Embelin inhibits pancreatic cancer progression by directly inducing cancer cell apoptosis and indirectly restricting IL-6 associated inflammatory and immune suppressive cells

Pancreatic cancer is an aggressive malignancy and unresponsive to conventional chemotherapies. Here, the anti-inflammatory and anti-tumor effects of embelin on pancreatic cancer were investigated. Embelin significantly attenuated cells invasion, proliferation and induced apoptosis through inhibition of STAT3 and activation of p53 signaling pathways. Embelin substantially reduced the tumorigenicity of pancreatic cancer cells in vivo, which was associated with reduced inflammatory cells and immune suppressive cells, IL-17A⁺ Th17, GM-CSF⁺ Th, MDSCs and Treg, through inhibition of IL-6 secretion. Moreover, embelin decrease IL-6-induced STAT3 phosphorylation. In summary, embelin represents a novel therapeutic drug candidate for the clinical treatment of pancreatic cancer.     

Activation of CD3+ T cells by Helicobacter pylori DNA vaccines in potential immunotherapy of gastric carcinoma

Most of gastric carcinoma (GC) is attributed to infection by Helicobacter pylori (H. pylori) but there is increasing evidence that the positive H. pylori status correlates with better prognosis in GC. The H. pylori-induced cellular immune response may suppress cancer and in this work, recombinant pcDNA3 plasmids encoding various fragments of H. pylori virulence genes of cagA, vacA and babA are constructed and combined into groups to immunize BALB/c mice. The activated splenic CD3⁺ T cells are purified and the anticancer effects are investigated in vitro and in vivo. The H. pylori DNA vaccines induce a shift in the response from Th1 to Th2 that mimicks the immune status in patients of GC with chronic H. pylori infection. The stimulated CD3⁺ T cells inhibit the growth of human GC cells in vitro and adoptive transfusions of the CD3⁺ T cells suppress the growth of GC xenograft in vivo. The effects may be caused by the larger ratios of infiltrated CD8⁺/CD4⁺ T cells, reduced infiltration of regulatory FOXP3⁺ T cells, and enhanced apoptosis induced by upregulation of Caspase-9/Caspase-3 and downregulation of Survivin. Our results reveal the potential immunotherapeutic value of H. pylori vaccine-activated CD3⁺ T cells in those with advanced GC.     

Patients with Helicobacter pylori-positive gastric cancer with human cytomegalovirus infection have a low tendency of advanced lymphatic metastasis in a Chinese population

Recognized as a group I carcinogen for gastric cancer (GC) and a factor involved in the development of GC, Helicobacter pylori serves a major part in GC research. However, most studies have focused on H. pylori itself, ignoring the complicated pathogenic microbiological environment of GC and neglecting the synergistic or antagonistic effects of H. pylori with other pathogenic microorganisms. Increasing evidence has revealed that the human cytomegalovirus (HCMV) is present in several types of tumors and serves an important role in the neoplastic process of certain human malignant tumors, including GC. The aim of the present study was to explore the role of HCMV and H. pylori co-infection in GC. HCMV and H. pylori infection was analyzed in paired gastric tumor and peri-tumoral tissues from 134 (98 male and 36 female) patients using PCR. The results revealed that a total of 74 (55.2%) patients had H. pylori infection, 58 patients (43.3%) had HCMV infection, and 34 (25.4%) patients had both HCMV and H. pylori infection. Univariate and multivariate analyses demonstrated that H. pylori infection was independently associated with advanced lymphatic metastasis [P=0.007; odds ratio (OR)=3.51]. Furthermore, compared with HCMV⁻/H. pylori⁻, neither HCMV⁺/H. pylori⁻ nor HCMV⁺/H. pylori⁺ were associated with metastasis, but HCMV⁻/H. pylori⁺ co-infection status was an independent risk factor for advanced lymphatic metastasis (P=0.005; OR=6.00). In conclusion, GC co-infected with HCMV and H. pylori exhibited a low tendency of lymph node metastasis. HCMV may interact with H. pylori to inhibit the process of lymphatic metastasis, and the mechanism requires further investigation.     

Genetic polymorphisms and tissue expression of interleukin-22 associated with risk and therapeutic response of gastric mucosa-associated lymphoid tissue lymphoma

Chronic Helicobacter pylori-stimulated immune reactions determine the pathogenesis of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. We aimed to explore the genetic predisposition to this lymphoma and its clinical implication. A total of 68 patients and 140 unrelated controls were genotyped for 84 single-nucleotide polymorphisms in genes encoding cytokines, chemokines and related receptors that play important roles in T cell-mediated gastrointestinal immunity. Five genotypes in IL-22, namely CC at rs1179246, CC at rs2227485, AA at rs4913428, AA at rs1026788 and TT at rs7314777, were associated with disease susceptibility. The former four genotypes resided in the same linkage disequilibrium block (r²=0.99) that conferred an approximately threefold higher risk. In vitro experiments demonstrated that co-culturing peripheral mononuclear cells or CD4⁺ T cells with H. pylori stimulated the secretion of interleukin-22 (IL-22), and that IL-22 induced the expression of antimicrobial proteins, RegIIIα and lipocalin-2, in gastric epithelial cells. Furthermore, patients with gastric tissue expressing IL-22 were more likely to respond to H. pylori eradication (14/22 vs 4/19, P<0.006). We conclude that susceptibility of gastric MALT lymphoma is influenced by genetic polymorphisms in IL-22, the product of which is involved in mucosal immunity against H. pylori and associated with tumor response to H. pylori eradication.     

ICOS+ Foxp3+ TILs in gastric cancer are prognostic markers and effector regulatory T cells associated with Helicobacter pylori

Regulatory T cells (Tregs) have an immunosuppressive role in the tumor microenvironment. Since effector Tregs (eTregs), which have highly suppressive functions, are located in a subpopulation of Foxp3⁺ CD4⁺ Tregs, the TCR‐inducible costimulatory receptor (ICOS) was applied as a marker of eTregs that infiltrated gastric cancer tissue and the induction pathway of ICOS⁺ Foxp3⁺ cells was analyzed by flow cytometry and immunohistochemistry. In tumor‐infiltrating lymphocytes (TILs), ICOS⁺ Foxp3⁺ CD4⁺ T cells were abundantly observed in the late stages of gastric cancer. ICOS⁺ CD4⁺ TILs exhibited the ability to produce IL‐10, but not IFN‐γ, TNF, or IL‐17 and also to suppress the proliferation of CFSE‐labeled responder CD8⁺ T cells. With the agonistic ICOS‐L protein (rICOS‐L Ig), ICOS⁺ Foxp3⁺ cells were efficiently induced from naive CD4⁺ T cells under a stimulation with TGF‐β and CD3/CD28 mAbs. Furthermore, when A*0201 PBMCs were cultured with the CMV or Melan‐A antigenic peptide and rICOS‐L Ig, the induction of CMV or Melan‐A tetramer‐binding CD8⁺ T cells, respectively, was inhibited. The expression of ICOS in Foxp3⁺ cells was closely related to plasmacytoid dendritic cells (pDCs) and their expression of ICOS‐L and TLR9 as well as Helicobacter pylori infection. Collectively, our results demonstrate the potential of ICOS as a promising target for direct Treg‐targeting therapeutic agents for gastric cancer, and that of eradicating therapy for H. pylori as an indirect immune therapy for gastric cancer.     

Dietary prevention of Helicobacter pylori-associated gastric cancer with kimchi

To prove whether dietary intervention can prevent Helicobacter pylori-induced atrophic gastritis and gastric cancer, we developed cancer preventive kimchi (cpKimchi) through special recipe and administered to chronic H. pylori-initiated, high salt diet-promoted, gastric tumorigenesis mice model. H. pylori-infected C57BL/6 mice were administered with cpKimchi mixed in drinking water up to 36 weeks. Gross and pathological gastric lesions were evaluated after 24 and 36 weeks, respectively and explored underlying molecular changes to explain efficacies. Cancer preventive actions of anti-inflammation and anti-mutagenesis were compared between standard recipe kimchi (sKimchi) and special recipe cpKimchi in in vitro H. pylori-infected cell model. The erythematous and nodular changes, mucosal ulcerative and erosive lesions in the stomach were noted at 24^th weeks, but cpKimchi administration significantly ameliorated. After 36^th weeks, scattered nodular masses, some ulcers, and thin nodular gastric mucosa were noted in H. pylori-infected mice, whereas these gross lesions were significantly attenuated in cpKimchi group. On molecular analysis, significant expressions of COX-2 and IL-6, activated NF-κB and STAT3, increased apoptosis, and marked oxidative stresses were noted in H. pylori-infected group relevant to tumorigenesis, but these were all significantly attenuated in cpKimchi group. cpKimchi extracts imparted significant selective induction of apoptosis only in cancer cells, led to inhibition of H. pylori-induced proliferation, while no cytotoxicity through significant HO-1 induction in non-transformed gastric cells. In conclusion, daily dietary intake of cpKimchi can be an effective way either to rejuvenate H. pylori-atrophic gastritis or to prevent tumorigenesis supported with the concerted actions of anti-oxidative, anti-inflammatory, and anti-mutagenic mechanisms.     

Late reactivation of sonic hedgehog by Helicobacter pylori results in population of gastric epithelial cells that are resistant to apoptosis: Implication for gastric carcinogenesis

As much as that a disturbance of tissue homeostasis through dysregulated apoptosis is generally associated with carcinogenesis, gastric carcinogenesis after Helicobacter pylori infection could be the accumulated consequence of imbalances between apoptosis and proliferation. Since sonic hedgehog (Shh) has been reported to play versatile roles in various tumorigenesis, we hypothesized that late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis. The Resistant Clones against H. pylori-induced Apoptosis (RCHA) were established and maintained up to 19th cell passages, during which the serial changes of Shh expression were measured. Apoptosis was measured in N-Shh over-expressed stable cell lines and compared with parent cell line after either infected with H. pylori or treated with cyclopamine. For clinical relevance, the expressions of Shh were compared in tissues from gastric adenoma or adenocarcinoma according to H. pylori infection. Longer passages of RCHA after H. pylori infection, the higher expressions of Shh, suggesting RCHA was associated with the reactivation of Shh. Significant decrement in subG1 phase of cell cycle and attenuated executions of apoptosis after H. pylori infection in cells of Shh overexpression, whereas either Shh siRNA or cyclopamine increased the H. pylori-induced cytotoxicity and significantly abrogated anti-apoptotic actions imposed by Shh. Significantly higher expressions of Shh were seen in H. pylori-associated gastric cancers than H. pylori-not associated gastric cancer. Late reactivation of sonic hedgehog by H. pylori infection results in population of gastric epithelial cells that are resistant to apoptosis and imposes proliferative changes under the background of atrophic gastritis, providing the carcinogenic basis.     

Skewed immunological balance between Th17 (CD4+IL17A+) and Treg (CD4+CD25+FOXP3+) cells in human oral squamous cell carcinoma

Background

Several studies have documented modulation of Th17 and T regulatory (Treg) cells in various human malignancies which may vary with the type and extent of the disease. However, such data in patients with oral cancer is scarce and hence the current study was designed to elaborate the immunological balance between these two T cell subsets in oral cancer.

Methods and results

We analyzed various T cell subsets in the peripheral blood of 45 oral squamous cell carcinoma (OSCC) patients and 40 healthy volunteers. We found that, compared with the healthy controls, patients had a significantly (p?<?0.0001) higher proportion of both Th17 (CD4⁺IL17A⁺) and Treg (CD4⁺CD25⁺FOXP3⁺) cells, which further showed a reciprocal balance in relation to clinico-pathological parameters in patients. We also detected a circulating CD8⁺ subset of these cells in both patients and healthy controls, although the difference between the two groups was statistically insignificant. Higher frequencies of Th17 cells were found in patients with early stages and without lymph node involvement, while an increased prevalence of Tregs was associated with higher clinical stages and lymph node involvement. Moreover, Th17 cells were quantitatively and positively correlated to CD4⁺T and CD8⁺T cells and inversely correlated with Tregs. Contrarily, Tregs showed a negative association with CD4⁺T and CD8⁺T cells.

Conclusions

Our results suggest an increase in Th17/Tregs ratio in early stages and a decrease in this ratio in higher stages of oral cancer. Such counter regulation of Th17 and Tregs may be a significant prognostic factor in oral cancer patients.     

Cost-effectiveness of screening with polymerase chain reaction for Helicobacter pylori to prevent gastric cancer and peptic ulcers

BackgroundHelicobacter pylori (H. pylori) is a major risk factor for gastric cancer. Screening and treatment of H. pylori may reduce the risk of gastric cancer and peptic ulcer disease (PUD). Polymerase chain reaction (PCR) of gastric biopsies provides superior sensitivity and specificity for the detection of H. pylori. This study explores whether population-based H. pylori screening with PCR is cost-effective in the US.MethodsA Markov cohort state-transition model was developed to compare three strategies: no screening with opportunistic eradication, ¹³C-UBT population screening and treating of H. pylori, and PCR population screening and treating of H. pylori. Estimates of risks and costs were obtained from published literature. Since the efficacy of H. pylori therapy in gastric cancer prevention is not certain, we broadly varied the benefit 30–100% in sensitivity analysis.ResultsPCR screening was cost-effective and had an incremental-cost effectiveness ratio per quality adjusted life-year (QALY) of $38,591.89 when compared to ¹³C-UBT strategy with an ICER of $2,373.43 per QALY. When compared to no screening, PCR population screening reduced cumulative gastric cancer incidence from 0.84% to 0.74% and reduced PUD risk from 14.8% to 6.0%. The cost-effectiveness of PCR screening was robust to most parameters in the model.ConclusionsOur modeling study finds PCR screening and treating of H. pylori to be cost-effective in the prevention of gastric cancer and PUD. However, the potential negative consequences of H. pylori eradication such as antibiotic resistance could change the balance of benefits of population screening.     

Infection with CagA+ Helicobacter pylori strains as a possible predictor of risk in the development of gastric adenocarcinoma in Mexico

Helicobacter pylori strains possessing the Cag pathogenicity island have been associated with increased gastric inflammation and with duodenal ulcer. In contrast, studies on the association of cagA⁺ H. pylori infections and gastric cancer have shown conflicting results. The aim of our study was to determine whether H. pylori and CagA status are associated with gastric cancer in Mexico. We selected serum samples from 3 geographic areas with gastric cancer mortality rates per 100,000 inhabitants of 2.5 (low risk), 4.5 (medium risk) and 6.4 (high risk). H. pylori infection was determined by the detection of antibodies to H. pylori whole cell antigen by an enzyme-linked immunosorbent assay (ELISA). To study the prevalence of infection with cagA⁺ strains, serum IgG antibodies to CagA were determined by ELISA using a recombinant CagA antigen. Of the 2,775 individuals studied, 1,931 were H. pylori seropositive and 1,710 had antibodies against CagA. The risk for gastric cancer in the 3 populations studied increased proportionally as infection with cagA⁺ strains increased (p < 0.001 for trend). H. pylori infection also showed association with gastric cancer (p < 0.05). Individuals seropositive for CagA, but seronegative for H. pylori whole cell antigen, were more frequent in areas with higher gastric cancer rates (p < 0.01). These results support the possible role of CagA(+) status as predictor of risk for gastric adenocarcinoma in Mexico; this is in agreement with results in European and American populations, but contrary to studies in some Asian countries. Int. J. Cancer 78:298–300, 1998.© 1998 Wiley-Liss, Inc.     

MUC4 is a novel mediator in H. pylori infection-related pancreatic cancer

Pancreatic cancer (PC) is a common malignant disease worldwide. Among the potential pathogenic factors, Helicobacter pylori (H. pylori) infection has been associated with the tumorigenesis of PC. The present study aimed to identify the differentially expressed genes (DEGs) of H. pylori infection-associated PC and to investigate the key factors involved in PC tumorigenesis. Using bioinformatics methods, overlapping DEGs and key gene were identified from H. pylori-infected gastric mucosa (GM) and H. pylori infection-associated PC. Survival and tumor stage analyses were performed to assess the clinical associations. In addition, mucin 4 (MUC4) mRNA expression levels were measured in patient blood and tumor samples. According to the correlation analyses of four genes co-expressed, potential biological processes were identified. MUC4 was identified to be associated with H. pylori infection, and its levels were significantly upregulated in PC samples compared with those in normal samples in TCGA dataset, the PC cell line and patient tissue samples. H. pylori infection was also associated with MUC4 expression in patients'' blood and tissue samples. In conclusion, the results of the present study revealed a potentially pathogenic role of MUC4 in H. pylori infection-associated PC. Thus, the tumorigenesis and metastasis of PC may be prevented by treating the H. pylori infection or using MUC4 antagonists.     

Distribution of Th17 cells and FoxP3(+) regulatory T cells in tumor‐infiltrating lymphocytes,tumor‐draining lymph nodes and peripheral blood lymphocytes in patients with gastric cancer

Although Th17 cells reportedly play critical roles in the development of autoimmunity and allergic reactions, information on Th17 cells in cancer‐bearing hosts is still limited. In the present study, we investigated the distribution of Th17 cells in relation to regulatory T cells (Treg) in the tumor‐infiltrating lymphocytes (TILs), regional lymph node lymphocytes, and peripheral blood lymphocytes of gastric cancer patients. Interleukin (IL)‐17‐producing CD4(+) cells as Th17 cells and CD4(+)CD25(+)FoxP3(+) cells as Treg were evaluated by flow cytometry and expressed as a percentage of the total CD4⁺ cells, in addition to performing a Th1/Th2 balance assay. Moreover, immunohistochemical staining for IL‐17 and FoxP3 were performed. In TILs from patients with early disease (n = 27), the frequency of Th17 cells was significantly higher than that in the normal gastric mucosa (23.7 ± 8.9 vs 4.5 ± 3.1%). In TILs from patients with advanced disease (n = 28), the frequency of Th17 cells was also significantly higher, but lower compared to early disease, than that in the normal gastric mucosa (15.1 ± 6.2 vs 4.0 ± 2.0%). This observation for Th17 cell‐distribution was also confirmed by immunohistochemistry. When the ratio of Th17/Treg in TILs was evaluated in individual cases, it was more markedly increased in early than in advanced disease. In conclusion, the accumulation of Th17 cells as well as Treg in the tumor microenvironment of gastric cancer occurred in early disease and then the infiltration of Th17 cells gradually decreased according to the disease progression, in contrast to increased Treg. (Cancer Sci 2010; 00: 00–00)     

No association between AICDA 7888 C/T polymorphism, Helicobacter pylori seropositivity, and the risk of atrophic gastritis and gastric cancer in Japanese

Background  

The aberrant expression of activation-induced cytidine deaminase (AICDA) was reportedly induced in gastric epithelial cells infected with cytotoxin-associated gene A (cagA)-positive Helicobacter pylori, resulting in the accumulation of alterations in the TP53 tumor suppressor gene in gastric cells. We investigated the association of the AICDA 7888 C/T polymorphism with H. pylori infection and the risk of gastric cancer and atrophic gastritis in Japanese subjects.     

Characterisation of inflammatory processes in Helicobacter pylori-induced gastric lymphomagenesis in a mouse model

Gastric MALT lymphoma (GML) can be induced by Helicobacter pylori infection in BALB/c mice thymectomised at day 3 post-birth (d3Tx). This represented a unique opportunity to investigate the inflammatory process involved in the recruitment, proliferation and structuration of lymphoid infiltrates in the gastric mucosa of mice developing GML. Complementary molecular and proteomic approaches demonstrated that Th1 and Th2 cytokines were upregulated, along with activators/regulators of the lymphoid response and numerous chemokines. Interleukin-4, interferon γ, lymphotoxin-α and -β were significantly upregulated and correlated with the inflammatory scores for all the d3Tx mice. GML lesions in d3Tx mice infected with H. pylori were associated with the presence of the inflammatory response. The dysregulation of numerous members of the tumour necrosis factor superfamily was also evident and suggests that they could play an important role in GML pathology, especially in light of their ability to promote and control lymphocyte proliferation.     

Effects of Helicobacter pylori eradication on the development of metachronous gastric cancer after endoscopic treatment: analysis of molecular alterations by a randomised controlled trial

Background:

Whether Helicobacter pylori eradication actually suppresses the development of metachronous gastric cancer (MGC) after endoscopic resection (ER) remains controversial. The aims of this study were to clarify (1) the molecular markers related to carcinogenesis in intestinal metaplasia (IM) by a cross-sectional study, and (2) the changes of those markers by an open-label, randomised controlled trial (RCT) of H. pylori treatment.

Methods:

First, we evaluated microsatellite instability (MSI), the methylation status at hMLH1, CDKN2A and APC genes, and immunoreactivity using the monoclonal antibody (mAb) Das-1 in IM in the background mucosa of 131 patients who underwent ER for gastric neoplasia and 22 chronic gastritis cases (control). Next, we performed an RCT to evaluate the changes of MSI between the H. pylori-eradicated (n=19) and non-eradicated patients (n=17) at 1 year among the H. pylori-positive patients.

Results:

Microsatellite instability and mAb Das-1 reactivity showed significantly higher incidences in both the H. pylori-positive and -negative patients compared with the control group, thus suggesting that MSI and mAb Das-1 reactivity are associated with gastric neoplasia (OR=5.06 for MSI; OR=2.51 for mAb Das-1 reactivity). The RCT showed that H. pylori eradication did not provide significant reversals of any molecular alterations including MSI (the primary end point) and other methylation statuses and mAb Das-1 reactivity (secondary end points).

Conclusions:

H. pylori eradication did not produce significant changes in the molecular alterations related to carcinogenesis, suggesting that H. pylori treatment may not prevent the development of MGC in background mucosa with IM.     

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.     

The Risk of Gastric Cancer in Patients with Duodenal and Gastric Ulcer: Research Progresses and Clinical Implications

Introduction

Although controversial, clinicians generally consider patients who present with gastric ulcer to have an increased risk of gastric cancer, while the risk for patients with duodenal ulcer is reduced in comparison with that of the general population. Infection with Helicobacter pylori and the use of non-steroidal anti-inflammatory drugs (NSAIDs) are the major causes for peptic ulcers, but their roles in relation to the risk of gastric cancer in patients with peptic ulcer may be different.

Methods and Results

This article reviewed existing literature to assess our understanding of the risk of gastric cancer in patients with gastric and duodenal ulcers more than 25 years after the discovery of H. pylori and also examined whether gastric ulcers induced by NSAID carry a lower risk of gastric cancer as compared to those induced by H. pylori infection or other causes.     

Regulatory T cells expressing abundant CTLA-4 on the cell surface with a proliferative gene profile are key features of human head and neck cancer

FOXP3⁺ regulatory T (Treg) cells suppress anti-tumor immunity. The suppression of Treg cells is regulated by cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4), whose expression on the cell surface is tightly regulated. Here we found that Treg cells expressing abundant CTLA-4 on the cell surface (surface-CTLA-4⁺ Treg) were expanded in human head and neck cancer tissues. RNA sequencing of surface-CTLA-4⁺ and surface-CTLA-4⁻ Treg cells infiltrating human head and neck cancer tissues revealed that surface-CTLA-4⁺ Treg cells have a previously undescribed gene expression profile correlating to cell cycle, cell proliferation, and DNA replication. Moreover, surface-CTLA-4⁺ Treg cells were PD-1⁺, actively proliferated and associated with CD45RA⁻ FOXP3^high Treg cells with strong suppressive function. Thus, surface-CTLA-4⁺ Treg cells with a proliferative gene expression signature and phenotype are key features of head and neck cancer. Targeting surface-CTLA-4⁺ Treg cells might be new strategies to evoke effective immune responses to head and neck cancer.     

The presence of a methylation fingerprint of Helicobacter pylori infection in human gastric mucosae

Aberrant DNA methylation is deeply involved in human cancers, but its inducers and targets are still mostly unclear. Helicobacter pylori infection was recently shown to induce aberrant methylation in gastric mucosae, and produce a predisposed field for cancerization. Here, we analyzed the presence of target genes in methylation induction by H. pylori and the mechanism for the gene specificity. Noncancerous gastric mucosae were collected from 4 groups of individuals (with and without a gastric cancer, and with and without current H. pylori infection; N = 11 for each group), and methylation of promoter CpG islands of 48 genes that can be methylated in gastric cancer cell lines was analyzed by methylation‐specific PCR. In total, 26 genes were consistently methylated in individuals with current or past infection by H. pylori, whereas 7 genes were not methylated at all. In addition, 14 genes were randomly or intermediately methylated in individuals with gastric cancers and the remaining 1 gene was methylated in all the cases. The methylation‐susceptible genes had significantly lower mRNA expression levels than the methylation‐resistant genes. H. pylori infection did not induce mRNA and protein expression of DNA methyltransferases; DNMT1, DNMT3A or DNMT3B. Gene specificity was present in the induction of aberrant DNA methylation by H. pylori infection, and low mRNA expression, which could precede methylation, was one of the mechanisms for the gene specificity. These findings open up the possibility that a methylation fingerprint can be used as a novel marker for past exposure to a specific carcinogenic factor. © 2008 Wiley‐Liss, Inc.