Interleukin-1B gene promoter variants are associated with an increased risk of gastric cancer in a Chinese population

Studies suggest that IL-1beta (encoded by IL-1B gene) is a pro-inflammatory cytokine and potent inhibitor of gastric acid secretion, which is proposed as a key determinant in gastric carcinogenesis. Two potentially functional polymorphisms (C-31T and T-511C) in the IL-1B promoter were suggested to be correlated with alteration of Helicobacter pylori infection and IL-1beta expression and therefore may be associated with risk of gastric cancer. To test the hypothesis that these two polymorphisms are associated with gastric cancer risk, we performed a case-control study of 280 histologically confirmed gastric cancer patients and 258 age, sex frequency-matched cancer-free controls in a Chinese population. Multivariate logistic regression analyses revealed that the risks (adjusted odds ratio [OR] and 95% confidence interval [CI]) associated with the IL-1B variant genotypes were 1.64 (95% CI, 1.01-2.66) for -31TT and 1.52 (95% CI, 0.91-2.54) for -511CC, respectively, compared with their wild-type homozygotes. The risks were significantly more evident in individuals with H. pylori infection (adjusted OR, 2.14; 95% CI, 1.13-4.06 for -31TT; adjusted OR, 2.00; 95% CI, 1.02-3.89 for -511CC), which was consistent with the biological effects of IL-1beta. When we used the haplotype analyses and assumed the IL-1B -31T and -511C as risk alleles, no synergistic effect was found between these two loci. These findings indicate that these two IL-1B promoter variants may contribute to the risk of developing gastric cancer in the Chinese population, especially in individuals with H. pylori infection.     

Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype.

BACKGROUND: Polymorphisms in the interleukin 1beta gene (IL-1B-31T/C and IL-1B-511C/T single nucleotide changes) and in the interleukin 1 receptor anatagonist gene (IL-1RN2 variable number of tandem repeats) have been studied with respect to gastric cancer susceptibility. Available data support an aetiologic role of these genetic variants in the presence of concomitant Helicobacter pylori infection. Their contribution without H. pylori infection is still an open field of investigation. MATERIALS AND METHODS: IL-1B and IL-1RN polymorphisms were investigated in 138 H. pylori-negative Italian patients with sporadic gastric cancer and 100 H. pylori-negative controls. Unconditional regression with odd ratios (OR) and 95% confidence intervals (CI), haplotype and linkage disequilibrium analyses were used to investigate the association of the polymorphisms with disease. RESULTS: In all gastric cancer cases, carriers of the homozygous IL-1B-511T/T genotype showed a significant risk for the development of the disease (OR 3.2 with 95% CI 1.27-8.05). In cases with intestinal-type gastric cancer, however, both IL-1B-511T and IL-1RN2 alleles were associated with disease. In this subgroup, the odds ratio for carriers of both IL-1B-511T and IL-1RN2 was 6.49 (95% CI 2.07-20.4). Haplotype analysis supported the aetiologic contribution of these alleles in gastric cancer of the intestinal histotype. CONCLUSIONS: In conclusion, IL-1B-511T and IL-1RN2 may contribute to intestinal gastric cancer risk in the absence of concomitant H. pylori infection. In this setting, future epidemiologic studies should consider dietary habits and exposure to carcinogens interacting with pro-inflammatory host genotypes.     

Smoking Behavior and Risk of Helicobacter Pylori Infection,Gastric Atrophy and Gastric Cancer in Japanese

Although many studies have shown that smoking is an established risk factor for gastric cancer, relatively few studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastric carcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastric cancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi Cancer Center Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched 1,742 cancer free controls were sampled, from whom those without serum samples or without information about smoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgG antibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smoking status was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as the OR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- and sex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62 (95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for current smokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased risk of gastric carcinogenesis from gastric atrophy, but had little influence on H. pylori infection or gastric atrophy development.     

Smoking Behavior and Risk of Helicobacter Pylori Infection,Gastric Atrophy and Gastric Cancer in Japanese

Although many studies have shown that smoking is an established risk factor for gastric cancer, relativelyfew studies have investigated on which step smoking has effects in Helicobacter pylori (H. pylori) related gastriccarcinogenesis. In this study we investigated the association of smoking with risk of three steps leading to gastriccancer: H. pylori infection, gastric atrophy, and gastric cancer. Among the participants who visited Aichi CancerCenter Hospital from year 2001 to 2005, 583 cases diagnosed as gastric cancer and age-and sex-frequency-matched1,742 cancer free controls were sampled, from whom those without serum samples or without information aboutsmoking habit were excluded, leaving 576 cases and 1,599 controls eligible for the analyses. Anti- H. pylori IgGantibody and serum pepsinogens (PG) were measured to detect H. pylori infection and gastric atrophy. Smokingstatus was asked by a self-administered questionnaire. The odds ratio (OR) of H. pylori infection, as well as theOR of gastric atrophy among the H. pylori seropositive controls was not significant for smokers. The age- andsex-adjusted OR of gastric cancer was significantly elevated relative to the subjects with gastric atrophy: OR=1.62(95% confidence interval (CI), 1.19-2.22; P=0.002) for ever smokers and 2.52 (1.75-3.64; P<0.001) for currentsmokers, relative to never smokers. This study revealed that smoking behavior contributed to the increased riskof gastric carcinogenesis from gastric atrophy, and had little influence on H. pylori infection or gastric atrophydevelopment.     

幽门螺杆菌致胃癌相关因素研究进展

幽门螺杆菌已被世界卫生组织国际癌症研究机构列为胃癌的第一类致癌物.虽然全世界超过半数人口感染幽门螺杆菌,但最终发展为胃腺癌者仅占感染人群的1％～3％.近年来的观点认为,胃癌是一种感染性疾病,毒力因子、宿主遗传因素和环境因素共同影响着幽门螺杆菌的致胃癌作用.其中,毒力因子在致胃癌初始发生的相关免疫反应中起重要作用,宿主遗传因素可影响炎性反应的严重度并可能加重胃黏膜损伤,而环境因素则可能改变幽门螺杆菌感染的临床结局.本文就幽门螺杆菌致胃癌相关因素的最新研究进展进行综述.     

Role of interleukin polymorphisms in gastric cancer: "Pros and cons"

Helicobacter pylori (H. pylori) infection is the leading cause of gastric cancer worldwide. Infection with this bacterium causes a chronic active immune response that persists for the life of the host. The combination of bacterial factors, environmental insults, and the host immune response drives the initiation and progression of mucosal atrophy, metaplasia, and dysplasia toward GC. Among the host factors, IL-1 gene cluster polymorphisms (IL-1B encoding IL-1β and IL-1RN encoding IL-1ra, its naturally occurring receptor antagonist) play a decisive role in modulating the risk of developing hypochlorhydria, gastric atrophy and GC in the presence of H. pylori infection. In particular, one single nucleotide polymorphism in the IL-1B promoter (IL-1B-511C⁄T), and the short allele of a 86-bp variable number of tandem repeats polymorphism in the IL-1RN second intron (IL-1RN*2) are associated with an increased risk for GC. However this hypothesis is still to be fully confirmed. This review focuses on the divergent results obtained by several epidemiological and functional in vitro and in vivo studies and show that IL-1 genotyping has still no role in the clinical management of patients with H. pylori infection.     

Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population

Helicobacter pylori infection and the cytokine-mediated inflammatory responses play important roles in gastric cancer pathogenesis. This case control study was conducted to assess the association between genetic polymorphisms in interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor alpha (TNFalpha), which are involved in H.pylori infection, and risk of gastric cancer. Genotypes were determined by PCR-based denaturing high-performance liquid chromatography analysis and direct DNA sequencing in 250 incident cases with gastric cancer and 300 controls recruited in Northern China. Serum levels of anti-H.pylori IgG and IgA were measured by enzyme-linked immunosorbent assay to indicate H.pylori infection. We found that the risk of gastric cancer was significantly elevated in subjects with the IL-8-251 AA [adjusted odds ratio (OR) 2.02; 95% confidence interval (CI) 1.27-3.21] or IL-10-1082 G (OR 2.02; 95% CI 1.24-3.29) or TNFalpha-308 AG (OR 1.81; 95% CI 1.04-3.14) genotype. An elevated risk of gastric cancer was observed in subjects with H.pylori infection and the IL-8-251 AA genotype (OR 2.54; 95% CI 1.38-4.72) or IL-10-1082 G carriers (OR 2.62; 95% CI 1.42-4.93). An increased OR was also suggested for IL-1B-31 and TNFalpha-238, but confidence intervals included the null value. There was no evidence of increased risk for any of the other polymorphisms evaluated. These findings suggest that genetic polymorphisms in IL-8, IL-10 and TNFalpha may play important roles in developing gastric cancer in the Chinese population.     

DNMT3a rs1550117 Polymorphism Association with Increased Risk of Helicobacter pylori Infection

Background: DNA methyltransferase-3a (DNMT3a) plays significant roles in embryogenesis and the generationof aberrant methylation in carcinogenesis. This study aimed to investigate associations between single nucleotidepolymorphisms (SNPs) of the DNMT3a gene and risk of Helicobacter pylori infection, gastric atrophy and gastriccancer. Methods: The subjects comprised 447 patients with gastric cancer; 111 individuals with gastric atrophyand 961 healthy controls. Two SNPs (rs1550117 and rs13420827) of the DNMT3a gene were genotyped by Taqmanassay. DNMT3a expression was analyzed in cancer tissues from 89 patients by tissue microarray technique. Oddsratio (ORs) and 95% confidence intervals were calculated by multivariate logistic regression. Results: Amonghealthy controls, risk of H.pylori infection was significantly higher in subjects with the rs1550117 AA genotype,compared to those with GG/AG genotypes of DNMT3a [OR=2.08, (95%CI: 1.02-4.32)]. However, no significantcorrelation was found between the two SNPs and risk of developing gastric atrophy or gastric cancer. In addition,no increase in DNMT3a expression was observed in the gastric cancer with H.pylori infection. Conclusions:This study revealed that DNMT3a rs1550117 polymorphism is significantly associated with an increased risk ofH. pylori infection, but did not support any evidence for contributions of DNMT3a rs1550117 and rs13420827to either gastric atrophy or gastric cancer. The biological roles of DNMT3a polymorphisms require furtherinvestigation.     

Genetic predisposition to Helicobacter pylori-induced gastric precancerous conditions

Gastric cancer is the most common malignancy of the gastrointestinal tract in East Asian populations and the second most frequent cause of cancer-related mortality in the world. While previous studies have investigated the genetic factors involved in gastric carcinogenesis, there still exist relatively few studies that have investigated the genetic traits associated with the risk of gastric precancerous conditions. In this paper we will review the biology and genetic polymorphisms involved in the genesis of gastric precancerous conditions reported to date and discuss the future prospects of this field of study. The associations of gastric precancerous conditions with polymorphisms in the cytotoxin-associated gene A-related genes (e.g. PTPN11 G/A at intron 3, rs2301756), those in the genes involved in host immunity against Helicobacter pylori (H. pylori) infection (e.g. TLR4 +3725G/C, rs11536889) or polymorphisms of the genes essential for the development/ differentiation of the gastric epithelial cells (e.g. RUNX3 T/A polymorphism at intron 3, rs760805) have been reported to date. Genetic epidemiological studies of the associations between H. pylori-induced gastric precancerous conditions and other gene polymorphisms in these pathways as well as polymorphisms of the genes involved in other pathways like oxidative DNA damage repair pathways would provide useful evidence for the individualized prevention of these H. pylori-induced gastric precancerous conditions.     

IL-17A G197A and C1249T polymorphisms in gastric carcinogenesis

Interleukin 17A (IL-17A) is a critical cytokine involved in inflammatory diseases and inflammation-associated cancers. Increasing case-control studies have implicated crucial roles of IL-17A single nucleotide polymorphisms (G197A and C1249T) in gastric carcinogenesis, but providing inconclusive findings. The present study is aimed to estimate the association of IL-17A G197A and C1249T polymorphisms with gastric cancer risk by pooling all available publications. A comprehensive literature search in PubMed, Embase, Web of Science, China National Knowledge Infrastructure (CNKI), and Wanfang databases was performed for eligible publications from their inception up to May 5, 2014. The pooled odds ratios (ORs) with corresponding 95 % confidence intervals (CIs) were calculated to estimate the effect of IL-17A polymorphisms on gastric carcinogenesis. Stratified analysis by ethnicity, Helicobacter pylori (H. pylori) infection, and smoking status were also conducted. All analyses were performed by using the Stata 12.0 software. There were five case-control studies with 2,774 cases and 3,162 controls and two case-control studies with 620 cases and 1,123 controls on the susceptibility of IL-17A G197A and C1249T polymorphisms to gastric cancer, respectively. Significant association was observed between IL-17A G197A polymorphism and gastric cancer risk, particularly among Asians. The status of H. pylori infection and smoking did not influence this association. In addition, the IL-17A C1249T polymorphism did not confer a risk effect on gastric carcinogenesis. The pooled results were not materially altered by sensitivity analysis. We firstly show that the polymorphism of IL-17A G197A but not C1249T is a risk factor for gastric cancer.     

Cancer risk to the gastric corpus in Japanese, its correlation with interleukin-1beta gene polymorphism (+3953*T) and Epstein-Barr virus infection

Polymorphisms of interleukin-1 (IL-1) genes have been reported to modify the risk of gastric carcinoma (GC) in Caucasians. The significance of IL-1beta gene polymorphisms was evaluated in Japanese GC patients with or without infection of Helicobacter pylori and Epstein Barr virus (EBV) with special reference to the topographic features of GC. IL-1beta gene polymorphisms at positions -511 and +3953 were evaluated by PCR-RFLP and a penta-allelic polymorphism of IL-1RA by PCR in healthy controls (n = 103) and GC (n =140; corpus 95, antrum 45). EBV-infection was determined in the neoplastic tissues by EBER1 in situ hybridization, and H. pylori infection in nonneoplastic gastric mucosa by PCR targeting of the H. pylori urease A gene. GC consisted of EBV-associated (n = 24) and EBV-negative (n = 116) patients, whereas H. pylori infection was positive in 130 cases. Among IL-1beta gene polymorphisms, genotype IL-1beta+3953 C/T was more frequent in the EBV-negative (21%) and corpus GC (23%) patients, compared to the controls (10%), respectively, although there was no genotype IL-1beta+3953 T/T in either group. Thus, the effect of IL-1beta+3953 T was statistically significant in logistic regression models adjusted for age in EBV negativity (odds ratio [OR] 2.27, 95% confidence interval [CI] 1.02-5.05) and in the corpus GC (2.70, 1.19-6.12) with highest OR 3.55 (1.54-8.23) in EBV-negative corpus GC. There was no significant influence of IL-1 gene polymorphism in EBV-associated GC, but it occurred predominantly in the corpus (24/24) compared to EBV-negative GC (71/116) (p = 0.00002). There was no correlation between H. pylori infection and IL-1 gene polymorphism in GC. The cancer risk of the gastric corpus in Japanese is influenced by IL-1beta+3953 polymorphisms. On the other hand, the risk of EBV-associated GC, which occurs predominantly in the corpus, is not influenced by this pro-inflammatory polymorphism.     

Interleukin-1beta gene in esophageal, gastric and colorectal carcinomas

Interleukin (IL)-1 gene polymorphisms are associated with development of gastric atrophy and with increased risk of gastric carcinoma. A -31C to T base transition in the promoter region of this gene is involved in carcinogenic changes within the stomach, especially in Helicobacter pylori infected individuals. We examined association between IL-1 locus polymorphisms and risk of esophageal, gastric and colorectal carcinomas in Japanese patients with H. pylori infection. IL-1B and IL-1RN polymorphisms were analyzed in 136 controls, 75 patients with esophageal carcinoma, 186 patients with gastric carcinoma, 69 patients with colorectal carcinoma, and 18 patients with ulcerative colitis (UC). For IL-1B-511 and -31 polymorphisms were determined by fluorescence-based polymerase chain reaction single-strand conformation polymorphism analysis. For IL-1 receptor antagonist gene (IL-1RN), penta-allelic variable number of tandem repeats (VNTR) was determined by PCR-standard agarose gel electrophoresis. For gastric carcinoma, IL-1B-511 heterozygotes (OR, 0.48; 95% CI, 0.3-0.9; p=0.0115) and T carriers (OR, 0.52; 95% CI, 0.3-1.0; p=0.0185) had a significantly reduced risk of carcinoma. For colorectal carcinoma, IL-1B-511 heterozygotes (OR, 0.34; 95% CI, 0.2-0.7; p=0.0028) and T carriers (OR, 0.43; 95% CI, 0.2-0.9; p=0.0015) had a significantly low risk of carcinoma. No significant difference was observed in the frequencies of IL-1B-31C/T and IL-1RN genotypes between controls and the esophageal carcinoma patients. Our results shows that IL-1B-511C/T and T carrier state may indicate less risk for gastric and colorectal carcinoma in the Japanese population.     

Development of gastric cancer associated with Helicobacter pylori infection

Helicobacter pylori infection is associated with histological gastritis, gastric atrophy, gastric cancer and mucosa-associated lymphoid tissue lymphoma in the stomach. However, gastric cancer only develops in a minority of infected individuals. Such clinical diversity is caused by variations in the interactions between H. pylori pathogenicity, host susceptibility, and environmental factors. Based on evidence from three prospective epidemiological studies, the International Agency for Research on Cancer and the World Health Organization (IARC/WHO) concluded in 1994 that H. pylori has a causal linkage to gastric carcinogenesis and is a definite carcinogen in humans. Two large-scale, prospective, epidemiological studies have recently been reported in Japan and have confirmed that H. pylori infection constitutes a high risk factor for the development of gastric cancer, at least in males. In order to obtain evidence that eradication of H. pylori leads to a reduction in the occurrence of gastric cancer, reversibility of precancerous lesions, gastric atrophy or intestinal metaplasia should be proven after eradication treatment. A biopsy specimen from the lesser curvature of the corpus is the most sensitive for evaluating the regression of gastric atrophy on histology, and the evaluation needs be conducted at least 13 months after treatment. In a Mongolian gerbil model with or without low-dose chemical carcinogens, it has been demonstrated that H. pylori can lead to the development of gastric cancer. Experimental studies have elucidated that virulence factors of H. pylori interact with gastric epithelial cell signaling related to carcinogenesis. The cag pathogenicity island (cagPAI) is a major virulence gene cluster; it encodes the type IV secretion machinery system forming a cylinder-like structure. The CagA protein is translocated into target cells via this secretion system and induces a hummingbird phenotype, a growth factor-like effect. The other gene products are probably translocated into target cells and accelerate cellular proliferation and apoptosis. The molecular mechanism of the interaction between H. pylori and gastric epithelial cells may provide a new strategy for effective prevention of the development of gastric cancer induced by H. pylori infection.     

Association of polymorphism of IL-10 and TNF-A genes with gastric cancer in Korea

We performed this study to determine the role of polymorphisms of the IL-10 and TNF-alpha promoter genes in the carcinogenesis/pathogenesis of gastric cancer (GC) and peptic ulcer diseases (PUD) in Korea. A total of 232 patients with gastric diseases and 120 healthy controls were included. Polymorphisms of IL-10-1082/-592 gene and TNF-A-308 gene were genotyped by PCR-RFLP. There were no differences in genotypes and allele frequencies of IL-10 and TNF-A polymorphism between study group with GC or PUD and control group. In addition, there were no differences in genotypic frequencies according to H. pylori infection status, location of GC, and histologic type of GC. In conclusion, IL-10-1082/-592 and TNF-A-308 genetic polymorphisms may not be the important contributors to GC in Korea.     

Allele 2 of the interleukin-1 receptor antagonist gene is associated with early gastric cancer.

PURPOSE: In advanced gastric cancer (tumor stages T2-T4), associations with polymorphisms of the interleukin-1 (IL-1) gene cluster have been made. In early-stage gastric cancer, which we defined as adenocarcinoma confined to the mucosa or submucosa (stage T1), the role of host genetic susceptibility remains to be determined. PATIENTS AND METHODS: Eighty-eight patients with early-stage gastric cancer (stage T1, 77 positive for Helicobacter pylori) and 145 controls were genotyped for polymorphisms in the IL-1 gene cluster and the tumor necrosis factor alpha (TNF-A) gene. Statistical analysis was performed using the chi2 test and the Fisher's exact test, respectively. RESULTS: The homozygous genotype IL-1RN*2/2 of the IL-RN gene was strongly associated with early-stage gastric cancer (P < .0001), whereas further associations with the IL-1 gene cluster were not observed. A weak association of the TNF-A-308A allele with the diffuse type of early-stage gastric cancer, and an association with a composite of two or three proinflammatory polymorphisms, which predispose to increased production of the proinflammatory cytokines IL-1beta and TNF-alpha, could also be demonstrated. CONCLUSION: The genotype IL-1RN*2/2 seems to be associated with early-stage gastric cancer. As opposed to advanced-stage gastric cancer, further proinflammatory cytokine polymorphisms were not associated independently, but might act in combination and mirror early steps of gastric carcinogenesis in hosts colonized by Helicobacter pylori. However, these findings await confirmation in future trials and should be underscored by gene expression studies.     

Helicobacter pylori infection-negative gastric cancer in Japanese hospital patients: incidence and pathological characteristics

We used Helicobacter pylori sero-positivity and mucosal atrophy as detected by the serum pepsinogen method to identify H. pylori infection-negative gastric cancer patients with or without atrophy. One hundred and six of 748 (14.2%) primary gastric cancer patients were infection-negative by a serum antibody detection system. Further, 121 (16.2%) of the 748 were negative for gastric mucosal atrophy by the pepsinogen method, of whom 15/748 (2.0%) were H. pylori-negative by pepsinogen I level (>70 ng/mL) and pepsinogen I/II ratio (>3.0). Twenty-seven of 782 (3.6%) gastric cancer patients were H. pylori-negative by antibodies and severe atrophy as determined by pepsinogen I level (<30 ng/mL) and pepsinogen I/II ratio (<2.0). H. pylori-negative gastric cancer patients with severe atrophy likely had a previous infection. These results indicate that the actual number of H. pylori-negative patients is 2.0% at minimum and 10.6% (14.2% minus 3.6%) at maximum in the general Japanese population. Five of 15 (33%) cases displaying neither anti-H. pylori antibodies nor atrophy were intestinal-type and 10 (67%) were diffuse-type adenocarcinomas. Thirteen surgical patients with primary gastric cancer displaying neither antibodies nor mucosal atrophy were further analyzed for pathological and phenotypic characteristics. The mucin phenotype was divided into four gastric, five gastric and intestinal, two intestinal and two null types, independent of histological classification. Intestinal phenotype elements were detected by Cdx2 immunohistochemical methods in nine of 13 (70%) cases examined. We conclude that a small fraction of gastric cancer patients displayed multifactorial carcinogenesis without H. pylori infection, indicating that gastric cancer risk still exists in the absence of H. pylori infection, at an incidence of 2.0% at minimum and 10.6% at maximum in the general Japanese population.     

No Association of an SDHC Gene Polymorphism with Gastric Cancer

It is widely reported that reactive oxygen species (ROS) cause apotosis and carcinogenesis. Marked infiltration ofactivated leukocyte and enhanced production of ROS appear to occur in the gastric mucosa infected with Helicobacterpylori (H. pylori). The previous studies reported that the mutation of the succinate dehydrogenase subunit C (SDHC)gene caused the increase in superoxide anion (O2-) and oxidative stress. To extend these findings, we epidemiologicallyinvestigated the association of a SDHC polymorphism at 3’-untranslated region of exon 6 (JST173800) with H. pyloriinfection, gastric atrophy and gastric cancer risk in Japan. The subjects consisted of 454 health checkup examineeswithout a history of cancer and 202 gastric cancer patients. The SDHC polymorphism was not associated with H.pylori infection seropositivity, gastric atrophy, and cancer risk in this study. Although the polymorphism at the 3’-untranslated region could be hypothesized to be functional, this study did not demonstrate any significant associationof the SDHC gene polymorphism with gastric atrophy and cancer.     

No Association between the CDX2 G543C Polymorphism and Risk of Gastric Atrophy and Cancer

Ectopic expression of CDX2 in the stomach is closely associated with chronic Helicobacter pylori (H. pylori)infection and intestinal metaplasia. Whether CDX2 has tumor suppression or tumorigenesis potential remainsto be elucidated. In this study, we investigated the association between the CDX2 G543C polymorphism (silentmutation) and the risk for H. pylori-induced gastric atrophy and cancer as well as H. pylori infection, using 454Japanese subjects undergoing a health checkup and 202 gastric cancer patients. The frequency of the minor allelewas the same as previously reported in China, but different from that reported in England. CDX2 G543C wasnot associated with risk of H. pylori infection, gastric atrophy, or gastric cancer, although the point estimate fornon-cardiac differentiated gastric cancer as compared to controls with gastric atrophy was 2.22 (95%CI=0.17-29.4). In conclusion, our results indicate that the CDX2 G543C polymorphism is unlikely to affect the H. pyloriinfection-gastric atrophy-gastric cancer sequence.     

Association between serum pepsinogens and polymorphismof PTPN11 encoding SHP-2 among Helicobacter pylori seropositive Japanese

Helicobacter pylori (H. pylori) plays a crucial role in the development of gastric atrophy and cancer, and cagA-positive strains, which are universal in Japan, increase the risk of these outcomes substantially. The CagA protein is injected from attached H. pylori into gastric epithelial cells and undergoes Src-dependent tyrosine phosphorylation and activation of the eukaryotic phosphatase SHP-2. The CagA/SHP-2 interactions elicit cellular changes that increase the risk of carcinogenesis. We investigated the association of a frequent single nucleotide polymorphism (SNP; JST057927; G-to-A) in the PTPN11 gene that encodes SHP-2 with gastric atrophy and gastric cancer in Japan. Gastric atrophy was assessed by measuring serum pepsinogen I and II levels. The subjects comprised 454 healthy controls (126 males; mean age, 58.4) and 202 gastric cancer cases (134 males and 68 females; mean age, 66.7). All gastric cancer cases and 250 (55%) controls were H. pylori seropositive; 179 (89%) of the gastric cancer cases had gastric atrophy compared to 137 (55%) of the H. pylori seropositive controls (p < 0.001). Among HP seropositive controls compared to the common PTPN11 G/G genotype, the odds ratio of atrophy was nonsignificantly reduced with the G/A genotype (0.70; 95% CI = 0.39-1.25) and significantly reduced with the A/A genotype (0.09; 95% CI = 0.01-0.72). Lower risk for gastric atrophy had a gene-dose association with the A allele (p = 0.01, trend test). There was a clear deficiency of the A/A genotype in those with atrophy compared to those without (1 subject in the gastric atrophy group vs. 8 in the group without). Cancer cases differed from controls in frequencies of PTPN11 G/A genotype only because of a higher prevalence of atrophy among the cancer cases. The G/A SNP in the PTPN11 gene appears to be a risk factor for gastric atrophy in subjects infected with cagA-positive H. pylori. This may explain why only a proportion of CagA-positive individuals develop gastric atrophy and gastric cancer, even though infection with cagA strains is universal in Asian countries such as Japan. The functional consequences of the G/A polymorphism remain to be elucidated.     

Genetic differences in interleukin-1 betapolymorphisms among four Asian populations: an analysis of the Asian paradox between H. pylori infection and gastric cancer incidence

The prevalence of Helicobacter pylori infection is high among Asian populations, but the incidences of gastric cancer differ greatly among northern and southern Asian populations. Here, we studied histopathological findings in stomach tissue using an updated Sydney System and the frequencies of interleukin (IL)-1betapolymorphisms, thought to be associated with an increased risk of gastric cancer, in four Asian populations. Endoscopic-guided biopsies from three regions of the stomach and the -511 T-to-C polymorphism in the IL-1betagene were examined in 228 Japanese, 116 Chinese, 159 Thai and 83 Vietnamese patients with gastric diseases. H. pylori colonization, inflammation and activity were more severe in the Japanese and Thai populations than in the Chinese and Vietnamese populations and these scores were more antrum-predominant in the Thai and Vietnamese populations than in the Japanese and Chinese populations, with the most severe degree of atrophy and intestinal metaplasia occurring in the angulus region of the Japanese population. The IL-1betapolymorphisms did not differ among the four populations overall, but in cases with severe mucosal atrophy (pepsinogen I/II ratio <3.0), the CC polymorphism was dominant in the Japanese population and the TT+TC polymorphism was dominant in the Chinese population; no difference in C and T allele frequencies was found in the Thai and Vietnamese populations. In conclusion, the incidence of gastric cancer is extremely low, but the prevalence of H. pylori infection is high in the Thai population (Asian paradox). In the Thai population, the scores for corpus gastritis and intestinal metaplasia, which are associated with a high risk of gastric cancer, were low in comparison with the Japanese population. IL-1betapolymorphisms were correlated with mucosal atrophy in the Japanese and Chinese populations, but not in the Thai and Vietnamese populations.