Changes of gene expression in gastric preneoplasia following Helicobacter pylori eradication therapy.

Helicobacter pylori causes gastric preneoplasia and neoplasia. Eradicating H. pylori can result in partial regression of preneoplastic lesions; however, the molecular underpinning of this change is unknown. To identify molecular changes in the gastric mucosa following H. pylori eradication, we used cDNA microarrays (with each array containing approximately 30,300 genes) to analyze 54 gastric biopsies from a randomized, placebo-controlled trial of H. pylori therapy. The 54 biopsies were obtained from 27 subjects (13 from the treatment and 14 from the placebo group) with chronic gastritis, atrophy, and/or intestinal metaplasia. Each subject contributed one biopsy before and another biopsy 1 year after the intervention. Significant analysis of microarrays (SAM) was used to compare the gene expression profiles of pre-intervention and post-intervention biopsies. In the treatment group, SAM identified 30 genes whose expression changed significantly from baseline to 1 year after treatment (0 up-regulated and 30 down-regulated). In the placebo group, the expression of 55 genes differed significantly over the 1-year period (32 up-regulated and 23 down-regulated). Five genes involved in cell-cell adhesion and lining (TACSTD1 and MUC13), cell cycle differentiation (S100A10), and lipid metabolism and transport (FABP1 and MTP) were down-regulated over time in the treatment group but up-regulated in the placebo group. Immunohistochemistry for one of these differentially expressed genes (FABP1) confirmed the changes in gene expression observed by microarray. In conclusion, H. pylori eradication may stop or reverse ongoing molecular processes in the stomach. Further studies are needed to evaluate the use of these genes as markers for gastric cancer risk.     

DNA methylation accumulation in gastric mucosa adjacent to cancer after Helicobacter pylori eradication

Molecular irreversibleness with Helicobacter pylori (H. pylori) infection might have a role in gastric tumorigenesis after H. pylori eradication. We performed comprehensive DNA methylation profiling of gastric mucosa after H. pylori eradication with or without gastric cancer. Using four different groups of biopsies obtained from gastric body without history of H. pylori infection (Hp-), gastric body without cancer after H. pylori eradication (cancer-free body), gastric body with early gastric cancer diagnosed after H. pylori eradication (EGC body) and their paired samples from adjacent mucosa of cancer (EGC ADJ), methylation status of five candidate genes (MYOD1, SLC16A12, IGF2, RORA and PRDM5) was examined by the bisulfite pyrosequencing. An Infinium Methylation EPIC BeadChip array was also used to characterize the methylation status of greater than 850,000 CpG sites. The EGC ADJ group showed highest methylation levels of five candidate genes among the four groups of biopsies. In the gastric body (cancer-free body + EGC body), methylation levels were significantly decreased in patients with longer period after eradication, while such association was not observed in EGC ADJ group. Hyper methylated samples were associated with shorter telomere, an indicator for rapid cell turnover, and higher DNMT1 protein expression, an enzyme related to methyl transfer reaction. The genome-wide methylation analysis demonstrated strikingly higher methylation levels especially at CpG islands in the EGC ADJ group. Exclusively hypermethylated promoter CpG islands in the same group frequently coded zinc finger proteins. Our data show that DNA methylation accumulation is associated with molecular irreversibleness and gastric carcinogenesis after H. pylori eradication.     

E-cadherin gene methylation in lung cancer

E-cadherin, a tumor repressor gene, has been shown to play an important role in maintaining the polarity and structural integrity of epithelial and is closely associated with tumorigenesis, invasion, and metastasis. The current study aimed to investigate the effects of E-cadherin methylation on lung cancer (LC) quantitatively through a meta-analysis. We searched electronic databases to identify eligible studies from their inception through September 30, 2013. Pooled odds ratio (OR) with 95 % confidence interval (CI) was used to assess the relationship between E-cadherin gene methylation and LC risk. A hazard ratio (HR) with 95 % CI was used to assess the impact of E-cadherin gene methylation on overall survival (OS) of LC patients. Seventeen studies comprising 983 LC cases and 669 controls met the inclusion criteria. Summary results revealed that hypermethylation frequencies in LC tissues were significantly higher than those in normal control tissues (OR?=?4.11, 95 % CI 2.78–6.07, P?相似文献   

The association of E-cadherin expression and the methylation status of the E-cadherin gene in nasopharyngeal carcinoma cells

Loss of E-cadherin (E-cad) has been associated with progression and poor survival in nasopharyngeal carcinoma (NPC). In this study, we investigated the role of methylation on E-cad inactivation in NPC cell lines, as well as in NPC tissue samples. Using 6 NPC cell lines, we found that methylation of the E-cad 5' CpG island promoter region was correlated with the loss of both mRNA and E-cad protein expression in these cell lines. In addition, using 29 NPC and 10 non-malignant nasopharyngeal samples, we also observed 5' CpG methylation of the E-cad gene in 52% (15 out of 29) NPC samples, but in only 10% (1 out of 10) of the non-malignant nasopharyngeal tissues. Our findings indicate that 5' CpG island methylation of the E-cad gene may play an important part in the inactivation of E-cad in NPC. Our results also suggest that reducing the methylation of the E-cad gene may be a potential therapeutic strategy for NPC.     

Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication.

PURPOSE: Cure of infection induces remissions in most patients with early stage Helicobacter pylori- (Hp) positive gastric MALT (mucosa-associated lymphoid tissue) lymphoma (GML). We tracked the long-term stability of remissions in this prospective, multicenter trial. PATIENTS AND METHODS: In 120 patients with stage I(1E) disease, we performed sequential endoscopic-bioptic follow-up after Hp eradication and polymerase chain reaction of the rearranged immunoglobulin heavy chain gene. The status of t(11;18) was assessed in 65 patients. RESULTS: Median follow-up was 75 months (range, one to 116). Five-year survival was 90%. Eighty percent of patients (96 of 120) achieved complete histologic remission (CR). Eighty percent of CRs are in continuous complete histologic remission (CCR). Three percent of CR patients (three of 96) relapsed and were referred for alternative treatment. Seventeen percent of CR patients (16 of 96) showed histologic residual disease (RD) during follow-up; a watch-and-wait strategy was applied, and all entered into a second CR. After a median follow-up of 63 months, 14 of 52 analyzed patients reaching CR showed ongoing B-cell monoclonality. Fifteen percent of GMLs were t(11;18) positive. Both t(11;18) and ongoing monoclonality were associated with a significantly higher risk for no response or relapse (P =.004, P =.007), but also present in patients in CCR. Early gastric cancer was diagnosed in three cases during follow-up. CONCLUSION: Cure of Hp infection results in CCR in most patients. Histologic RD, B-cell monoclonality, and t(11;18) were present in a considerable number of CR patients. A watch-and-wait strategy is justified when close follow-up is guaranteed.     

Prospective study of Helicobacter pylori eradication therapy in stage I(E) high-grade mucosa-associated lymphoid tissue lymphoma of the stomach.

PURPOSE: High-grade mucosa-associated lymphoid tissue (MALT) lymphomas of the stomach are generally believed to be Helicobacter pylori-independent, autonomously growing tumors. However, anecdotal cases of regression of high-grade lymphomas after the cure of H pylori infection had been described. The present prospective study was conducted to evaluate the effect of anti-H pylori therapy in stage I(E) high-grade gastric MALT lymphomas. PATIENTS AND METHODS: Sixteen patients with H pylori infection and stage I(E) gastric high-grade MALT lymphoma consented to a brief antibiotic therapy as first-line treatment from June 1995 through April 2000. Then, patients underwent intensive endoscopic follow-up examinations (+/- endoscopic ultrasonography) with biopsy to evaluate tumor response. Patients with significant improvement of gross lesions that accompanied regression of large cells were followed up without additional treatment. Patients without significant improvement were immediately referred to systemic chemotherapy. RESULTS: Eradication of H pylori was achieved in 15 patients and was accompanied by rapid gross tumor regression and disappearance of large cells in 10. All 10 of these patients with early response had subsequent complete histologic remission of lymphoma. The complete remission rate was 62.5% (95% confidence interval, 35.8% to 89.1%). The response rate was not affected by the tumor grading (proportion of large blast cells within the tumor) but was adversely affected by the depth of tumor invasion. At a median follow-up of 43.5 months (range, 21.1 to 67.4 months), all 10 of these patients remained lymphoma-free. The median duration of complete response was 31.2 months (range, 14.4 to 49.1 months). CONCLUSION: These results suggest that high-grade transformation is not necessarily associated with the loss of H pylori dependence in early-stage MALT lymphomas of the stomach.     

Reversibility of heterotopic proliferative glands in glandular stomach of Helicobacter pylori-infected Mongolian gerbils on eradication.

Helicobacter pylori (Hp) infection is an important factor in human gastric disorders. Mongolian gerbils can be easily infected with Hp and represent excellent experimental models to clarify the role of Hp in chronic active gastritis, peptic ulcers, intestinal metaplasia, and gastric carcinoma. We have proved the enhancing effects of Hp infection on all histological types of gastric cancers in Mongolian gerbils exposed to chemical carcinogens. Heterotopic proliferative glands (HPGs) also frequently develop with Hp infection in the glandular stomach of infected gerbils, with a slightly dysplastic change of constituent cells. Distinguishing reversible inflammatory lesions from true neoplasms upon eradication is necessary for further biological or histochemical investigations using this model. We employed an experimental model of long-term Hp infection and eradication in gerbils. HPGs finally developed with a phenotypic shift of intestinalization with Paneth cells. After eradication, HPGs were obviously reduced, and gastric lesions in mucosa also improved with few remnants of the former injury. This shows that reversible HPGs are frequently induced solely by Hp infection in this animal species, and are related to severe gastritis, rather than being malignant in character. Thus, distinguishing reversible lesions from true neoplasms is necessary to investigate the relationship of Hp infection and gastric carcinogenesis in this animal model.     

Helicobacter pylori and stomach cancer: a case-control study in Venezuela.

The role of Helicobacter pylori infection in gastric cancer was evaluated in a high-risk population in Venezuela using serological assays in a study of 302 cases and 483 neighborhood controls. To investigate the claim that assays for H. pylori should use antigens derived from local strains, four different assays derived from Venezuelan and European strains were used. Prevalence of IgG H. pylori antibodies in controls was very high, with estimates between 72 and 92%. Prevalence was similar in cases and controls. However, cases had lower antibody titers. This effect was observed only in subjects with low pepsinogen (PG) levels PGI/PGII <3.0), which suggested that extensive atrophy in cases causes a loss of H. pylori infection, with a consequent reduction in antibody titer. In addition, advanced cases (stage II or higher) had lower antibody titers than less advanced cases, which indicated that the lower antibody titers in cases may be attributable partially to a diminished immune response. All of the four assays for anti-H. pylori antibodies gave similar results. No evidence was found for the superiority of the assay based on Venezuelan strains. These results are consistent with other case-control studies in high-risk populations and highlight the difficulties of investigating H. pylori infection in retrospective studies.     

Emphasizing the importance of successful eradication of Helicobacter pylori on initial treatment

Helicobacter pylori (H. pylori) infection is the most important risk factor for gastric cancer and plays an initiating role in the development of intestinal-type gastric cancer. Eradication of H. pylori significantly reduces the incidence and mortality of gastric cancer. International expert consensus recommends eradication treatment for all infected individuals unless competing considerations. However, large-scale H. pylori eradication treatments have led to increasing rates of resistance to multiple antibiotics, together with factors such as coccoid transformation, host CYP2C19 gene polymorphisms, and inappropriate treatment regimens, resulting in a gradual decline in H. pylori eradication rates. Currently, empirical and repeated eradication of H. pylori treatment is common in clinical practice, which will certainly lead to a further increase in antibiotic resistance, resulting in a great waste of medical resources and an increased psychological burden on patients and their relatives. Therefore, successful eradication of H. pylori on initial treatment should be given high priority, and the implementation of personalized treatment is essential.     

Efficacy of Helicobacter pylori eradication on the chronic mucosal inflammation of the remnant stomach after distal gastrectomy for early gastric cancer

Although eradication of Helicobacter pylori (Hp) after early gastric carcinoma has been recommended, very limited studies have been reported and the method differs from standard therapy. Here, we attempted the eradication of Hp in the remnant stomach after surgery for primary gastric cancer with the standardized method. We examined efficacy and the safeness of the treatment. Thirty-three H. pylori-positive patients after distal gastrectomy were treated with proton pump inhibitor (PPI)-based triple therapies. After eradication, endoscopic and histological changes were classified on the basis of the Updated Sydney System. The eradication rate in the remnant stomach was 90.9% (30 out of 33 cases) after triple therapy. Temporal minor side effects were notified in 3 cases. After eradication, the remnant stomach showed significant decreases in inflammation- and activity-scores. Moreover, significant improvement in glandular atrophy to normal mucosa was found. In conclusion, PPI-based standard therapy is just as effective for Hp eradication in the remnant stomach than it is in the non-operative stomach. Eradication therapy could be performed safely and resulted in a significant improvement in inflammation and atrophy of the mucosal layer in the remnant stomach after early gastric cancer surgery.     

Risk of gastric cancer development after eradication of Helicobacter pylori

Helicobacter pylori (H. pylori) infection is the most important risk factor for gastric cancer (GC) development through the Correa’s gastric carcinogenesis cascade. However, H. pylori eradication alone does not eliminate GC, as pre-neoplastic lesions (atrophic gastritis, intestinal metaplasia and dysplasia) may have already developed in some patients. It is therefore necessary to identify patients at high-risk for gastric cancer after H. pylori eradication to streamline the management plan. If the patients have not undergone endoscopy with histologic assessment, the identification of certain clinical risk factors and non-invasive testing (serum pepsinogen) can predict the risk of atrophic gastritis. For those with suspected atrophic gastritis, further risk stratification by endoscopy with histologic assessment according to validated histologic staging systems would be advisable. Patients with higher stages may require long-term endoscopic surveillance. Apart from secondary prevention to reduce deaths by diagnosing GC at an early stage, identifying medications that could potentially modify the GC risk would be desirable. The potential roles of a number of medications have been suggested by various studies, including proton pump inhibitors (PPIs), aspirin, statins and metformin. However, there are currently no randomized clinical trials to address the impact of these medications on GC risk after H. pylori eradication. In addition, most of these studies failed to adjust for the effect of concurrent medications on GC risk. Recently, large population-based retrospective cohort studies have shown that PPIs were associated with an increased GC risk after H. pylori eradication, while aspirin was associated with a lower risk. The roles of other agents in reducing GC risk after H. pylori eradication remain to be determined.     

Helicobacter pylori infection and gastric diseases--pathogenesis and effects of eradication

H. pylori infection is associated with major gastroduodenal diseases, i.e. peptic ulcer, cancer and MALT lymphoma in the stomach. The pathogenesis of H. pylori in these diseases has been elucidated. Non-atrophic diffuse antral gastritis is correlated with duodenal ulcer and multifocal atrophic gastritis is correlated with both gastric ulcer and cancer. It is well known that Japanese tend to have multifocal atrophic gastritis. H. pylori eradication therapy dramatically reduces the recurrence rates of gastroduodenal ulcers in humans and bacterial eradication for peptic ulcer patients has been recommended in many countries. Mongolian gerbils have provided an excellent model of gastric carcinogenesis and H. pylori enhanced (promoted) chemical carcinogen-induced carcinogenesis in the stomach using this model. H. pylori eradication reduced the incidence of gastric cancer in the Mongolian gerbil model. It was a recently discovered that a transforming clone carrying the translocation t (11;18) (q21;q21) forms a MALT lymphoma, the growth of which is independent of H. pylori and will not respond to bacterial eradication. In the early stage, the tumor can be successfully treated by eradication, but at a later stage additional genetic abnormality in the lymphoma may show no response to H. pylori eradication therapy.     

Gastric cancer development after the successful eradication of Helicobacter pylori

Gastric cancer (GC) develops as a result of inflammation-associated carcinogenesis due to Helicobacter pylori (H. pylori) infection and subsequent defects in genetic/epigenetic events. Although the indication for eradication therapy has become widespread, clinical studies have revealed its limited effects in decreasing the incidence of GC. Moreover, research on biopsy specimens obtained by conventional endoscopy has demonstrated the feasibility of the restoration of some genetic/epigenetic alterations in the gastric mucosa. Practically, the number of sporadic cases of primary/metachronous GC that emerge after successful eradication has increased, while on-going guidelines recommend eradication therapy for patients with chronic gastritis and those with background mucosa after endoscopic resection for GC. Accordingly, regular surveillance of numerous individuals who have received eradication therapy is recommended despite the lack of biomarkers. Recently, the focus has been on functional reversibility after successful eradication as another cue to elucidate the mechanisms of restoration as well as those of carcinogenesis in the gastric mucosa after H. pylori eradication. We demonstrated that Congo-red chromoendoscopy enabled the identification of the multi-focal distribution of functionally irreversible mucosa compared with that of restored mucosa after successful eradication in individuals at extremely high risk for GC. Further research that uses functional imaging may provide new insights into the mechanisms of regeneration and carcinogenesis in the gastric mucosa post-eradication and may allow for the development of useful biomarkers.     

幽门螺杆菌根除后胃癌发病的相关因素

胃癌是常见癌症之一.幽门螺杆菌感染是胃癌发生的主要致病因素.根除幽门螺杆菌可明显降低胃癌的发病率.但仍有部分患者在幽门螺杆菌根除后仍进展为胃癌.因此,早期识别幽门螺杆菌根除后的胃癌高危人群是一种经济、有效的胃癌预防手段.本文就目前报道的可预示幽门螺杆菌根除后原发性胃癌发病的相关因素及可能影响除菌后胃癌发病风险的药物进行...     

Changes in aberrant DNA methylation after Helicobacter pylori eradication: A long‐term follow‐up study

Changes of DNA methylation in gastric mucosae after eradication of Helicobacter pylori have not been clarified yet. From this background, we investigated time course of DNA methylation following H. pylori eradication in 221 successfully H. pylori eradicated subjects with endoscopic follow‐up at least for 6 months, including 114 controls, 53 subjects with gastric dysplasia and 54 patients with early gastric cancer. All dysplasia and gastric cancer patients underwent endoscopic resection at the time of enrollment. The methylation levels in LOX, APC and MOS genes from noncancerous gastric mucosae using quantitative methylation‐specific PCR, as well as the histologic findings of gastric mucosae, were compared before and after eradication. Average follow‐up duration was 26.0 months (range: 6 to 76 months). H. pylori eradication decreased methylation levels in LOX (p‐value for slope < 0.001) but not in APC. In MOS, decrease of its methylation level following H. pylori eradication was significant among controls without intestinal metaplasia (IM) (p‐value for slope < 0.05); however, it was not observed among patients with IM or those with dysplasia or gastric cancer. After H. pylori eradication, methylation level in MOS persistently increased in patients with dysplasia or gastric cancer (p < 0.01). In conclusion, H. pylori eradication decreases aberrant DNA methylation with gene‐specific manner. Methylation level in MOS is associated with IM and may be used as a surrogate marker for gastric cancer risk, regardless of H. pylori eradication history.     

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

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

DNA甲基化和E-cadherin基因甲基化与胃癌关系研究进展

目的：总结DNA甲基化和E-cadherin基因甲基化与胃癌关系的研究现状。方法：应用PubMed及万方数据知识服务平台检索系统,以“胃癌、DNA甲基化、Eu钙黏蛋白基因和CpG岛”等为关键词,检索1979-01-2013-05的相关文献,共检索到英文文献2093篇,中文文献672篇。纳入标准：1）关键词包括胃癌及DNA甲基化;2）文中包括E-钙黏蛋白基因启动子区CpG岛甲基化。剔除标准：1）非E-钙黏蛋白基因启动子区CpG岛的甲基化;2）关键词有E-钙黏蛋白但文中无甲基化描述。符合纳入标准的中文文献56篇,英文文献43篇,根据剔除标准剔除中文文献46篇,英文文献23篇,最后纳入分析30篇文献。结果：DNA甲基化在基因表达、调控过程中发挥重要作用,其功能紊乱在恶性肿瘤形成过程中具有重要作用,与胃癌的发生密切相关。E-cadherin基因能抑制肿瘤细胞的浸润和转移,E-cadherin基因启动子区CpG岛甲基化是胃肠道肿瘤E-cadherin基因失活的主要原因,可引起E-cadherin表达下降或缺失,与胃癌的发生、浸润、转移和预后密切相关。结论：DNA甲基化和E-cadherin基因甲基化与胃癌的形成、浸润和转移等关系密切,但其要成为胃癌防治的靶点仍需进一步研究。     

Cancer precursor lesions in intact stomach Helicobacter pylori gastritis and in resected stomach gastritis

Hemigastrectomy for benign disease and Helicobacter pylori infection are risk conditions for the development of gastric cancer. Aim of the study was to compare gastric histology and precursor lesions of malignancy in these two conditions. The hemigastrectomy group included 351 consecutively endoscoped subjects operated for gastroduodenal benign disease. Six to ten biopsy specimens were routinely taken from the residual gastric mucosa. The intact stomach group included 2097 consecutively endoscoped symptomatic subjects, who did not receive eradication therapy against H. pylori. The histological findings were classified as normal mucosa (NM), chronic non atrophic gastritis (CNAG), chronic atrophic gastritis (CAG), intestinal metaplasia (IM) and dysplasia (DYS). One thousand and three intact stomachs were H. pylori negative, and 1094 showed H. pylori colonization. The age over fifty was a significant risk factor for the occurrence of IM (OR 2.52, P < or = 0.001) and DYS (OR 3.46, P < or = 0.001), while Hp-positivity was a risk factor for CNAG (OR 1.81, P < or = 0.001) and CAG (OR 3.88, P < or = 0.001). Gastroresection was associated to higher risk for CNAG (OR 1.53, P < or = 0.001) and DYS (OR 4.31, P < or = 0.001) and to a lower risk of CAG (OR 0.49, P < or = 0.001). Both in males and females the risk for CNAG was significantly higher in Hp-positive (males OR 1.92, P=0.000; females OR 1.70, P=0.000) and gastrectomized subjects (males OR 2.06, P=0.000; females OR 2.43, P=0.000). Gastrectomized males, furthermore, showed an increased risk for DYS (OR 5.82, P=0.000). The aged Hp-negative and Hp-positive subjects evidenced a significant risk for IM (respectively OR's 3.42, P=0.000 and 4.85, P=0.000); the risk for DYS was significant in aged Hp-negative subjects (OR 4.09 P < or = 0.020). The Hp-positive individuals evidenced a significant risk for metaplastic mucosal changes (OR 38.17, P=0.000). Subjects aged over forty at the time of surgery and those with a longer postoperative follow up endoscopy presented an increased risk for CNAG of the residual mucosa (respectively OR's 2.75, P=0.000 and 5.25, P=0.000). CNAG and IM were the most frequently observed mucosal lesions both in subjects operated for duodenal and gastric ulcer (respectively OR's 4.02, P=0.000 and 3.00, P=0.000). Our data support that hemigastrectomy for benign disease and H. pylori infection may induce an increased incidence for histological precursor lesions for gastric malignancy and suggest that carcinogenesis in a resected stomach may be different from that in the intact stomach.