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1.
Gut ; 2019 Dec 19.
Artigo em Inglês | MEDLINE | ID: mdl-31857433

RESUMO

OBJECTIVE: Gastrointestinal microbiota may be involved in Helicobacter pylori-associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from H. pylori infection. DESIGN: Deep sequencing of the microbial 16S ribosomal RNA gene was used to investigate alterations in paired gastric biopsies and stool samples in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment, relative to 49 H . pylori negative subjects. RESULTS: In H. pylori positive subjects, richness and Shannon indexes increased significantly (both p<0.001) after successful eradication and showed no difference to those of negative subjects (p=0.493 for richness and p=0.420 for Shannon index). Differential taxa analysis identified 18 significantly altered gastric genera after eradication. The combination of these genera into a Microbial Dysbiosis Index revealed that the dysbiotic microbiota in H. pylori positive mucosa was associated with advanced gastric lesions (chronic atrophic gastritis and intestinal metaplasia/dysplasia) and could be reversed by eradication. Strong coexcluding interactions between Helicobacter and Fusobacterium, Neisseria, Prevotella, Veillonella, Rothia were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased Bifidobacterium after successful H. pylori eradication and more upregulated drug-resistant functional orthologs after failed treatment. CONCLUSION: H. pylori infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful H. pylori eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.

2.
BMJ ; 366: l5016, 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31511230

RESUMO

OBJECTIVE: To assess the effects of Helicobacter pylori treatment, vitamin supplementation, and garlic supplementation in the prevention of gastric cancer. DESIGN: Blinded randomized placebo controlled trial. SETTING: Linqu County, Shandong province, China. PARTICIPANTS: 3365 residents of a high risk region for gastric cancer. 2258 participants seropositive for antibodies to H pylori were randomly assigned to H pylori treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 H pylori seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design. INTERVENTIONS: H pylori treatment with amoxicillin and omeprazole for two weeks; vitamin (C, E, and selenium) and garlic (extract and oil) supplementation for 7.3 years (1995-2003). MAIN OUTCOME MEASURES: Primary outcomes were cumulative incidence of gastric cancer identified through scheduled gastroscopies and active clinical follow-up through 2017, and deaths due to gastric cancer ascertained from death certificates and hospital records. Secondary outcomes were associations with other cause specific deaths, including cancers or cardiovascular disease. RESULTS: 151 incident cases of gastric cancer and 94 deaths from gastric cancer were identified during 1995-2017. A protective effect of H pylori treatment on gastric cancer incidence persisted 22 years post-intervention (odds ratio 0.48, 95% confidence interval 0.32 to 0.71). Incidence decreased significantly with vitamin supplementation but not with garlic supplementation (0.64, 0.46 to 0.91 and 0.81, 0.57 to 1.13, respectively). All three interventions showed significant reductions in gastric cancer mortality: fully adjusted hazard ratio for H pylori treatment was 0.62 (95% confidence interval 0.39 to 0.99), for vitamin supplementation was 0.48 (0.31 to 0.75), and for garlic supplementation was 0.66 (0.43 to 1.00). Effects of H pylori treatment on both gastric cancer incidence and mortality and of vitamin supplementation on gastric cancer mortality appeared early, but the effects of vitamin supplementation on gastric cancer incidence and of garlic supplementation only appeared later. No statistically significant associations were found between interventions and other cancers or cardiovascular disease. CONCLUSIONS: H pylori treatment for two weeks and vitamin or garlic supplementation for seven years were associated with a statistically significant reduced risk of death due to gastric cancer for more than 22 years. H pylori treatment and vitamin supplementation were also associated with a statistically significantly reduced incidence of gastric cancer. TRIAL REGISTRATION: ClinicalTrials.gov NCT00339768.


Assuntos
Infecções por Helicobacter/terapia , Lesões Pré-Cancerosas/terapia , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antiulcerosos/administração & dosagem , Biópsia , China/epidemiologia , Suplementos Nutricionais , Quimioterapia Combinada/métodos , Feminino , Seguimentos , Alho/química , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastroscopia , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Extratos Vegetais/administração & dosagem , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Inibidores da Bomba de Prótons/administração & dosagem , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle , Análise de Sobrevida , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Vitaminas/administração & dosagem
3.
Clin Transl Gastroenterol ; 10(1): e00004, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30702489

RESUMO

OBJECTIVES: Molecular prognostic biomarkers for gastric cancer (GC) are still limited. We aimed to identify potential messenger RNAs (mRNAs) associated with GC prognosis and further establish an mRNA signature to predict the survival of GC based on the publicly accessible databases. METHODS: Discovery of potential mRNAs associated with GC survival was undertaken for 441 patients with GC based on the Cancer Genome Atlas (TCGA), with information on clinical characteristics and vital status. Gene ontology functional enrichment analysis and pathway enrichment analysis were conducted to interrogate the possible biological functions. We narrowed down the list of mRNAs for validation study based on a significance level of 1.00 × 10, also integrating the information from the methylation analysis and constructing the protein-protein interaction network for elucidating biological processes. A total of 54 mRNAs were further studied in the validation stage, using the Gene Expression Omnibus (GEO) database (GSE84437, n = 433). The validated mRNAs were used to construct a risk score model predicting the prognosis of GC. RESULTS: A total of 13 mRNAs were significantly associated with survival of GC, after the validation stage, including DCLK1, FLRT2, MCC, PRICKLE1, RIMS1, SLC25A15, SLCO2A1, CDO1, GHR, CD109, SELP, UPK1B, and CD36. Except CD36, DCLK1, and SLCO2A1, other mRNAs are newly reported to be associated with GC survival. The 13 mRNA-based risk score had good performance on distinguishing GC prognosis, with a higher score indicating worse survival in both TCGA and GEO datasets. CONCLUSIONS: We established a 13-mRNA signature to potentially predict the prognosis of patients with GC, which might be useful in clinical practice for informing patient stratification.


Assuntos
Biomarcadores Tumorais/metabolismo , RNA Mensageiro/metabolismo , Neoplasias Gástricas/mortalidade , Idoso , Biomarcadores Tumorais/genética , Conjuntos de Dados como Assunto , Feminino , Seguimentos , Perfilação da Expressão Gênica/métodos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos/métodos , Prognóstico , RNA Mensageiro/genética , Medição de Risco/métodos , Neoplasias Gástricas/genética , Transcriptoma
4.
Cancer Prev Res (Phila) ; 11(11): 717-726, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30213786

RESUMO

Nonclustered protocadherins (PCDH) family is a group of cell-cell adhesion molecules. We have found differentially methylated genes in the nonclustered PCDHs family associated with Helicobacter pylori (H. pylori) infection in prior genome-wide methylation analysis. To further investigate the methylation and expression of nonclustered PCDHs encoding genes in H. pylori--related gastric carcinogenesis process, four candidate genes including PCDH7, PCDH10, PCDH17, and PCDH20 were selected, which were reported to be tumor suppressors for digestive cancers. A total of 747 participants with a spectrum of gastric lesions were enrolled from a high-risk population of gastric cancer. Promoter methylation levels of four genes were significantly higher in H. pylori-positive subjects than the negative group (all P < 0.001). Elevated methylation levels of PCDH10 and PCDH17 were observed with the increasing severity of gastric lesions (both P trend < 0.001). In the protein expression analysis, PCDH17 expression was inversely associated with gastric lesions; the OR [95% confidence interval (CI)] was 0.49 (0.26-0.95) for chronic atrophic gastritis (CAG), 0.31 (0.15-0.63) for intestinal metaplasia, and 0.38 (0.19-0.75) for indefinite dysplasia and dysplasia, compared with superficial gastritis. In addition, PCDH10 expression was significantly lower in CAG (OR, 0.40; 95% CI, 0.24-0.68). The inverse association between methylation and protein expression of PCDH10 and PCDH17 was further supported when we explored the methylation and mRNA expression in The Cancer Genome Atlas database (all P < 0.001). Our study found elevated promoter methylation and decreased expression of PCDH10 and PCDH17 in advanced gastric lesions, suggesting that elevated PCDH10 and PCDH17 methylation may be an early event in gastric carcinogenesis. Cancer Prev Res; 11(11); 717-26. ©2018 AACR.


Assuntos
Caderinas/genética , Metilação de DNA , Infecções por Helicobacter/genética , Lesões Pré-Cancerosas/genética , Biópsia , Caderinas/metabolismo , Carcinogênese/genética , Conjuntos de Dados como Assunto , Feminino , Mucosa Gástrica/diagnóstico por imagem , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastroscopia , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/microbiologia , Infecções por Helicobacter/patologia , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Metaplasia/diagnóstico , Metaplasia/genética , Metaplasia/microbiologia , Metaplasia/patologia , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/diagnóstico , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Regiões Promotoras Genéticas/genética , Índice de Gravidade de Doença , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Neoplasias Gástricas/prevenção & controle
5.
Cancer Epidemiol Biomarkers Prev ; 27(12): 1472-1479, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30158280

RESUMO

BACKGROUND: Helicobacter pylori is the leading cause of gastric cancer, yet the majority of infected individuals will not develop neoplasia. Previously, we developed and replicated serologic H. pylori biomarkers for gastric cancer risk among prospective cohorts in East Asia and now seek to validate the performance of these biomarkers in identifying individuals with premalignant lesions. METHODS: This cross-sectional study included 1,402 individuals from Linqu County screened by upper endoscopy. H. pylori protein-specific antibody levels were assessed using multiplex serology. Multivariable-adjusted logistic regression models were used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for prevalent intestinal metaplasia, indefinite dysplasia, or dysplasia, compared with superficial or mild atrophic gastritis. RESULTS: Compared with individuals seronegative to Omp and HP0305, individuals seropositive to both were seven times more likely to have precancerous lesions (OR, 7.43; 95% CI, 5.59-9.88). A classification model for precancerous lesions that includes age, smoking, and seropositivity to H. pylori, Omp, and HP0305 resulted in an area under the curve (AUC) of 0.751 (95% CI, 0.725-0.777), which is significantly better than the same model, including the established gastric cancer risk factor CagA (AUC, 0.718; 95% CI, 0.691-0.746, P difference = 0.0002). CONCLUSIONS: The present study of prevalent precancerous gastric lesions provides support for two new serum biomarkers of gastric cancer risk, Omp and HP 0305. IMPACT: Our results support further research into the serological biomarkers Omp and HP0305 as possible improvements over the established virulence marker CagA for identifying individuals with precancerous lesions in East Asia.


Assuntos
Biomarcadores/sangue , Neoplasias Gástricas/diagnóstico , Estudos Transversais , Feminino , Humanos , Masculino , Fatores de Risco , Neoplasias Gástricas/epidemiologia
6.
Artigo em Inglês | MEDLINE | ID: mdl-29971220

RESUMO

Eradication of Helicobacter pylori has been found to be effective for gastric cancer prevention, but uncertainties remain about the possible adverse consequences such as the potential microbial dysbiosis. In our study, we investigated the association between gut microbiota and H. pylori-related gastric lesions in 47 subjects by deep sequencing of microbial 16S ribosomal RNA (rRNA) gene in fecal samples. The dominant phyla in fecal samples were Bacteroidetes, Firmicutes, and Proteobacteria with average relative abundances of 54.77, 31.37 and 12.91%, respectively. Microbial diversity analysis showed that observed species and Shannon index were increased in subjects with past or current H. pylori infection compared with negative subjects. As for the differential bacteria, the average relative abundance of Bacteroidetes was found to significantly decrease from H. pylori negative (66.16%) to past infection group (33.01%, p = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, p = 0.027). For Firmicutes and Proteobacteria, the average relative abundances showed elevated trends in the past H. pylori infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, p = 0.068 and 0.246, respectively), and similar increased trends were also found from normal (18.23, 5.05%) to gastritis (35.31, 7.23%, p = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both p < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of Bacteroidetes, Firmicutes and Proteobacteria, may be involved in the process of H. pylori-related gastric lesion progression and provide hints for future evaluation of microbial changes after H. pylori eradication.


Assuntos
DNA Bacteriano/genética , Microbioma Gastrointestinal/genética , Infecções por Helicobacter/microbiologia , Helicobacter pylori/genética , Neoplasias Gástricas/microbiologia , Adulto , Idoso , Disbiose/microbiologia , Disbiose/patologia , Fezes/microbiologia , Feminino , Mucosa Gástrica/microbiologia , Mucosa Gástrica/patologia , Gastrite/microbiologia , Gastrite/patologia , Infecções por Helicobacter/diagnóstico , Humanos , Masculino , Metaplasia/microbiologia , Metaplasia/patologia , Pessoa de Meia-Idade , Neoplasias Gástricas/patologia
7.
Sci Rep ; 7(1): 2072, 2017 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-28522798

RESUMO

The performance of diagnostic tests in intervention trials of Helicobacter pylori (H.pylori) eradication is crucial, since even minor inaccuracies can have major impact. To determine the cut-off point for 13C-urea breath test (13C-UBT) and to assess if it can be further optimized by serologic testing, mathematic modeling, histopathology and serologic validation were applied. A finite mixture model (FMM) was developed in 21,857 subjects, and an independent validation by modified Giemsa staining was conducted in 300 selected subjects. H.pylori status was determined using recomLine H.pylori assay in 2,113 subjects with a borderline 13C-UBT results. The delta over baseline-value (DOB) of 3.8 was an optimal cut-off point by a FMM in modelling dataset, which was further validated as the most appropriate cut-off point by Giemsa staining (sensitivity = 94.53%, specificity = 92.93%). In the borderline population, 1,468 subjects were determined as H.pylori positive by recomLine (69.5%). A significant correlation between the number of positive H.pylori serum responses and DOB value was found (rs = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for 13C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of 13C-UBT was necessary and recommended.


Assuntos
Algoritmos , Testes Respiratórios/métodos , Infecções por Helicobacter/diagnóstico , Técnicas de Diagnóstico Molecular/normas , Neoplasias Gástricas/diagnóstico , Adulto , Isótopos de Carbono , Ensaios Clínicos como Assunto , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Neoplasias Gástricas/microbiologia , Ureia
8.
Int J Cancer ; 140(3): 591-599, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27759938

RESUMO

Epidemiological findings on the association between fruit and vegetable consumption and gastric cancer risk remain inconsistent. The present analysis included 810 prospectively ascertained non-cardia gastric cancer cases and 1,160 matched controls from the Helicobacter pylori Biomarker Cohort Consortium, which collected blood samples, demographic, lifestyle, and dietary data at baseline. Conditional logistic regression adjusting for total energy intake, smoking, and H. pylori status, was applied to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for gastric cancer risk across cohort- and sex-specific quartiles of fruit and vegetable intake. Increasing fruit intake was associated with decreasing risk of non-cardia gastric cancer (OR = 0.71, 95% CI: 0.52-0.95, p trend = 0.02). Compared to low-fruit consumers infected with CagA-positive H. pylori, high-fruit consumers without evidence of H. pylori antibodies had the lowest odds for gastric cancer incidence (OR = 0.12, 95% CI: 0.06-0.25), whereby the inverse association with high-fruit consumption was attenuated among individuals infected with CagA-positive H. pylori (OR = 0.82, 95% CI: 0.66-1.03). To note, the small number of H. pylori negative individuals does influence this finding. We observed a weaker, nondose-response suggestion of an inverse association of vegetable intake with non-cardia gastric cancer risk. High fruit intake may play a role in decreasing risk of non-cardia gastric cancer in Asia.


Assuntos
Anticorpos Antibacterianos/imunologia , Infecções por Helicobacter/complicações , Neoplasias Gástricas/etiologia , Idoso , Estudos de Casos e Controles , China , Dieta , Ingestão de Energia/fisiologia , Feminino , Frutas , Infecções por Helicobacter/imunologia , Helicobacter pylori , Humanos , Incidência , Japão , Estilo de Vida , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , República da Coreia , Fatores de Risco , Neoplasias Gástricas/microbiologia , Verduras
9.
Oncotarget ; 7(24): 37132-37144, 2016 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-27206798

RESUMO

PURPOSE: To investigate Helicobacter pylori (H.pylori) associated genome-wide aberrant methylation patterns in gastric mucosa and blood leukocyte DNA, a population-based study was conducted in Linqu County. RESULTS: A total of 3000 and 386 CpGs were differentially methylated after successful H.pylori eradication in gastric mucosa and blood leukocyte DNA respectively, and 17 were the same alteration trend in the both tissues. The differentially methylated CpGs were located more frequently in promoters or CpG islands for gastric mucosa and gene body or open sea for blood leukocyte DNA. In eradicated gastric mucosa, the hypermethylated CpGs were enriched across inflammatory pathways, while the hypomethylated CpGs in tube morphogenesis, development and so on. The final validation found lower SPI1, PRIC285 and S1PR4 methylation levels in H.pylori positive subjects by case-control comparison, and increased methylation levels in H.pylori eradicated gastric mucosa by self-comparison. The Cancer Genome Atlas (TCGA) database analysis suggested that the up-regulation of the three genes by hypomethylation might be associated with gastric carcinogenesis. EXPERIMENTAL DESIGN: Infinium HumanMethylation 450K BeadChip was used to compare methylation profiles prior to and after eradication treatment. The methylation levels of identified candidate differentially methylated genes before and after H.pylori eradication were further validated by two stages (Stage I: self-comparison of 16 subjects before and after anti-H.pylori treatment; Stage II: case-control comparison of 25 H.pylori positive and 25 negative subjects and self-comparison of 50 anti-H.pylori treated subjects). CONCLUSIONS: Novel H.pylori associated aberrant methylated genes were identified across the whole genome both in gastric mucosa and blood leukocyte DNA.


Assuntos
Metilação de DNA , Mucosa Gástrica/metabolismo , Infecções por Helicobacter/genética , Helicobacter pylori/metabolismo , Leucócitos/metabolismo , Adulto , Carcinogênese/genética , Estudos de Casos e Controles , Ilhas de CpG/genética , Feminino , Regulação da Expressão Gênica , Infecções por Helicobacter/sangue , Infecções por Helicobacter/tratamento farmacológico , Infecções por Helicobacter/microbiologia , Helicobacter pylori/isolamento & purificação , Humanos , Masculino , Pessoa de Meia-Idade , Regiões Promotoras Genéticas , Proteínas Proto-Oncogênicas/metabolismo , Receptores de Lisoesfingolipídeo/metabolismo , Neoplasias Gástricas/genética , Transativadores/metabolismo , Regulação para Cima
10.
Cancer Prev Res (Phila) ; 9(6): 484-90, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27020655

RESUMO

To explore the epigenetic mechanisms underlying the effects of anti-Helicobacter pylori (H. pylori) alone and combined with COX-2 inhibitor (celecoxib), we dynamically evaluated the associations between COX-2 methylation alterations and gastric lesion evolution during the process of interventions. In a total of 809 trial participants COX-2 methylation levels were quantitatively detected before and after treatment. The self-comparison at the same stomach site for each subject showed significant methylation alteration differences among intervention groups (P < 0.001). With placebo group as reference, COX-2 methylation levels were decreased in anti-H. pylori [OR, 3.30; 95% confidence interval (CI), 2.16-5.02], celecoxib (OR, 2.04; 95% CI, 1.36-3.07), and anti-H. pylori followed by celecoxib (OR, 2.10; 95% CI, 1.38-3.17) groups. When stratified by baseline histology, the three active arms significantly decreased COX-2 methylation levels in indefinite dysplasia/dysplasia subjects, and ORs were 3.65 (95% CI, 1.96-6.80) for anti-H. pylori, 2.43 (95% CI 1.34-4.39) for celecoxib, and 2.80 (95% CI, 1.52-5.15) for anti-H. pylori followed by celecoxib, respectively. No additive effect on COX-2 methylation was found for anti-H. pylori followed by celecoxib than two treatments alone. Compared with subjects without methylation reduction, higher opportunity for gastric lesion regression was found in subjects with decreased COX-2 methylation levels, especially for indefinite dysplasia/dysplasia subjects (OR, 1.92; 95% CI, 1.03-3.60). These findings suggest that anti-H. pylori or celecoxib treatment alone could decrease COX-2 methylation levels in gastric mucosa. COX-2 methylation alteration was associated with the regression of indefinite dysplasia/dysplasia, which might serve as a potential biomarker for chemoprevention efficacy. Cancer Prev Res; 9(6); 484-90. ©2016 AACR.


Assuntos
Antibacterianos/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/genética , Metilação de DNA/efeitos dos fármacos , Neoplasias Gástricas/genética , Adulto , Cromatografia Líquida de Alta Pressão , Feminino , Infecções por Helicobacter/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/prevenção & controle
11.
Cancer Epidemiol ; 41: 122-8, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26943853

RESUMO

BACKGROUND: To explore the association between hypomethylation of repetitive elements (LINE-1, Sat2, and ALU) in blood leukocyte DNA and risks of gastric lesions, and development of gastric cancer (GC), a population-based study was conducted in a high-risk area of GC in China. MATERIALS: Methylation levels were determined by MethyLight in 902 subjects with various gastric lesions from two cohort studies at baseline and 276 subjects with long-term follow-up data. RESULTS: The frequency of LINE-1 or Sat2 hypomethylation was significantly increased in subjects with dysplasia (DYS) compared with superficial gastritis/chronic atrophic gastritis. The odds ratios (ORs) were 2.22 [95% confidence interval (CI): 1.45-3.40] for LINE-1 and 1.58 (95% CI: 1.14-2.21) for Sat2. A dose-response pattern was found for the risk of DYS and LINE-1 hypomethylation (P-trend<0.001). Further stratified analysis indicated that the frequency of LINE-1 or Sat2 hypomethylation was higher in subjects with Helicobacter pylori infection. The ORs were 1.83 (95% CI: 1.12-2.99) for LINE-1 and 1.44 (95% CI: 1.01-2.05) for Sat2. The follow-up data indicated that the risk of progression to GC was increased in intestinal metaplasia (IM) subjects with LINE-1 hypomethylation (OR=2.82; 95% CI: 1.17-6.77) or Sat2 hypomethylation (OR=2.78; 95% CI: 1.15-6.74). The risk of progression to GC was also increased in DYS subjects with Sat2 hypomethylation (OR=5.24; 95% CI: 2.00-13.74). CONCLUSIONS: These findings suggest that hypomethylation of repetitive elements in blood leukocytes is associated with the risks of advanced gastric lesions and development of GC.


Assuntos
Metilação de DNA , Infecções por Helicobacter/epidemiologia , Lesões Pré-Cancerosas/epidemiologia , Neoplasias Gástricas/epidemiologia , Adulto , Idoso , Grupo com Ancestrais do Continente Asiático/genética , China , Estudos de Coortes , Progressão da Doença , Feminino , Infecções por Helicobacter/genética , Humanos , Leucócitos/patologia , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Risco , Neoplasias Gástricas/genética
12.
Gut ; 65(1): 9-18, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-25986943

RESUMO

OBJECTIVE: To clarify the full range of benefits and adverse consequences of Helicobacter pylori eradication as a strategy for gastric cancer prevention, the community-based intervention trial was launched in Linqu County, China. DESIGN: A total of 184,786 residents aged 25-54 years were enrolled in this trial and received (13)C-urea breath test. H. pylori positive participants were assigned into two groups, either receiving a 10-day quadruple anti-H. pylori treatment or lookalike placebos together with a single dosage of omeprazole and bismuth. RESULTS: The prevalence of H. pylori in trial participants was 57.6%. A total of 94,101 subjects completed the treatment. The overall H. pylori eradication rate was 72.9% in the active group. Gender, body mass index, history of stomach disease, baseline delta over baseline-value of (13)C-urea breath test, missed medication doses, smoking and drinking were independent predictors of eradication failure. The missed doses and high baseline delta over baseline-value were important contributors in men and women (all Ptrend<0.001). However, a dose-response relationship between failure rate and smoking or drinking index was found in men (all Ptrend<0.001), while high body mass index (Ptrend<0.001) and history of stomach disease were significant predictors in women. The treatment failure rate increased up to 48.8% (OR 2.87, 95% CI 2.24 to 3.68) in men and 39.4% (OR 2.67, 95% CI 1.61 to 4.42) in women with multiple factors combined. CONCLUSIONS: This large community-based intervention trial to eradicate H. pylori is feasible and acceptable. The findings of this trial lead to a distinct evaluation of factors influencing eradication that should be generally considered for future eradication therapies. TRIAL REGISTRATION NUMBER: ChiCTR-TRC-10000979 in accordance with WHO ICTRP requirements.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori , Neoplasias Gástricas/prevenção & controle , Adulto , Antiulcerosos/uso terapêutico , China , Método Duplo-Cego , Quimioterapia Combinada , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/diagnóstico , Humanos , Masculino , Metronidazol/uso terapêutico , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias Gástricas/microbiologia , Tetraciclina/uso terapêutico , Resultado do Tratamento
13.
Tumour Biol ; 37(2): 2233-42, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26358252

RESUMO

Helicobacter pylori (H. pylori) infection and cytokine-mediated inflammatory responses play important roles in gastric cancer (GC) pathogenesis. To investigate an association between genetic polymorphisms in interleukin (IL)-1ß, IL-4R, IL-8, IL-10, IL-16, IL-18RAP, IL-22, and IL-32 and risks of GC and its precursors, a population-based study was conducted in Linqu County. Genotypes were determined by Sequenom MassARRAY platform in 132 GC cases and 1198 subjects with gastric lesions. The H. pylori status was determined by (13)C-urea breath test ((13)C-UBT) or enzyme-linked immunosorbent assay (ELISA). Among 11 candidate single nucleotide polymorphisms (SNPs), subjects carrying IL-18RAP rs917997 AA genotype were associated with risk of GC [adjusted odds ratio (OR) = 1.83, 95 % confidence interval (CI) 1.14-2.92] or chronic atrophic gastritis (CAG; OR = 1.55, 95 % CI 1.07-2.24). The risk of GC was also increased in subjects carrying IL-32 rs2015620 A allele (AA + AT; OR = 1.92, 95 % CI 1.09-3.39). Moreover, elevated risks of CAG (OR = 2.64, 95 % CI 1.89-3.69), intestinal metaplasia (IM; OR = 5.58, 95 % CI 3.86-8.05), and dysplasia (DYS; OR = 1.64, 95 % CI 1.18-2.26) were observed in subjects with IL-22 rs1179251 CC genotype. Stratified analysis indicated that risks of GC and its precursors were elevated in subjects with IL-32 rs2015620 A allele (AA + AT) or IL-22 rs1179251 CC genotype and H. pylori infection, and significant interactions between these two SNPs and H. pylori infection were found. These findings suggested that IL-18RAP rs917997, IL-32 rs2015620, IL-22 rs1179251, and interactions between these polymorphisms and H. pylori infection were associated with risks of gastric lesions. Genetic polymorphisms of interleukins may play crucial roles in H. pylori-induced gastric carcinogenesis.


Assuntos
Predisposição Genética para Doença/genética , Subunidade beta de Receptor de Interleucina-18/genética , Interleucinas/genética , Polimorfismo de Nucleotídeo Único , Lesões Pré-Cancerosas/genética , Neoplasias Gástricas/genética , Adulto , Grupo com Ancestrais do Continente Asiático/genética , Ensaio de Imunoadsorção Enzimática , Feminino , Genótipo , Infecções por Helicobacter/complicações , Infecções por Helicobacter/genética , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Lesões Pré-Cancerosas/microbiologia , Neoplasias Gástricas/microbiologia
14.
BMC Cancer ; 15: 979, 2015 Dec 16.
Artigo em Inglês | MEDLINE | ID: mdl-26674784

RESUMO

BACKGROUND: Methylation is a common epigenetic modification which may play a crucial role in cancer development. To investigate the association between methylation of COX-2 in blood leukocyte DNA and risk of gastric cancer (GC), a nested case-control study was conducted in Linqu County, Shandong Province, a high risk area of GC in China. METHODS: Association between blood leukocyte DNA methylation of COX-2 and risk of GC was investigated in 133 GCs and 285 superficial gastritis (SG)/ chronic atrophic gastritis (CAG). The temporal trend of COX-2 methylation level during GC development was further explored in 74 pre-GC and 95 post-GC samples (including 31 cases with both pre- and post-GC samples). In addition, the association of DNA methylation and risk of progression to GC was evaluated in 74 pre-GC samples and their relevant intestinal metaplasia (IM)/dysplasia (DYS) controls. Methylation level was determined by quantitative methylation-specific PCR (QMSP). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression analysis. RESULTS: The medians of COX-2 methylation levels were 2.3% and 2.2% in GC cases and controls, respectively. No significant association was found between COX-2 methylation and risk of GC (OR, 1.15; 95% CI: 0.70-1.88). However, the temporal trend analysis showed that COX-2 methylation levels were elevated at 1-4 years ahead of clinical GC diagnosis compared with the year of GC diagnosis (3.0% vs. 2.2%, p=0.01). Further validation in 31 GCs with both pre- and post-GC samples indicated that COX-2 methylation levels were significantly decreased at the year of GC diagnosis compared with pre-GC samples (1.5% vs. 2.5%, p=0.02). No significant association between COX-2 methylation and risk of progression to GC was found in subjects with IM (OR, 0.50; 95% CI: 0.18-1.42) or DYS (OR, 0.70; 95% CI: 0.23-2.18). Additionally, we found that elder people had increased risk of COX-2 hypermethylation (OR, 1.55; 95% CI: 1.02-2.36) and subjects who ever infected with H. pylori had decreased risk of COX-2 hypermethylation (OR, 0.54; 95% CI: 0.34-0.88). CONCLUSIONS: COX-2 methylation exists in blood leukocyte DNA but at a low level. COX-2 methylation levels in blood leukocyte DNA may change during GC development.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Ciclo-Oxigenase 2/genética , Leucócitos , Neoplasias Gástricas/genética , Idoso , Estudos de Casos e Controles , DNA , Metilação de DNA/genética , Feminino , Infecções por Helicobacter/complicações , Infecções por Helicobacter/epidemiologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Reação em Cadeia da Polimerase em Tempo Real , Fatores de Risco , Neoplasias Gástricas/sangue , Neoplasias Gástricas/enzimologia
15.
Carcinogenesis ; 36(12): 1572-9, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26449252

RESUMO

To investigate the role of cyclooxygenase (COX)-2/prostaglandin E2 (PGE2) in the process of Helicobacter pylori-induced gastric carcinogenesis, a prospective study based on an intervention trial was conducted in Linqu County, China. A total of 1401 subjects with histopathologic diagnosis were investigated at baseline, among those, 919 completed subsequent interventions (anti-H.pylori and/or celecoxib treatment). Expressions of COX-2 and Ki-67 were assessed by immunohistochemistry, and PGE2 levels were measured by enzyme immunoassay before and after interventions, respectively. We found a grade-response relationship between COX-2 expression level and risk of advanced gastric lesions at baseline. Stratified analysis indicated an additive interaction between COX-2 expression and H.pylori infection on the elevated risk of advanced gastric lesions. The odds ratios (ORs) for both factors combined were 9.31 [95% confidence interval (CI): 4.13-20.95] for chronic atrophic gastritis, 16.26 (95% CI: 7.29-36.24) for intestinal metaplasia and 21.13 (95% CI: 7.87-56.75) for dysplasia, respectively. After interventions, COX-2 expression and Ki-67 labeling index (LI) were decreased in anti-H.pylori group (OR: 1.65, 95% CI: 1.36-1.99 for COX-2; OR: 1.78, 95% CI: 1.49-2.12 for Ki-67) or anti-H.pylori followed by celecoxib group (OR: 1.41, 95% CI: 1.17-1.70 for COX-2; OR: 1.63, 95% CI: 1.37-1.94 for Ki-67). PGE2 levels were decreased in all treatment groups. Furthermore, the regression of gastric lesions was associated with the decrease of COX-2 expression or Ki-67 LI after interventions. Our findings indicate that H.pylori-induced COX-2/PGE2 pathways play an important role on the progression of precancerous gastric lesions in a Chinese population.


Assuntos
Celecoxib/uso terapêutico , Inibidores de Ciclo-Oxigenase 2/uso terapêutico , Ciclo-Oxigenase 2/metabolismo , Infecções por Helicobacter/tratamento farmacológico , Lesões Pré-Cancerosas/tratamento farmacológico , Neoplasias Gástricas/prevenção & controle , Adulto , Amoxicilina/uso terapêutico , Antibacterianos/uso terapêutico , China , Claritromicina/uso terapêutico , Dinoprostona/metabolismo , Método Duplo-Cego , Feminino , Infecções por Helicobacter/enzimologia , Infecções por Helicobacter/microbiologia , Helicobacter pylori/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Omeprazol/uso terapêutico , Lesões Pré-Cancerosas/enzimologia , Lesões Pré-Cancerosas/microbiologia , Estômago/enzimologia , Estômago/imunologia , Estômago/microbiologia , Neoplasias Gástricas/enzimologia , Neoplasias Gástricas/microbiologia
16.
PLoS One ; 10(5): e0124949, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-25933107

RESUMO

BACKGROUND: Genetic variants of nucleotide-binding oligomerization domain-containing protein (NOD) may influence the outcome of Helicobacter pylori (H. pylori) infection and gastric carcinogenesis. To explore genetic variants of NOD1 and NOD2 in association with gastric cancer (GC) and its precursors, a population-based study was conducted in Linqu County, China. METHODS: TagSNPs of NOD1 and NOD2 were genotyped by Sequenom MASS array in 132 GCs, and 1,198 subjects with precancerous gastric lesions, and were correlated with evolution of gastric lesions in 766 subjects with follow-up data. RESULTS: Among seven tagSNPs, NOD1 rs2709800 and NOD2 rs718226 were associated with gastric lesions. NOD1 rs2709800 TG genotype carriers had a decreased risk of intestinal metaplasia (IM, OR: 0.53; 95% CI: 0.31-0.92), while NOD2 rs718226 G allele (AG/GG) showed increased risks of dysplasia (DYS, OR: 2.96; 95% CI: 1.86-4.71) and GC (OR: 2.35; 95% CI: 1.24-4.46). Moreover, an additive interaction between rs718226 and H. pylori was found in DYS or GC with synergy index of 3.08 (95% CI: 1.38-6.87) or 3.99 (95% CI: 1.55-10.22), respectively. The follow-up data indicated that NOD2 rs2111235 C allele (OR: 0.52; 95% CI: 0.32-0.83) and rs7205423 G allele (OR: 0.56; 95% CI: 0.35-0.89) were associated with decreased risk of progression in H. pylori-infected subjects. CONCLUSIONS: NOD1 rs2709800, NOD2 rs718226, rs2111235, rs7205423 and interaction between rs718226 and H. pylori infection may be related to risk of gastric lesions.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Proteína Adaptadora de Sinalização NOD1/genética , Proteína Adaptadora de Sinalização NOD2/genética , Polimorfismo de Nucleotídeo Único/genética , Lesões Pré-Cancerosas/genética , Neoplasias Gástricas/genética , Progressão da Doença , Feminino , Infecções por Helicobacter/complicações , Humanos , Masculino , Pessoa de Meia-Idade , Lesões Pré-Cancerosas/patologia , Fatores de Risco , Neoplasias Gástricas/microbiologia
17.
Infect Genet Evol ; 31: 263-9, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25687912

RESUMO

Genetic polymorphisms of Toll-like receptor (TLR) 1 and 10 may influence Helicobacter pylori (H. pylori) susceptibility. To evaluate associations between TLR1 and 10 polymorphisms, H. pylori infection, and precancerous gastric lesions, a population-based study was conducted in a high-risk Chinese population. Three single-nucleotide polymorphisms, TLR1 rs4833095, TLR10 rs10004195, and TLR10 rs4129009 were genotyped by TaqMan SNP genotyping assay in 2553 participants with diverse gastric lesions. The status of H. pylori infection was determined by (13)C-urea breath test. TLR1 rs4833095 T and TLR10 rs10004195 T alleles were the minor alleles and showed in linkage disequilibrium (D'=0.98, r(2)=0.73) in the Chinese population. A decreased risk of H. pylori infection was observed in subjects with TLR1 rs4833095 CT genotype [adjusted odds ratio (OR)=0.80; 95% confidence interval (CI): 0.66-0.96] or T allele (OR=0.82; 95%CI: 0.69-0.99). Moreover, subjects carrying TLR1 rs4833095 TT genotype were associated with reduced risks of chronic atrophic gastritis (CAG, OR=0.66; 95%CI: 0.45-0.97) and intestinal metaplasia (IM, OR=0.57; 95%CI: 0.36-0.90). The risk of CAG was also decreased in subjects carrying TLR10 rs10004195 T allele (OR=0.75; 95%CI: 0.57-0.99). Furthermore, haplotype analysis indicated that haplotype TT of rs4833095 and rs10004195 had a protective effect on H. pylori infection (OR=0.83; 95%CI: 0.72-0.96) or precancerous gastric lesions (OR=0.78; 95%CI: 0.64-0.96 for CAG, and OR=0.74; 95%CI: 0.57-0.96 for IM). These findings suggest that TLR1 rs4833095 and TLR10 rs10004195 may play crucial roles in H. pylori susceptibility and gastric pathogenesis.


Assuntos
Suscetibilidade a Doenças , Infecções por Helicobacter/genética , Helicobacter pylori , Polimorfismo Genético , Gastropatias/etiologia , Receptor 10 Toll-Like/genética , Receptor 1 Toll-Like/genética , Adulto , Alelos , Grupo com Ancestrais do Continente Asiático/genética , China , Feminino , Predisposição Genética para Doença , Genótipo , Haplótipos , Infecções por Helicobacter/diagnóstico , Infecções por Helicobacter/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Polimorfismo de Nucleotídeo Único , Fatores de Risco , Gastropatias/patologia , Neoplasias Gástricas/etiologia , Neoplasias Gástricas/patologia
19.
Cancer Epidemiol Biomarkers Prev ; 23(10): 2019-26, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25086101

RESUMO

BACKGROUND: To evaluate the relationship between methylation status of blood leukocyte DNA and risk of gastric cancer, a population-based study was conducted in Linqu County. METHODS: Methylation levels of IGFII and N33 were determined by quantitative methylation-specific PCR. The temporal trend of methylation levels during gastric cancer development was investigated in 133 gastric cancer cases from two cohorts with pre- and/or post-gastric cancer samples. As the references of pre-GCs, 204 intestinal metaplasia (IM) or dysplasia (DYS) subjects who did not progress to gastric cancer during the follow-up period were selected. Meanwhile, 285 subjects with superficial gastritis/chronic atrophic gastritis (SG/CAG) were also selected as controls. RESULTS: IGFII median methylation level was significantly higher in gastric cancer cases than those with SG/CAG (61.47% vs. 49.73%; P < 0.001). IGFII and N33 methylation levels were elevated at least 5 years ahead of clinical gastric cancer diagnosis comparing with SG/CAG (63.38% vs. 49.73% for IGFII, 9.12% vs. 5.70% for N33; all P < 0.001). Furthermore, the frequency of hypermethylated IGFII was markedly increased in IM or DYS subjects who progressed to gastric cancer in contrast to those who remained with IM and DYS, and adjusted ORs were 12.52 [95% confidence interval (CI), 3.81-41.15] for IM and 10.12 (95% CI, 2.68-38.22) for DYS. Similar results were also found for N33 in subjects with IM (OR, 3.77; 95% CI, 1.20-11.86). CONCLUSIONS: Our findings suggested that hypermethylated IGFII and N33 in blood leukocyte DNA were associated with risk of gastric cancer in a Chinese population. IMPACT: IGFII and N33 methylation status may be related to gastric carcinogenesis.


Assuntos
Grupo com Ancestrais do Continente Asiático/genética , Metilação de DNA/genética , Fator de Crescimento Insulin-Like II/genética , Proteínas de Membrana/genética , Lesões Pré-Cancerosas/genética , Neoplasias Gástricas/genética , Proteínas Supressoras de Tumor/genética , Idoso , Biomarcadores Tumorais/genética , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Leucócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Neoplasias Gástricas/sangue
20.
J Natl Cancer Inst ; 106(7)2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24925350

RESUMO

Among 2258 Helicobacter pylori-seropositive subjects randomly assigned to receive one-time H. pylori treatment with amoxicillin-omeprazole or its placebo, we evaluated the 15-year effect of treatment on gastric cancer incidence and mortality in subgroups defined by age, baseline gastric histopathology, and post-treatment infection status. We used conditional logistic and Cox regressions for covariable adjustments in incidence and mortality analyses, respectively. Treatment was associated with a statistically significant decrease in gastric cancer incidence (odds ratio = 0.36; 95% confidence interval [CI] = 0.17 to 0.79) and mortality (hazard ratio = 0.26; 95% CI = 0.09 to 0.79) at ages 55 years and older and a statistically significant decrease in incidence among those with intestinal metaplasia or dysplasia at baseline (odds ratio = 0.56; 95% CI = 0.34 to 0.91). Treatment benefits for incidence and mortality among those with and without post-treatment infection were similar. Thus H. pylori treatment can benefit older members and those with advanced baseline histopathology, and benefits are present even with post-treatment infection, suggesting treatment can benefit an entire population, not just the young or those with mild histopathology.


Assuntos
Antibacterianos/uso terapêutico , Infecções por Helicobacter/tratamento farmacológico , Helicobacter pylori/efeitos dos fármacos , Lesões Pré-Cancerosas/tratamento farmacológico , Neoplasias Gástricas/epidemiologia , Neoplasias Gástricas/prevenção & controle , Adulto , Fatores Etários , Idoso , Amoxicilina/uso terapêutico , Quimioterapia Combinada , Feminino , Seguimentos , Infecções por Helicobacter/complicações , Humanos , Incidência , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Razão de Chances , Omeprazol/uso terapêutico , Lesões Pré-Cancerosas/microbiologia , Lesões Pré-Cancerosas/patologia , Modelos de Riscos Proporcionais , Ensaios Clínicos Controlados Aleatórios como Assunto , Neoplasias Gástricas/microbiologia , Neoplasias Gástricas/mortalidade , Resultado do Tratamento
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