Risk Of Gastric Cancer Development Research Articles

Cyclooxygenase-2 polymorphisms were associated with the risk of gastric cancer: evidence from a meta-analysis based on case–control studies

The associations between cyclooxygenase-2 (COX-2) polymorphisms (-765G>C, -1195G>A, and -587G>A) and risk of gastric cancer have been investigated, but the results were inconsistent. The aim of this study was to explore the associations between COX-2 polymorphisms and risk of gastric cancer using a meta-analytic method. We searched the databases of PubMed, Embase, and Wanfang (Chinese database) to identify the eligible studies. Odds ratio and 95 % confidence interval (OR and 95% CI) were used as effect size, and combined analyses were conducted using fixed- or random-effects model. Overall, ten studies for COX-2-765G>C, six studies for -1195G>A, and three studies for -587G>A were included in this study. The results for combined analysis for COX-2-765G>C indicated that C allele was significantly associated with increased risk of gastric cancer compared with G allele, especially for Asians (OR and 95 % CI: 1.58 (1.06-2.35), P(z-test) = 0.03, and P heterogeneity <0.01 for CC+GC vs. GG). In addition, the A allele of COX-2-1195G>A was also significantly associated with risk of gastric cancer compared with G allele (OR and 95 % CI: 1.20 (1.09-1.32), P(z-test) <0.001, and P(heterogeneity) = 0.82 for A carriers vs. G carriers). In contrast, the COX-2-587G>A polymorphism was not associated with risks of gastric cancer. In summary, this meta-analysis indicated that the COX-2-765G>C and -1195G>A polymorphisms were significantly associated with risk of gastric cancer development.

Sa1977 A Preliminary Longitudinal Assessment of Mutational Load in Patients With Barrett's Esophagus

INTRODUCTION: Chronic Atrophic Gastritis (CAG) is the most important independent risk condition for gastric cancer, histology being considered the gold standard for both diagnosis and follow up. The Operative Link for Gastritis Assessment (OLGA) is an innovative histological system proposed for staging atrophic gastritis in a prognostic view. GastroPanel (Biohit, Helsinki, Finland) is a serological kit for a non-invasive diagnosis of chronic atrophic gastritis (CAG), including serum pepsinogen I (PGI), pepsinogen II (PGII), gastrin-17 (G17) and IgG anti-Helicobacter pylori antibodies (IgG-Hp). Clinical practice is lacking of a non invasive instrument useful to predict and to follow the stage of atrophic gastritis. AIMS& METHODS: To evaluate correlation between GastroPanel and OLGA stage, in a cohort of dyspeptic patients referred from a primary care setting to our G.I. Unit Histological evaluation of gastric biopsies was performed in 125 pts (83 females, mean age 53 yrs). Atrophy was assessed according to the OLGA staging system. OLGA stages III and IV are considered at high risk for gastric cancer development. From each subject, a blood sample was taken for GastroPanel analysis. RESULTS: GastroPanel analysis showed that 79 pts (63,2%) have no gastritis, 22 pts (17,6%) a Hp-related chronic gastritis and 24 (19,2%) atrophic gastritis picture. Comparing GastroPanel results to the histological findings, 48 pts of the first group were confirmed normal at histology, 27 pts have an OLGA stage 0-II, 4 pts have an OLGA stage III, none stage IV. Among the patients with Hp-related gastritis, 1 pt results normal at the histological evaluation, 20 pts have an OLGA stage 0-II, 1 pt has an OLGA stage III; 6 out of the 24 pts with evidence of CAG at GastroPanel have an OLGA stage 0-II, 18 pts have an OLGA stage III-IV. The negative predictive value (NPV) of GastroPanel for CAG is 95,0%, being the positive predictive value (PPV) 75,0%. CONCLUSION: GastroPanel shows an high NPV to predict absence of atrophic gastritis. The relationship beetween GastroPanel and OLGA system seems to confirm the clinical performances of the test

Epigenetic Deregulations in Gastric Cancer

Abnormal functioning of many cellular processes such as cell cycle, DNA repair, angiogenesis and cell-cell adhesion has been reported in all types of cancer. In the context of cancer, genes responsible to sustain integrity of the cells can be categorized into tumor suppressor genes and oncogenes. In normal conditions, these genes maintain a state of equilibrium and imbalance of these two groups of genes leads to a malignant form of cells known as Cancer. Genetics and epigenetics are the two main mechanisms that regulate expression of these genes. Silencing of tumor suppressor genes has been observed in different cancer while, on the other hand, silent oncogenes are active in cancer and confer growth advantage to malignant cells as compared with the contemporary normal cells. Gastric cancer (GC), like other cancers, is a complex disease. Multiple factors including bacterial infection, dietary habits, smoking and genetic polymorphisms determine the risk for GC development. Epigenetic modifications have been attributed as an initial event in the development of GC. Here, we have summarized recent findings in the field of epigenetics which correlated with GC.

Helicobacter pylori: Gastric Cancer and Extragastric Intestinal Malignancies

The greatest challenge in Helicobacter pylori-related diseases continues to remain prevention of gastric cancer. New evidence supports the beneficial effect of H. pylori eradication not only on prevention of gastric cancer but also on the regression of preneoplastic conditions of the gastric mucosa. Concerning early detection of gastric cancer there are still no adequate means and there is urgent need to define appropriate markers, for example, by genome-wide research approaches. Currently, the best available method is the "serologic" biopsy based on pepsinogen I and the pepsinogen I/II ratio for identification of patients with severe gastric atrophy at increased risk for gastric cancer development. The treatment of early gastric cancer by endoscopic techniques can be performed safely and efficiently, but patients need meticulous follow-up for detection of metachronous lesions. In case of advanced disease, laparoscopically assisted surgical procedures are safe and favorable compared to open surgery. Two phase III trials support the role of adjuvant systemic treatment with different regimens. Unfortunately, there is still only slow progress in the development of palliative treatment regimens or modification of the existing therapy protocols. There is accumulating evidence for a role of H. pylori infection also in colorectal carcinogenesis. Seropositive individuals are at higher risk for the development of colorectal adenomas and consequently adenocarcinomas of this anatomical region. This phenomenon can partly be attributed to the increase of serum gastrin as response to atrophic changes of the gastric mucosa.

Effect Modification by Drinking Water Hardness of the Association Between Nitrate Levels and Gastric Cancer: Evidence from an Ecological Study

The objectives of this study were to (1) examine the relationship between nitrate levels in public water supplies and risk of death from gastric cancer and (2) determine whether calcium (Ca) and magnesium (Mg) levels in drinking water might modify the effects of nitrate on the risk of gastric cancer development. A matched cancer case-control study was used to investigate the relationship between the risk of death attributed to gastric cancer and exposure to nitrate in drinking water in Taiwan. All deaths due to gastric cancer in Taiwan residents from 2006 through 2010 were obtained from the Bureau of Vital Statistics of the Taiwan Provincial Department of Health. Deaths from other causes served as controls and were pair-matched to cancer cases by gender, year of birth, and year of death. Information on the levels of nitrate-nitrogen (NO3-N), Ca, and Mg in drinking water were collected from Taiwan Water Supply Corporation (TWSC). The municipality of residence for cancer cases and controls was presumed to be the source of the subject's NO3-N, Ca, and Mg exposure via drinking water. Relative to individuals whose NO3-N exposure levels were <0.38 ppm, the adjusted odds ratio (OR) and 95% confidence interval (CI) for gastric cancer occurrence was 1.16 (1.05–1.29) for individuals who resided in municipalities served by drinking water with a NO3-N exposure ≥0.38 ppm. There was apparent evidence of an interaction between drinking water NO3-N levels and low Ca and Mg intake via drinking water. Our findings showed that the correlation between NO3-N exposure and risk of gastric cancer development was influenced by Ca and Mg levels in drinking water. This is the first study to report effects modification by Ca and Mg intake from drinking water on the relationship between NO3-N exposure and risk of gastric cancer occurrence. Increased knowledge of the mechanistic interactions between Ca, Mg, and NO3-N in reducing risk of gastric cancer development will aid in public policy decisions and setting threshold standards.

First‐degree relatives of patients with early‐onset gastric carcinoma show even at young ages a high prevalence of advanced OLGA/OLGIM stages and dysplasia

First-degree relatives (FDRs) of early-onset gastric carcinoma (EOGC) patients are at increased risk of cancer development. OLGA/OLGIM (Operative Link on Gastritis/Intestinal Metaplasia Assessment) classifications have been proposed for the identification of individuals at high risk of gastric cancer development. To estimate the prevalence and severity of premalignant conditions and lesions in FDRs of EOGC patients. A case-control study was conducted encompassing 103 FDRs of EOGC patients (cases) and 101 age- and gender-matched controls, all submitted to upper GI endoscopy and OLGA and OLGIM used for staging as well as modified versions with exclusion of the biopsies from incisura angularis in the analysis. Helicobacter pylori infection was present in 82% of cases (P = 0.001). Atrophy was present in 70% of cases (OLGA stages I-IV). High-risk stages (III-IV) were identified only in cases (19%) (P < 0.001). Dysplasia was diagnosed only in cases (n = 7, P = 0.007). The application of OLGIM, modified OLGA and modified OLGIM classifications led to downgrade of stages in comparison with the original OLGA classification (27%, 15% and 30% respectively). In all classification systems, dysplastic lesions clustered (86%) in high-risk stages. FDRs of EOGC patients have, even at young ages, a high prevalence of H. pylori infection, high-risk OLGA and OLGIM stages and dysplasia. These patients should undergo accurate endoscopic observation with at least four biopsies in antrum and corpus to allow adequate staging and follow-up of premalignant conditions and lesions scored in high-risk stages, in accordance with international guidelines recently proposed.

Mo1565 Helicobacter pylori Infection and Development of Gastric Cancer a 10-Year Follow-up Population-Based Study in a High Incidence Area

Backgrounds & Aim: H. pylori (HP) infection is the most important etiology of gastric cancer (GC) in the world but it causes GC in only a minority of those infected .Eradication of HP can decrease the development of GC only in the subgroup of HP infected subjects without precancerous lesions. Strategies of HP eradication is still not well defined in countries with high mortality rates secondary to GC with almost universal HP infection in adults. The aim of the present study was to investigate the predictors of GC in an adult population with almost universal HP infection in an area with highest rate of gastric cancer in the world. Methods: 1011 healthy subjects 40 years and older, permanent residents of Ardabil and Meshkinshahr districts in northwest Iran, were randomly selected and enrolled in an endoscopic screening study during 2000 to 2001 year. Data on demographics and potential risk factors were collected using a well-structured questionnaire. Upper gastrointestinal endoscopy with multiple biopsy sampling was performed to detect HP infection and endoscopic precancerous lesions.Participants have been followed up until 2011. During followup period data on the occurrence of GC, mortality, and cause of death were obtained from cancer and death registries, and when neccessary by direct contacting to participants, and their families. The cumulative incidence and person-time incidence rate were calculated. The effect of other risk factors in addition to H. pylori infection on the risk of GC development were estimated by fitting multivariate hazard model using Cox proportional regression analysis, and were presented as hazard ratio (HR) and corresponding 96% confidence interval (95%CI). Results: During 10-year follow up, 36 participants (3.6%) developed GC yielding an incidence rate of 3.6 per 1000 person-years. The significant risk factors of GC included age over 50 (HR 4.8; 95%CI 1.4-16.2), a positive family history of stomach cancer (6.4; 3.1-13.1), smoking (5.7; 2.5-12.6), gastric atrophy (2.3; 1.0-5.1), intestinal metaplasia (4.5; 2.3-8.9) and presence of gastric ulcer (4.8; 1.9-11.5). Joint presence of precancerous lesion and one of the other risk factors significantly increased risk of stomach cancer as (46.5; 10.8-98.6) for a positive family history of stomach cancer; (27.6; 6.5-116.4) for smoking and (25.1; 16.3-105.3) for age>50. Conclusion: Combining the information on family history, lifestyle risk factors and the type of precancerous lesion may be helpful in order to identify high risk HP infected patients who need more intensive surveillance for early detection of GC. Key words: Stomach cancer, Precancerous lesions, Risk factors, H. pylori, Ardabil,Iran.

Gastric Precancerous lesions among Nigerians with Chronic Gastritis

To investigate the frequency of precancerous lesions in H. pylori gastritis in Nigerians Previously, the slides of all endoscopic gastroduodenal biopsies seen at the Pathology Department of Obafemi Awolowo University Teaching Hospital, Ile-Ife between 1994 and 2003 were reviewed and published. The current review examined interplay of intestinal metaplasia, glandular atrophy and epithelial dysplasia with H.pylori. The H.pylori, intestinal metaplasia and glandular atrophy were graded based on updated Sydney classification scheme while Vienna classification was used for dysplasia. Out of 1036 biopsies seen during the study period, 135 (13%) had associated precancerous lesions. Intestinal metaplasia was the commonest (9.2%), followed by severe atrophic gastritis (4.3%) and low grade dysplasia (0.7%) occurring either alone or in various combinations. Most of these lesions were seen in patients above 40 years of age and over 80% were H.pylori positive. Frequency of precancerous lesions is low among Nigerians with H.pylori gastritis. Intestinal metaplasia was the commonest lesion and was mostly type I with relatively low risk for gastric cancer development. The relatively high prevalence H.pylori infection among these cases could have resulted from repeated infection and most were localised to the corpus relative to the antral region where the precancerous lesions were seen.

Matrix metalloproteinase3 gene promoter polymorphisms and their haplotypes are associated with gastric cancer risk in eastern Indian population

Single nucleotide polymorphisms (SNPs) of matrix metalloproteinase3 (MMP3) promoter in the development and progression of gastric cancer of whole stomach has never been investigated in any population. We conducted a hospital-based case-control study to explore the MMP3 SNPs and their haplotypes with the risk of gastric cancer for the first time in eastern Indian population. A total of 218 gastric cancer patients and 175 healthy controls were genotyped for MMP3-1612 5A/6A (rs3025058) by PCR-RFLP and rechecked 10% by DNA sequencing. MMP3-707 A/G (rs522616) and MMP3-375 C/G (rs617819) were genotyped by DNA sequencing among 209 patients and 154 controls. MMP3-1612 5A6A genotype (P = 0.026, odds ratio (OR) = 1.756, confidence interval (CI) = 1.070-2.883), combined 5A5A and 5A6A genotype (P = 0.015, OR = 1.791, CI = 1.122-2.858) and 5A allele (P = 0.002, OR = 1.75, CI = 1.21-2.53) and; MMP3-707 GG genotype (P = < 0.0001; OR = 9.612; 95% CI = 3.403-27.147), combined GG and AG genotype (P = 0.001, OR = 2.201, CI = 1.385-3.498) and G allele (P = <0.0001, OR = 2.189, CI = 1.582-3.033) conferred significant risk for gastric cancer development. Also, tobacco addicted individuals with combined 5A5A and 5A6A genotype (P = 0.005, OR = 2.952, CI = 1.377-6.327) at -1612 position of MMP3 promoter displayed a higher risk to gastric cancer development. The genotypic combinations of all three MMP3 promoter polymorphisms and their haplotypes with increasing risk allele in a dose-dependent manner showed a potential risk for developing gastric cancer. The analyses suggested that the MMP3-707 G/G and MMP3-1612 5A/6A polymorphisms are potential independent predictors of gastric cancer risk development.

Diverse H. pylori strains, IL-10 promoter polymorphisms with high morbidity of gastric cancer in Hexi area of Gansu Province, China

In Hexi area of Gansu Province, people have a higher susceptibility of gastric cancer than people in the rest area of China. There is substantial geographic variation in the incidence of gastric cancer. In this article, the present author explored the roles of H. pylori infection and IL-10 promoter polymorphisms in development of gastric cancer in this area. A total of 304 participants were admitted to our study, and they were divided into two groups: control group and case group. Blood samples from all subjects were collected for gene extraction using DNA extraction kits. IL-10 polymorphisms were determined by SNaPshot Multiplex. To test H. pylori infection and its typing H. pylori antibody Immunoblotting Kits were used. This research suggested that environmental factor played an important role in the pathogenesis of gastric carcinoma in the area, H. pylori infection increased the risk of gastric cancer (OR = 2.612, 95% CI 1.636-4.170) and subject with H. pylori I-type positive was at significantly higher risk for progression to gastric cancer (OR = 4.712, 95% CI 2.656-8.537). For subjects with the ATA/GCC or GCC/GCC haplotype of the IL-10-1082/-819/-592 polymorphism relative to the ATA/ATA haplotype group, the risk of gastric cancer development was significantly increased. It has been demonstrated that the presence of IL-10-819 C alleles and IL-10-592 C alleles was associated with an increased risk for gastric cancer development in H. pylori-infected patients and IL-10 promoter polymorphisms and H. pylori have a synergistic effect on gastric cancer in Hexi population.

Gastric Cancer: Clinical Aspects, Epidemiology and Molecular Background

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.

Epigenetic regulation of microRNA-10b and targeting of oncogenic MAPRE1 in gastric cancer

MicroRNAs act as negative regulators of gene expression, and the altered expression of microRNAs by epigenetic mechanisms is strongly implicated in carcinogenesis. Here we report that the microRNA-10b gene (miR-10b) was silenced in gastric cancer cells by promoter methylation. In this study, using a methylation array and bisulfate pyrosequencing analysis, we found that miR-10b promoter CpGs were heavily methylated in gastric cancers. Clinicopathologic data showed that miR-10b methylation increased with patient age and occurred significantly more frequently in intestinal-type (28/44, 64%) than in diffuse-type (22/56, 39%) gastric cancers (P = 0.016). In addition, miR-10b methylation was also associated with an increase in expression of the oncogene that encodes microtubule-associated protein, RP/EB family, member 1 (MAPRE1; P = 0.004), which was identified as a potential miR-10b target. After 5-aza-2′-deoxycytidine treatment of gastric cancer cells, miR-10b methylation was significantly decreased, and expression of miR-10b and HOXD4, which is 1 kb downstream of miR-10b, was greatly restored. Moreover, decreased MAPRE1 expression coincided with increased miR-10b expression, suggesting that miR-10b targets MAPRE1 transcription. We also found that transfection with precursor miR-10b into gastric cancer cells dramatically decreased MAPRE1 mRNA and protein, resulting in a significant decrease in colony formation and cell growth rates. Thus, we show a tumor-suppressive role for miR-10b in gastric carcinogenesis. miR-10b methylation may be a useful molecular biomarker for assessing the risk of gastric cancer development, and modulation of miR-10b may represent a therapeutic approach for treating gastric cancer.

How to assess the severity of atrophic gastritis.

Atrophic gastritis, is the main consequence of long-standing Helicobacter pylori infection, and is linked to the development of gastric cancer. The severity of atrophic gastritis is related to the lifetime risk of gastric cancer development, especially in terms of its degree and extent of mucosal damage. Therefore, it is important for clinicians to assess the severity of atrophic gastritis, interfere with the disease progress, and reverse gastric mucosal atrophy. In the article, we demonstrated some methods (conventional endoscopy, modern endoscopic technology and noninvasive methods) that may help assess the severity of atrophic gastritis and select the reasonable treatment protocols.

M1179 Targeting Epidermal Growth Factor Receptor With Polyethylene Glycol: Applications for Digestive Cancer Prevention

Introduction: H. pylori transactivates the epidermal growth factor (EGFR) and induces extracellular-signal related kinase (ERK) phosphorylation in gastric epithelial cells which may be important in the pathway to gastric carcinogenesis. The green tea catechin epigallocatechin-3-gallate (EGCG) has been reported in some studies to have chemoprotective properties against development of gastric cancer. The aim of this study was to investigate if H. pyloriinduced ERK phosphorylation in A431 epithelial cells was inhibited by EGCG.Methods: H. pylori (NCTC 11637, cag PAI+) were co-cultured with A431 epithelial cells for 2.5 hrs. EGF (100 ng/ml) was used as a positive control. “In-Cell Western” (ICW) assay, which is a rapid quantitative method for determining the inhibitory effects of chemicals of interest on H. pylori epithelial cell signalling responses (REF Du Y et al., 2007), was used to examine the effects of EGCG on ERK1/2 phosphorylation (pERK) in A431 epithelial cells. EGCG (1-200 μM) was pre-incubated with A431 cells for 1 hr prior to the co-culture experiments. Results: EGF significantly (p<0.001, n=4) increased pERK in A431 cells compared to unstimulated controls. EGCG at concentrations greater than 50 μM caused a small but significant (p< 0.01) increase in pERK in A431 cells. EGCG dose-dependently significantly inhibited EGF (100 ng/ml)-induced pERK at a concentration of 10 μM and above (p<0.01, n=4). H. pylori strain NCTC 11637 significantly (p<0.01, n=4) increased pERK in A431 cells compared to unstimulated controls. EGCG dose-dependently inhibited pERK induced by H. pylori. EGCG at 100 μM significantly inhibited (p<0.05, n=4) H. pylori-induced pERK 2.5 hrs postculture. Conclusions: H. pylori-induced ERK phosphorylation in A431 epithelial cells was significantly inhibited by green tea catechin EGCG in a dose-dependent manner. The use of EGCG as dietary phytochemical for H. pylori-induced gastric cancer chemoprevention is plausible, at least in a specific group of patients with higher risk of gastric cancer development but failure for H. pylori eradication.

M1176 MicroRNA 132 Regulation in Human Colon Carcinogenesis: Potential Role in NSAID Chemoprevention

Introduction: H. pylori transactivates the epidermal growth factor (EGFR) and induces extracellular-signal related kinase (ERK) phosphorylation in gastric epithelial cells which may be important in the pathway to gastric carcinogenesis. The green tea catechin epigallocatechin-3-gallate (EGCG) has been reported in some studies to have chemoprotective properties against development of gastric cancer. The aim of this study was to investigate if H. pyloriinduced ERK phosphorylation in A431 epithelial cells was inhibited by EGCG.Methods: H. pylori (NCTC 11637, cag PAI+) were co-cultured with A431 epithelial cells for 2.5 hrs. EGF (100 ng/ml) was used as a positive control. “In-Cell Western” (ICW) assay, which is a rapid quantitative method for determining the inhibitory effects of chemicals of interest on H. pylori epithelial cell signalling responses (REF Du Y et al., 2007), was used to examine the effects of EGCG on ERK1/2 phosphorylation (pERK) in A431 epithelial cells. EGCG (1-200 μM) was pre-incubated with A431 cells for 1 hr prior to the co-culture experiments. Results: EGF significantly (p<0.001, n=4) increased pERK in A431 cells compared to unstimulated controls. EGCG at concentrations greater than 50 μM caused a small but significant (p< 0.01) increase in pERK in A431 cells. EGCG dose-dependently significantly inhibited EGF (100 ng/ml)-induced pERK at a concentration of 10 μM and above (p<0.01, n=4). H. pylori strain NCTC 11637 significantly (p<0.01, n=4) increased pERK in A431 cells compared to unstimulated controls. EGCG dose-dependently inhibited pERK induced by H. pylori. EGCG at 100 μM significantly inhibited (p<0.05, n=4) H. pylori-induced pERK 2.5 hrs postculture. Conclusions: H. pylori-induced ERK phosphorylation in A431 epithelial cells was significantly inhibited by green tea catechin EGCG in a dose-dependent manner. The use of EGCG as dietary phytochemical for H. pylori-induced gastric cancer chemoprevention is plausible, at least in a specific group of patients with higher risk of gastric cancer development but failure for H. pylori eradication.

Pathophysiology of intestinal metaplasia of the stomach: emphasis on CDX2 regulation

IM (intestinal metaplasia) of the stomach is a pre-neoplastic lesion that usually follows Helicobacter pylori infection and that confers increased risk for gastric cancer development. After setting the role played by CDX2 (Caudal-type homeobox 2) in the establishment of gastric IM, it became of foremost importance to unravel the regulatory mechanisms behind its de novo expression in the stomach. In the present paper, we review the basic pathology of gastric IM as well as the current knowledge on molecular pathways involved in CDX2 regulation in the gastric context.

Multiple Gene Status in Helicobacter pylori Strains and Risk of Gastric Cancer Development

Background/Aim: The identification of the vacA intermediate region has provided new insights into the role of vacA heterogeneity in relation to gastro-duodenal pathogenesis. The aim of this study was to assess vacA polymorphism in Iranian Helicobacter pylori strains and its association with cagA as a major virulence determinant, gastric histopathology and disease. Methods:vacA polymorphism and serum antibody responses were studied in 207 H. pylori-infected (139 NUD, 34 PUD, and 34 GC) patients and correlated with gastric histopathology. Results: Multivariate logistic regression analysis found intermediate region typing superior to signal or mid region typing for screening high risk patients. vacA i1 allele was identified as an independent predictor of dysplasia (OR = 9.044; 95% CI: 1.11–73.33). Possession of s1/i1/cagA⁺ strains was also identified as a predictor of intestinal metaplasia (OR = 3; 95% CI: 1.13–7.95), dysplasia (OR = 9.9; 95% CI: 1.23–80.86) and risk of GC (OR = 6.9; 95% CI: 2.5–18.66) as well as induction of anti-VacA sero-positivity (OR = 5.04; 95% CI: 1.8–13.6). Anti-VacA serology correctly detected 83.8% of s1/i1/cagA⁺ strains carried by high-risk patients. Conclusions: The current study emphasizes the implication of vacA polymorphic structure, especially the s1/i1/cagA⁺ genotype, in increasing the risk of GC by revealing their association with gastric pre-neoplastic changes and their reflection in VacA sero-positivity which encourages the application of noninvasive procedures in population screening.

Perceived risk for gastric cancer among the general Korean population: a population‐based survey

We measured the perceived risk for developing gastric cancer and investigated how a range of socio-demographic, lifestyle, health, and psychological factors were associated with risk perception in a population-based sample in Korea. This study was based on the 2006 Korean National Cancer Screening Survey conducted by the National Cancer Center, in which trained interviewers met face-to-face with participants selected by a nationally representative random sampling. The participants included 1673 adults, aged 40 years or older, who had not previously been diagnosed with cancer. Simple and multiple ordinal regression were used to determine the associations between perceived risk and socio-demographic, lifestyle, health, and psychological factors. Almost half of the subjects (48.3%) thought their chance of developing gastric cancer was lower than that of other men or women of the same age. A higher level of worry concerning gastric cancer was strongly associated with a higher perceived risk for gastric cancer development. Those who drink alcohol two or more days per week, and who are unmarried all perceived their risk as being higher. However, those without a previous gastric cancer screening, a personal history of gastric disease, or a good overall health status had a lower perceived risk for gastric cancer development. This study found comparative optimism about the risk for developing gastric cancer in a Korean population. It is necessary to increase people's ability to accurately perceive their risk for cancer.

Monocyte and Macrophage Killing of Helicobacter pylori: Relationship to Bacterial Virulence Factors

Helicobacter pylori infection is an important health problem, as it involves approximately 50% of the world's population, causes chronic inflammatory disease and increases the risk of gastric cancer development. H. pylori infection elicits a vigorous immune response, but this does not usually result in bacterial clearance. We have investigated whether the persistence of H. pylori in the host could be partly due to an inability of macrophages to kill this bacterium. Monocytes and macrophages isolated from the peripheral blood of normal human controls were infected in vitro with five H. pylori isolates. The isolates were characterized for known H. pylori virulence factors; vacuolating cytotoxin (VacA), the cag pathogenicity island (cagPAI), urease, and catalase by Western blot and polymerase chain reaction analysis. The ability of primary human monocytes and macrophages to kill each of these H. pylori strains was then defined at various time points after cellular infection. The five H. pylori strains showed contrasting patterns of the virulence factors. There were different rates of killing for the bacterial strains. Macrophages had less capacity than monocytes to kill three H. pylori strains. There appeared to be no correlation between the virulence factors studied and differential killing in monocytes. Primary human monocytes had a higher capacity to kill certain strains of H. pylori when compared to macrophages. The VacA, cagPAI, urease, and catalase virulence factors were not predictive of the capacity to avoid monocyte and macrophage killing, suggesting that other factors may be important in H. pylori intracellular pathogenicity.

Key elements of the BMP/SMAD pathway co‐localize with CDX2 in intestinal metaplasia and regulate CDX2 expression in human gastric cell lines

Helicobacter pylori infection induces intestinal metaplasia of the stomach, a preneoplastic lesion associated with an increased risk for gastric cancer development. Intestinal metaplasia is induced by the intestine-specific transcription factor CDX2 but the mechanisms responsible for this ectopic expression have never been described. We hypothesized that the BMP/SMAD pathway has a role in CDX2 regulation, in this context, for the following reasons: (1) the BMP pathway is crucial for normal intestinal differentiation and (2) there is an influx of BMP2 and BMP4-producing cells to the stomach upon Helicobacter pylori infection. We evaluated the expression of key elements of the BMP pathway in human stomach specimens with IM. Growth factor treatments, with BMP2 and BMP4, were performed in cultured cells and a knock-down experiment of SMAD4 was done using RNAi. We showed overexpression in IM of BMP2/4, BMPR1A, and SMAD4 in 56% of IM foci, and pSMAD1/5/8 in 100% of IM foci as compared to adjacent mucosa. In vitro, treatment of AGS cells with BMP2 and BMP4 increased endogenous CDX2 expression as well as the intestinal differentiation markers MUC2 and LI-cadherin. On the other hand, SMAD4 knock-down led to decreased endogenous CDX2, MUC2, and LI-cadherin in AGS. Treatment of the SMAD4 knock-down cells had no influence on CDX2 expression as opposed to wild-type cells. A 9.3 kb CDX2 promoter could be transactivated by SMAD4 and SMAD1 in a cell-dependent manner. In conclusion, we identified for the first time that the BMP pathway is active in intestinal metaplasia and that BMP2 and BMP4 regulate CDX2 expression and promote intestinal differentiation through the canonical signal transducers.