CAG, and indicate that strategies for prevention of stomach cancer should target the early stage to eliminate H. pylori infection in high-risk populations.