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BackgroundEvidence from epidemiological studies on the role of tea drinking in gastric cancer risk remains inconsistent. We aimed to investigate and quantify the relationship between tea consumption and gastric cancer in the Stomach cancer Pooling (StoP) Project consortium.MethodsA total of 9438 cases and 20,451 controls from 22 studies worldwide were included. Odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) of gastric cancer for regular versus non-regular tea drinkers were estimated by one and two-stage modelling analyses, including terms for sex, age and the main recognised risk factors for gastric cancer.ResultsCompared to non-regular drinkers, the estimated adjusted pooled OR for regular tea drinkers was 0.91 (95% CI: 0.85-0.97). When the amount of tea consumed was considered, the OR for consumption of 1-2 cups/day was 1.01 (95% CI: 0.94-1.09) and for >3 cups/day was 0.91 (95% CI: 0.80-1.03). Stronger inverse associations emerged among regular drinkers in China and Japan (OR: 0.67, 95% CI: 0.49-0.91) where green tea is consumed, in subjects with H. pylori infection (OR: 0.68, 95% CI: 0.58-0.80), and for gastric cardia cancer (OR: 0.64, 95% CI: 0.49-0.84).ConclusionOur results indicate a weak inverse association between tea consumption and gastric cancer.

BackgroundThe causal pathway between high education and reduced risk of gastric cancer (GC) has not been explained. The study aimed at evaluating the mediating role of lifestyle factors on the relationship between education and GC METHODS: Ten studies with complete data on education and five lifestyle factors (smoking, alcohol drinking, fruit and vegetable intake, processed meat intake and salt consumption) were selected from a consortium of studies on GC including 4349 GC cases and 8441 controls. We created an a priori score based on the five lifestyle factors, and we carried out a counterfactual-based mediation analysis to decompose the total effect of education on GC into natural direct effect and natural indirect effect mediated by the combined lifestyle factors. Effects were expressed as odds ratios (ORs) with a low level of education as the reference category.ResultsThe natural direct and indirect effects of high versus low education were 0.69 (95% CI: 0.62-0.77) and 0.96 (95% CI: 0.95-0.97), respectively, corresponding to a mediated percentage of 10.1% (95% CI: 7.1-15.4%). The mediation effect was limited to men.ConclusionsThe mediation effect of the combined lifestyle factors on the relationship between education and GC is modest. Other potential pathways explaining that relationship warrants further investigation.

BackgroundThe role of allium vegetables on gastric cancer (GC) risk remains unclear.MethodsWe evaluated whether higher intakes of allium vegetables reduce GC risk using individual participant data from 17 studies participating in the "Stomach cancer Pooling (StoP) Project", including 6097 GC cases and 13,017 controls. Study-specific odds ratios (ORs) were pooled using a two-stage modelling approach.ResultsTotal allium vegetables intake was inversely associated with GC risk. The pooled OR for the highest versus the lowest study-specific tertile of consumption was 0.71 (95% confidence interval, CI, 0.56-0.90), with substantial heterogeneity across studies (I2 > 50%). Pooled ORs for high versus low consumption were 0.69 (95% CI, 0.55-0.86) for onions and 0.83 (95% CI, 0.75-0.93) for garlic. The inverse association with allium vegetables was evident in Asian (OR 0.50, 95% CI, 0.29-0.86) but not European (OR 0.96, 95% CI, 0.81-1.13) and American (OR 0.66, 95% CI, 0.39-1.11) studies. Results were consistent across all other strata.ConclusionsIn a worldwide consortium of epidemiological studies, we found an inverse association between allium vegetables and GC, with a stronger association seen in Asian studies. The heterogeneity of results across geographic regions and possible residual confounding suggest caution in results interpretation.

BackgroundHelicobacter pylori is the most important risk factor for non-cardia gastric cancer (NCGC); however, the magnitude of the association varies across epidemiological studies. This study aimed to quantify the association between H. pylori infection and NCGC, using different criteria to define infection status.MethodsA pooled analysis of individual-level H. pylori serology data from eight international studies (1325 NCGC and 3121 controls) from the Stomach Cancer Pooling (StoP) Consortium was performed. Cases and controls with a negative H. pylori infection status were reclassified as positive considering the presence of anti-Cag A antibodies, gastric atrophy, or advanced stage at diagnosis, as available and applicable. A two-stage approach was used to pool study-specific adjusted odds ratios (OR), and 95% confidence intervals (95% CI). A meta-analysis of published prospective studies assessing H. pylori seropositivity in NCGCs was conducted.ResultsThe OR for the association between serology-defined H. pylori and NCGC was 1.45 (95% CI: 0.87-2.42), which increased to 4.79 (95% CI: 2.39-9.60) following the reclassification of negative H. pylori infection. The results were consistent across strata of sociodemographic characteristics, clinical features and lifestyle factors, though significant differences were observed according to geographic region-a stronger association in Asian studies. The pooled risk estimates from the literature were 3.01 (95% CI: 2.22-4.07) for ELISA or EIA and 9.22 (95% CI: 3.12-27.21) for immunoblot or multiplex serology.ConclusionThe NCGC risk estimate from StoP based on the reclassification of H. pylori seronegative individuals is consistent with the risk estimates obtained from the literature. Our classification algorithm may be useful for future studies.

BackgroundPrior epidemiologic studies on the association between diabetes and gastric cancer risk provided inconclusive findings, while traditional, aggregate data meta-analyses were characterized by high between-study heterogeneity.ObjectiveTo investigate the association between type 2 diabetes and gastric cancer using data from the 'Stomach Cancer Pooling (StoP) Project', an international consortium of more than 30 case-control and nested case-control studies, which is large and provides harmonized definition of participants' characteristics across individual studies. The data have the potential to minimize between-study heterogeneity and provide greater statistical power for subgroup analysis.MethodsWe included 5592 gastric cancer cases and 12 477 controls from 14 studies from Europe, Asia, North America, and South America in a two-stage individual-participant data meta-analysis. Random-effect models were used to estimate summary odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) by pooling study-specific ORs.ResultsWe did not find an overall association between diabetes and gastric cancer (pooled OR = 1.01, 95% CI, 0.94-1.07). However, the risk of cardia gastric cancer was significantly higher among individuals with type 2 diabetes (OR = 1.16, 95% CI, 1.02-1.33). There was no association between diabetes and gastric cancer risk in strata of Helicobacter pylori infection serostatus, age, sex, BMI, smoking status, alcohol consumption, fruit/vegetable intake, gastric cancer histologic type, and source of controls.ConclusionThis study provides additional evidence that diabetes is unrelated to gastric cancer overall but may be associated with excess cardia gastric cancer risk.

BackgroundGastric cancer (GC) is the fifth most common type of cancer and the fourth most common cause of cancer-related mortality. Although the risk of GC and peptic ulcer disease (PUD) is known to be increased by H. pylori infection, evidence regarding the direct relationship between PUD and GC across ethnicities is inconclusive. Therefore, we investigated the association between PUD and GC in the Stomach cancer Pooling (StoP) consortium.MethodsHistory of peptic ulcer disease was collected using a structured questionnaire in 11 studies in the StoP consortium, including 4106 GC cases and 6922 controls. The two-stage individual-participant data meta-analysis approach was adopted to generate a priori. Unconditional logistic regression and Firth's penalized maximum likelihood estimator were used to calculate study-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between gastric ulcer (GU)/duodenal ulcer (DU) and risk of GC.ResultsHistory of GU and DU was thoroughly reported and used in association analysis, respectively, by 487 cases (12.5%) and 276 controls (4.1%), and 253 cases (7.8%) and 318 controls (6.0%). We found that GU was associated with an increased risk of GC (OR = 3.04, 95% CI: 2.07-4.49). No association between DU and GC risk was observed (OR = 1.03, 95% CI: 0.77-1.39).ConclusionsIn the pooled analysis of 11 case-control studies in a large consortium (i.e., the Stomach cancer Pooling (StoP) consortium), we found a positive association between GU and risk of GC and no association between DU and GC risk.

Background: Inconsistent findings have been reported regarding the relationship between dietary iron intake and the risk of gastric cancer (GC). Methods: We pooled data from 11 case-control studies from the Stomach Cancer Pooling (StoP) Project. Total dietary iron intake was derived from food frequency questionnaires combined with national nutritional tables. We derived the odds ratios (ORs) and 95% confidence intervals (CIs) for quartiles of dietary iron through multivariable unconditional logistic regression models. Secondary analyses stratified by sex, smoking status, caloric intake, anatomical subsite and histological type were performed. Results: Among 4658 cases and 12247 controls, dietary iron intake was inversely associated with GC (per quartile OR 0.88; 95% CI: 0.83-0.93). Results were similar between cardia (OR = 0.85, 95% CI = 0.77-0.94) and non-cardia GC (OR = 0.87, 95% CI = 0.81-0.94), and for diffuse (OR = 0.79, 95% CI = 0.69-0.89) and intestinal type (OR = 0.88, 95% CI = 0.79-0.98). Iron intake exerted an independent effect from that of smoking and salt intake. Additional adjustment by meat and fruit/vegetable intake did not alter the results. Conclusions: Dietary iron is inversely related to GC, with no difference by subsite or histological type. While the results should be interpreted with caution, they provide evidence against a direct effect of iron in gastric carcinogenesis.

ObjectiveThis study aimed to evaluate and quantify the relationship between coffee and gastric cancer using a uniquely large dataset from an international consortium of observational studies on gastric cancer, including data from 18 studies, for a total of 8198 cases and 21 419 controls.MethodsA two-stage approach was used to obtain the pooled odds ratios (ORs) and the corresponding 95% confidence intervals (CIs) for coffee drinkers versus never or rare drinkers. A one-stage logistic mixed-effects model with a random intercept for each study was used to estimate the dose-response relationship. Estimates were adjusted for sex, age and the main recognized risk factors for gastric cancer.ResultsCompared to never or rare coffee drinkers, the estimated pooled OR for coffee drinkers was 1.03 (95% CI, 0.94-1.13). When the amount of coffee intake was considered, the pooled ORs were 0.91 (95% CI, 0.81-1.03) for drinkers of 1-2 cups per day, 0.95 (95% CI, 0.82-1.10) for 3-4 cups, and 0.95 (95% CI, 0.79-1.15) for five or more cups. An OR of 1.20 (95% CI, 0.91-1.58) was found for heavy coffee drinkers (seven or more cups of caffeinated coffee per day). A positive association emerged for high coffee intake (five or more cups per day) for gastric cardia cancer only.ConclusionsThese findings better quantify the previously available evidence of the absence of a relevant association between coffee consumption and gastric cancer.

The consumption of processed meat has been associated with noncardia gastric cancer, but evidence regarding a possible role of red meat is more limited. Our study aims to quantify the association between meat consumption, namely white, red and processed meat, and the risk of gastric cancer, through individual participant data meta-analysis of studies participating in the "Stomach cancer Pooling (StoP) Project". Data from 22 studies, including 11,443 cases and 28,029 controls, were used. Study-specific odds ratios (ORs) were pooled through a two-stage approach based on random-effects models. An exposure-response relationship was modeled, using one and two-order fractional polynomials, to evaluate the possible nonlinear association between meat intake and gastric cancer. An increased risk of gastric cancer was observed for the consumption of all types of meat (highest vs. lowest tertile), which was statistically significant for red (OR: 1.24; 95% CI: 1.00-1.53), processed (OR: 1.23; 95% CI: 1.06-1.43) and total meat (OR: 1.30; 95% CI: 1.09-1.55). Exposure-response analyses showed an increasing risk of gastric cancer with increasing consumption of both processed and red meat, with the highest OR being observed for an intake of 150 g/day of red meat (OR: 1.85; 95% CI: 1.56-2.20). This work provides robust evidence on the relation between the consumption of different types of meat and gastric cancer. Adherence to dietary recommendations to reduce meat consumption may contribute to a reduction in the burden of gastric cancer.

Phenolic compounds may exert a favorable effect on the risk of several cancer types, including gastric cancer (GC). However, selected polyphenol classes have not been adequately investigated in relation to GC. The aim of this study is to evaluate the association between the intake of polyphenols in relation to GC risk. We used data from the Stomach cancer Pooling (StoP) Project, including 10 studies from six countries (3471 GC cases and 8344 controls). We carried out an individual participant data pooled analysis using a two-stage approach. The summary odds ratios (ORs) of GC for each compound, and the corresponding 95% confidence intervals (95% CI), were computed by pooling study specific ORs obtained through multivariate logistic regression, using random effect models. Inverse associations with GC emerged for total polyphenols (OR = 0.67, 95% CI = 0.54-0.81, for the highest versus lowest quartile of intake), total flavonoids (OR = 0.73, 95% CI = 0.55-0.90), anthocyanidins (OR = 0.74, 95% CI = 0.56-0.92), flavanols (OR = 0.77, 95% CI = 0.66-0.88), flavanones (OR = 0.57, 95%CI = 0.44-0.69), total phenolic acids (OR = 0.75, 95%CI = 0.55-0.94), and hydroxybenzoic acids (OR = 0.73, 95%CI = 0.57-0.89). Results were consistent across strata of age, sex, social class, and smoking habit. Suggestive inverse associations were also found for flavonols (OR = 0.76, 95%CI = 0.51-1.01) and hydroxycinnamic acids (OR = 0.82, 95%CI = 0.58-1.06). Further investigations from longitudinal data are needed to confirm this association.

Anatomic subsite risk factors for gastric cancer differ substantially, and subsite-specific distribution of risk factors (such as Helicobacter pylori) can vary by race and ethnicity and neighborhood socioeconomic status (nSES). We examined differences in gastric cancer incidence by subsite, stratified by race and ethnicity and nSES, using Surveillance Epidemiology and End Results Program 2000-2014 data for 77,881 incident gastric cancer cases (cardia, n = 23,651; non-cardia, n = 35,825; overlapping or unspecified, n = 18,405). Compared with non-Hispanic whites, cardia cancer multivariable-adjusted incidence rate ratios were 35%-47% lower for blacks, Hispanics, Asian or Pacific Islanders, and American Indian or Alaska Natives; conversely, non-cardia incidence rate ratios were 1.7- to 3.9-fold higher for blacks, Hispanics, Asian or Pacific Islanders, and American Indian or Alaska Natives. Higher adjusted incidence rate ratios with decreasing nSES (lowest vs highest nSES quintile) were observed for all gastric (1.3-fold) and non-cardia (1.3-fold) cancers but were borderline significant for cardia cancers (1.1-fold). In conclusion, non-cardia cancer incidence is higher in minorities and varies by nSES, but cardia cancer incidence is higher in non-Hispanic whites and does not vary substantially by nSES. Clarifying reasons for higher cardia risk in non-Hispanic whites and targeted interventions to address non-cardia cancer risk in minorities could lessen the burden of gastric cancer.

Integrin αvβ3 has been implicated as a driver of aggressive and metastatic disease, and is upregulated during glioblastoma progression. Here, we demonstrate that integrin αvβ3 allows glioblastoma cells to counteract senescence through a novel tissue-specific effector mechanism involving recruitment and activation of the cytoskeletal regulatory kinase PAK4. Mechanistically, targeting either αvβ3 or PAK4 led to emergence of a p21-dependent, p53-independent cell senescence phenotype. Notably, glioblastoma cells did not exhibit a similar requirement for either other integrins or additional PAK family members. Moreover, αvβ3/PAK4 dependence was not found to be critical in epithelial cancers. Taken together, our findings established that glioblastomas are selectively addicted to this pathway as a strategy to evade oncogene-induced senescence, with implications that inhibiting the αvβ3-PAK4 signaling axis may offer novel therapeutic opportunities to target this aggressive cancer.

Tumour cells, with stem-like properties, are highly aggressive and often show drug resistance. Here, we reveal that integrin α(v)β₃ serves as a marker of breast, lung and pancreatic carcinomas with stem-like properties that are highly resistant to receptor tyrosine kinase inhibitors such as erlotinib. This was observed in vitro and in mice bearing patient-derived tumour xenografts or in clinical specimens from lung cancer patients who had progressed on erlotinib. Mechanistically, α(v)β₃, in the unliganded state, recruits KRAS and RalB to the tumour cell plasma membrane, leading to the activation of TBK1 and NF-κB. In fact, α(v)β₃ expression and the resulting KRAS-RalB-NF-κB pathway were both necessary and sufficient for tumour initiation, anchorage independence, self-renewal and erlotinib resistance. Pharmacological targeting of this pathway with bortezomib reversed both tumour stemness and erlotinib resistance. These findings not only identify α(v)β₃ as a marker/driver of carcinoma stemness but also reveal a therapeutic strategy to sensitize such tumours to RTK inhibition.

Background: The initial step for noncardia gastric carcinogenesis is atrophic gastritis, driven by either Helicobacter pylori infection or autoimmunity. In recent decades, the prevalence rates of these two major causes declined and increased, respectively, with changes in Western lifestyles. We therefore assessed gastric cancer incidence trends for US race/ethnic groups, 1995-2013.Methods: Age-standardized rates (ASRs) from 45 North American Association of Central Cancer Tumor Registries were summarized by estimated annual percentage change (EAPC) and 95% confidence intervals (CIs). Age period cohort models supplemented standard descriptive techniques and projected future trends.Results: There were 137 447 noncardia cancers in 4.4 billion person-years of observation. Among non-Hispanic whites, the ASR was 2.2 per 100 000 person-years, with an EAPC of -2.3% (95% CI = -2.0% to -2.6%). Notwithstanding this overall decline, EAPCs rose 1.3% (95% CI = 0.6% to 2.1%) for persons younger than age 50 years and fell -2.6% (95% CI = -2.4% to -2.9%) for older individuals. These converging trends manifested a birth cohort effect more pronounced among women than men, with incidence among women born in 1983 twofold (95% CI = 1.1-fold to 3.6-fold) greater than those born in 1951. Age interaction was also statistically significant among Hispanic whites, with slightly increasing vs decreasing EAPCs for younger and older individuals, respectively. Incidence declined regardless of age for other races. Current trends foreshadow expected reversals in both falling incidence and male predominance among non-Hispanic whites.Conclusions: Dysbiosis of the gastric microbiome associated with modern living conditions may be increasing risk of autoimmune gastritis and consequent noncardia cancer. The changing face by age and sex of gastric cancer warrants analytical studies to identify potential causal mechanisms. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Interleukin-1β plays an important role in inflammation and gastric physiology. Polymorphisms of the IL1B gene have been associated with gastric atrophy and increased cancer risk, especially in Helicobacter pylori-infected subjects. The aim of this study was to evaluate the relationship between IL1B and IL1 receptor antagonist gene polymorphisms and the risk of multifocal atrophic gastritis in African Americans and Caucasians. METHODS: Genomic DNA was extracted from gastric biopsies of 269 adult outpatients (172 African Americans and 97 Caucasians) undergoing diagnostic upper gastrointestinal endoscopy. Histological diagnosis was evaluated according to the updated Sydney System and H. pylori status was assessed by Steiner silver stain. Polymorphisms of the IL1B gene (−511, −31, and +3954) and the IL1 receptor antagonist were investigated by PCR-RFLP. Logistic regression models were used to identify variables associated with multifocal atrophic gastritis in terms of odds ratios and 95% confidence intervals. RESULTS: Considering subjects with normal histology and nonatrophic gastritis as controls, a significant association was found between IL1B+ 3954T carrier and multiatrophic gastritis (OR 2.23, 95% CI 1.28, 3.88). Analyses stratified by ethnic group demonstrated similar associations in both African Americans (OR 2.23, 95% CI 1.14, 4.37) and Caucasians (OR 2.04, 95% CI 0.74, 5.65). A positive but not significant association was found between the allele 2 of the IL1RN and the presence of multifocal atrophic gastritis. The remaining proinflammatory polymorphisms were not associated with this precancerous lesion. CONCLUSIONS: Our results suggest that the presence of IL1B+ 3954T allele is a risk marker for multifocal atrophic gastritis in the population studied. [ABSTRACT FROM AUTHOR]