[Show abstract][Hide abstract] ABSTRACT: Stomach carcinogenesis involves mucosal and luminal changes that favor spontaneous disappearance of Helicobacter pylori. Therefore, the association between the infection and cancer risk might typically be underestimated. As acquisition of the infection almost invariably occurs before adulthood, the serostatus at age 16-40 should best reflect the lifetime occurrence of the infection. We therefore conducted a case-control study nested within a historic cohort of about 400,000 individuals who donated sera before age 40 to either of two large Swedish Biobanks between 1968 and 2006, and whose records were linked to complete nationwide registers. For each stomach adenocarcinoma case occurring at least 5 years after serum donation 2 controls were selected matched on age, sex and year of donation and biobank. Serum immunoglobulin G antibodies against H. pylori cell-surface antigens (Hp-CSAs) were measured with an enzyme-linked immunosorbent assay and antibodies against CagA with an immunoblot assay. Conditional logistic regression models were used to estimate odds ratios (ORs) for stomach adenocarcinoma among H. pylori infected relative to uninfected. We confirmed 59 incident cases of stomach adenocarcinoma (41 non-cardia tumors) during follow-up. ORs for non-cardia stomach adenocarcinoma among subjects with Hp-CSA antibodies (regardless of CagA serostatus), antibodies against CagA (regardless of Hp-CSA serostatus), and antibodies to both, relative to those who were seronegative to both, were 17.1 (95% confidence interval [CI] 4.0-72.9), 10.9 (95% CI 3.2-36.9), and 48.5 (95% CI 5.8-407.4), respectively. H. pylori infection is a much stronger risk factor for non-cardia stomach adenocarcinoma than initially realized. However, further studies are needed to answer whether it is a necessary cause, as the possibility of misclassification of H. pylori status could not be ruled out in our study.
[Show abstract][Hide abstract] ABSTRACT: Circulating pepsinogens can indicate atrophic gastritis, a precursor of gastric cancer. We tested the association between gastric cancer and plasma pepsinogens and antibodies against Helicobacter pylori in a case-control study nested in a prospective cohort.
We selected 141 gastric cancer cases and 282 incidence-density sampled controls. Plasma concentrations of pepsinogens 1 and 2 were measured using ELISA kits, and anti-H. pylori antibodies were measured using a kit specific to Chinese strains. Associations were estimated using conditional logistic regression models adjusted for potential confounders.
Gastric cancer subjects were more likely to be anti-H. pylori positive than controls, 97 vs 92%. A plasma pepsinogen 1 (PG1) concentration <50 ng ml(-1) (15% of cases) was associated with a significantly increased risk of gastric cancer (OR 4.23; (95% CI: 1.86-9.63), whereas a plasma pepsinogen 2 (PG2) concentration >6.6 ng ml(-1) (75% of cases) was also associated with a significantly increased risk of gastric cancer (OR 3.62; (95% CI: 1.85-7.09). We also found that the PG1 : 2 ratio had a nearly linear association with gastric cancer risk.
Lower plasma PG1 : 2 ratios are associated with a higher risk of gastric cancer. Furthermore, it appears that circulating pepsinogens 1 and 2 may be independently associated with the risk of gastric cancer.
Full-text · Article · Mar 2011 · British Journal of Cancer
[Show abstract][Hide abstract] ABSTRACT: MUC1, MUC5AC, and MUC6 are main constituents of the mucus barrier in the stomach, which protects the underlying epithelium from acid, proteases, mechanical trauma, and pathogenic microorganisms. Accumulating evidence implicates potential roles of MUC1, MUC5AC, and MUC6 genetic variation in the development of stomach cancer.
We evaluated the relationship between common genetic variations in these genes and stomach cancer risk, using an LD-based tagSNP approach in a population-based case-control study conducted in Warsaw, Poland, during 1994-1996. We genotyped 6, 8, and 14 tagSNPs in MUC1, MUC5AC, and MUC6 genes, respectively, among 273 cases newly diagnosed with stomach cancer and 377 controls.
Each of the six tagSNPs tested across the MUC1 region showed statistically significant associations with an increased risk of stomach cancer. Carriers of the haplotype ACTAA rare alleles of rs4971052, rs4276913, rs4971088, rs4971092, and rs4072037 had a nearly doubled risk (OR = 1.93, 95% CI = 1.49-2.48) compared to the referent haplotype GTAAG. Out of the eight tagSNPs across MUC5AC region, only minor allele of rs868903 was significantly associated with an increased risk of stomach cancer (OR = 1.80, 95% CI = 1.22-2.63).
Overall, our data provide evidence that some common variations in MUC1 and MUC5AC genes contribute to an elevated risk of stomach cancer. Further studies are needed to confirm these novel findings.
Full-text · Article · Nov 2009 · Cancer Causes and Control
[Show abstract][Hide abstract] ABSTRACT: Helicobacter pylori, a known risk factor of gastric cancer, rarely colonize the deeper portion of normal gastric glands, where the mucus is rich in alpha-1,4-linked N-acetylglucosamine capped O-glycans, that strongly inhibit H. pylori growth in vitro.
We investigated the association between genetic variation in the O-glycan transferase encoding gene (a4GnT) and H. pylori infection and gastric cancer risk using a Polish population-based case-control study (273 gastric cancer patients and 377 controls).
A haplotype at the rs2622694-rs397266 locus was associated with H. pylori infection, with the A-A haplotype associated with a higher risk compared with the most frequent G-G haplotype (odds ratio 2.30; 95% confidence interval 1.35-3.92). The association remained significant after correction for multiple tests (global p value: nominal 0.002, empirical 0.045). Neither this haplotype nor the tagSNPs were associated with overall gastric cancer risk.
a4GnT genetic variation may be relevant to H. pylori infection, but not to gastric cancer risk.
[Show abstract][Hide abstract] ABSTRACT: Helicobacter pylori (H. pylori) infection stimulates the production of interleukin (IL)-1 beta, a pro-inflammatory cytokine and suppressor of gastric acid secretion. As both inflammation and hypochlorhydria, which might facilitate proximal colonization of H. pylori and other bacterial species alike, have been implicated in gastric carcinogenesis, much attention has been directed to functional genetic polymorphisms that affect the production of IL-1 beta. The purpose of this study was to clarify the role of these polymorphisms.
We analysed a population-based, case-control study in 5 Swedish counties and a hospital-based, case-control study conducted in 8 Swedish hospitals, with a total of 351 gastric cancer cases and 539 controls. The IL1B-31, IL1B-511 and IL1B+3954 biallelic polymorphisms were genotyped using pyrosequencing. The variable number of tandem repeats (VNTR) polymorphism of IL1-RN was analysed using polymerase chain reaction (PCR) followed by gel electrophoresis. Relative risks were estimated by odds ratios with 95% confidence intervals, derived from unconditional logistic regression.
The risk of gastric cancer was unrelated to genotype in all of the studied polymorphic loci, and the absence of any association was confirmed in both the population-based and hospital-based case-control studies. Analyses confined to histological subtypes (intestinal or diffuse) and site-specific tumours (cardia or distal stomach), as well as analyses stratified by H. pylori infection status and family history of gastric cancer, did not reveal any significant increases or decreases in risk.
Our results do not lend support to the hypothesis that human genetic polymorphisms related to the production of IL-1 beta are associated with the risk of gastric cancer.
No preview · Article · Dec 2008 · Scandinavian Journal of Gastroenterology
[Show abstract][Hide abstract] ABSTRACT: The incidence of gastric cancer is two-fold to three-fold greater in men than in women. We investigated the reasons for this discrepancy by evaluating the impact of female reproductive factors on gastric cancer risk in the Japan Public Health Center-based Prospective Study. Among the 44,453 women enrolled, 368 cases of gastric cancer were newly diagnosed during follow-up from 1990 to 2004. The influence of female reproductive factors on risk was estimated using a multivariable Cox proportional hazards model after adjustment for potential confounders. Participants were stratified by menopause and gastric cancer status and further subdivided by histological type and anatomic subsite. No statistically significant association between female reproductive factors and gastric cancer risk was seen in general. Compared with those in late menarche (> or =15), however, women in early menarche (< or =12) had a close to 50% decreased risk of stomach cancer (hazard ratio 0.65, 95% confidence interval 0.43-0.98; P trend <0.01). Similar results were obtained in subgroup analyses categorized by histological subtype and anatomic subsite. Although early estrogen exposure may have some protective effect, female reproductive factors may have no substantial influence on gastric cancer development.
No preview · Article · Aug 2008 · European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP)
[Show abstract][Hide abstract] ABSTRACT: Fruits and vegetables have been suggested to confer protection against diseases such as cancer through the effects of antioxidants, often represented by carotenoids. We investigated the impact of carotenoids, retinol and tocopherol on gastric cancer development in a large nested case-control study among Japanese with known Helicobacter pylori infection status. A total of 36 745 subjects aged 40-69 in the Japan Public Health Center-based Prospective Study who responded to the baseline questionnaire and provided blood samples in 1990-1995 were followed until 2004. Plasma levels of carotenoids in 511 gastric cancer cases and 511 matched controls were measured by high-performance liquid chromatography. Odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated using conditional logistic regression models. Plasma level of beta-carotene was inversely associated with the risk of gastric cancer (compared with the lowest quartile: OR = 0.63, 95% CI = 0.31-0.75; OR = 0.48, 95% CI = 0.31-0.75 and OR = 0.46, 95% CI = 0.28-0.75, for quartile 2, 3 and 4, respectively, P(trend) < 0.01). Inverse associations were evident in men for alpha-carotene (P(trend) = 0.04) and beta-carotene (P(trend) < 0.01), but not in women, who had relatively higher plasma levels compared with men. We found no statistically significant association between plasma levels of lutein/zeaxanthin, lycopene, retinol, alpha- or gamma-tocopherol and gastric cancer risk. Our findings suggest that those who have very low plasma levels of alpha-carotene and beta-carotene are at a higher risk of gastric cancer.