Publications by authors named "Wei-Cheng You"

91 Publications

Proteomic profiling identifies signatures associated with progression of precancerous gastric lesions and risk of early gastric cancer.

EBioMedicine 2021 Nov 21;74:103714. Epub 2021 Nov 21.

State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China. Electronic address:

Background: Molecular features underlining the multistage progression of gastric lesions and development of early gastric cancer (GC) are poorly understood, restricting the ability to GC prevention and management.

Methods: We portrayed proteomic landscape and explored proteomic signatures associated with progression of gastric lesions and risk of early GC. Tissue proteomic profiling was conducted for a total of 324 subjects. A case-control study was performed in the discovery stage (n=169) based on populations from Linqu, a known high-risk area for GC in China. We then conducted two-stage validation, including a cohort study from Linqu (n = 56), with prospective follow-up for progression of gastric lesions (280-473 days), and an independent case-control study from Beijing (n = 99).

Findings: There was a clear distinction in proteomic features for precancerous gastric lesions and GC. We derived four molecular subtypes of gastric lesions and identified subtype-S4 with the highest progression risk. We found 104 positively-associated and 113 inversely-associated proteins for early GC, with APOA1BP, PGC, HPX and DDT associated with the risk of gastric lesion progression. Integrating these proteomic signatures, the ability to predict progression of gastric lesions was significantly strengthened (areas-under-the-curve=0.88 (95%CI: 0.78-0.99) vs. 0.56 (0.36-0.76), Delong's P = 0.002). Immunohistochemistry assays and examination at mRNA level validated the findings for four proteins.

Interpretation: We defined proteomic signatures for progression of gastric lesions and risk of early GC, which may have translational significance for identifying particularly high-risk population and detecting GC at an early stage, improving potential for targeted GC prevention.

Funding: The funders are listed in the Acknowledgement.
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http://dx.doi.org/10.1016/j.ebiom.2021.103714DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8617343PMC
November 2021

Identification and Validation of Plasma Metabolomic Signatures in Precancerous Gastric Lesions That Progress to Cancer.

JAMA Netw Open 2021 Jun 1;4(6):e2114186. Epub 2021 Jun 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.

Importance: Metabolic deregulation plays an important role in gastric cancer (GC) development. To date, no studies have comprehensively explored the metabolomic profiles along the cascade of gastric lesions toward GC.

Objective: To draw a metabolic landscape and define metabolomic signatures associated with the progression of gastric lesions and risk of early GC.

Design, Setting, And Participants: A 2-stage, population-based cohort study was initiated in 2017 in Linqu County, Shandong Province, China, a high-risk area for GC. Prospective follow-up was conducted during the validation stage (June 20, 2017, to May 27, 2020). A total of 400 individuals were included based on the National Upper Gastrointestinal Cancer Early Detection Program in China. The discovery stage involved 200 individuals with different gastric lesions or GC (high-grade intraepithelial neoplasia or invasive GC). The validation stage prospectively enrolled 152 individuals with gastric lesions who were followed up for 118 to 1063 days and 48 individuals with GC.

Exposures: Metabolomic profiles and metabolite signatures were examined based on untargeted plasma metabolomics assay.

Main Outcomes And Measures: The risk of GC overall and early GC (high-grade intraepithelial neoplasia), and progression of gastric lesions.

Results: Of the 400 participants, 124 of 200 (62.0%) in the discovery set were men; mean (SD) age was 56.8 (7.5) years. In the validation set, 136 of 200 (68.0%) were men; mean (SD) age was 57.5 (8.1) years. Distinct metabolomic profiles were noted for gastric lesions and GC. Six metabolites, including α-linolenic acid, linoleic acid, palmitic acid, arachidonic acid, sn-1 lysophosphatidylcholine (LysoPC)(18:3), and sn-2 LysoPC(20:3) were significantly inversely associated with risk of GC overall and early GC (high-grade intraepithelial neoplasia). Among these metabolites, the first 3 were significantly inversely associated with gastric lesion progression, especially for the progression of intestinal metaplasia (α-linolenic acid: OR, 0.42; 95% CI, 0.18-0.98; linoleic acid: OR, 0.43; 95% CI, 0.19-1.00; and palmitic acid: OR, 0.32; 95% CI, 0.13-0.78). Compared with models including only age, sex, Helicobacter pylori infection, and gastric histopathologic findings, integrating these metabolites significantly improved the performance for predicting the progression of gastric lesions (area under the curve [AUC], 0.86; 95% CI, 0.70-1.00 vs AUC, 0.69; 95% CI, 0.50-0.88; P = .02) and risk of early GC (AUC, 0.83; 95% CI, 0.58-1.00 vs AUC, 0.61; 95% CI, 0.31-0.91; P = .03).

Conclusions And Relevance: This study defined metabolite signatures that might serve as meaningful biomarkers for assessing high-risk populations and early diagnosis of GC, possibly advancing targeted GC prevention and control.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.14186DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8220475PMC
June 2021

DNA methylation signatures associated with prognosis of gastric cancer.

BMC Cancer 2021 May 25;21(1):610. Epub 2021 May 25.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fucheng Rd, Haidian District, Beijing, 100142, People's Republic of China.

Background: Few studies have examined prognostic outcomes-associated molecular signatures other than overall survival (OS) for gastric cancer (GC). We aimed to identify DNA methylation biomarkers associated with multiple prognostic outcomes of GC in an epigenome-wide association study.

Methods: Based on the Cancer Genome Atlas (TCGA), DNA methylation loci associated with OS (n = 381), disease-specific survival (DSS, n = 372), and progression-free interval (PFI, n = 383) were discovered in training set subjects (false discovery rates < 0.05) randomly selected for each prognostic outcome and were then validated in remaining subjects (P-values < 0.05). Key CpGs simultaneously validated for OS, DSS, and PFI were further assessed for disease-free interval (DFI, n = 247). Gene set enrichment analyses were conducted to explore the Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathways simultaneously enriched for multiple GC prognostic outcomes. Methylation correlated blocks (MCBs) were identified for co-methylation patterns associated with GC prognosis. Based on key CpGs, risk score models were established to predict four prognostic outcomes. Spearman correlation analyses were performed between key CpG sites and their host gene mRNA expression.

Results: We newly identified DNA methylation of seven CpGs significantly associated with OS, DSS, and PFI of GC, including cg10399824 (GRK5), cg05275153 (RGS12), cg24406668 (MMP9), cg14719951(DSC3), and cg25117092 (MED12L), and two in intergenic regions (cg11348188 and cg11671115). Except cg10399824 and cg24406668, five of them were also significantly associated with DFI of GC. Neuroactive ligand-receptor interaction pathway was suggested to play a key role in the effect of DNA methylation on GC prognosis. Consistent with individual CpG-level association, three MCBs involving cg11671115, cg14719951, and cg24406668 were significantly associated with multiple prognostic outcomes of GC. Integrating key CpG loci, two risk score models performed well in predicting GC prognosis. Gene body DNA methylation of cg14719951, cg10399824, and cg25117092 was associated with their host gene expression, whereas no significant associations between their host gene expression and four clinical prognostic outcomes of GC were observed.

Conclusions: We newly identified seven CpGs associated with OS, DSS, and PFI of GC, with five of them also associated with DFI, which might inform patient stratification in clinical practices.
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http://dx.doi.org/10.1186/s12885-021-08389-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8152126PMC
May 2021

Microbiota alteration at different stages in gastric lesion progression: a population-based study in Linqu, China.

Am J Cancer Res 2021 1;11(2):561-575. Epub 2021 Feb 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute Beijing, China.

In addition to Helicobacter pylori (H.pylori), gastric microbiota may be involved in carcinogenesis process. However, the longitudinal study to assess changes in the gastric microbiota associated with the development of gastric carcinogenesis is still limited. The aim of this study is to explore dynamic microbial alterations in gastric cancer (GC) development based on a 4-year endoscopic follow-up cohort in Linqu County, China. Microbial alterations were investigated by deep sequencing of the microbial 16S ribosomal RNA gene in 179 subjects with various gastric lesions, and validated in paired gastric biopsies prospectively collected before and after lesion progression and in non-progression controls. Significant differences were found in microbial diversity and community structure across various gastric lesions, with 62 candidate differential taxa between at least two lesion groups. Further validations identified Helicobacter, Bacillus, Capnocytophaga and Prevotella to be associated with lesion progression-to-dysplasia (DYS)/GC (all P < 0.05), especially for subjects progressing from intestinal metaplasia (IM) to DYS/GC. The combination of the four genera in a microbial dysbiosis index showed a significant difference after lesion progression-to-DYS/GC compared to controls (P = 0.027). The panel including the four genera identified subjects after progression-to-DYS/GC with an area under the receiver-operating curve (AUC) of 0.941. Predictive significance was found before lesion progression-to-DYS/GC with an AUC = 0.776 and an even better AUC (0.927) for subjects progressing from IM to DYS/GC. Microbiota may play different roles at different stages in gastric carcinogenesis. A panel of bacterial genera associated with gastric lesions may help to assess gastric microbial dysbiosis and show potential predictive values for lesion progression. Our findings provide new clues for the microbial mechanism of H.pylori-associated carcinogenesis.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868750PMC
February 2021

Immunostimulatory membrane proteins potentiate -induced carcinogenesis by enabling CagA translocation.

Gut Microbes 2021 Jan-Dec;13(1):1-13

Department of Veterinary Science, University of Kentucky , Lexington, KY, USA.

Infection with is the single greatest risk factor for developing gastric adenocarcinoma. In prospective, population-based studies, seropositivity to the uncharacterized proteins Hp0305 and Hp1564 was significantly associated with cancer risk in East Asia. However, the mechanism underlying this observation has not been elucidated. Here, we show that Hp0305 and Hp1564 act in concert with previously ascribed virulence mechanisms to orchestrate cellular alterations that promote gastric carcinogenesis. In samples from 546 patients exhibiting premalignant gastric lesions, seropositivity to Hp0305 and Hp1564 was significantly associated with increased gastric atrophy across all stomach conditions. , depletion of and significantly reduced levels of gastric cell-associated bacteria and markedly impaired the ability of to stimulate pro-inflammatory cytokine production. Remarkably, our studies revealed that is required for translocation of the oncoprotein CagA into gastric epithelial cells. Our data provide experimental insight into the molecular mechanisms governing novel pathogenicity factors that are strongly associated with gastric disease and highlight the potential of Hp0305 and Hp1564 as robust molecular tools that can improve identification of individuals that are highly susceptible to gastric cancer. We demonstrate that Hp0305 and Hp1564 augment -mediated inflammation and gastric cancer risk by promoting key bacteria-gastric cell interactions that facilitate delivery of oncogenic microbial cargo to target cells. Thus, therapeutically targeting microbial interactions driven by Hp0305/Hp1564 may enable focused eradication strategies to prevent development of gastric malignancies in high-risk populations.
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http://dx.doi.org/10.1080/19490976.2020.1862613DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781638PMC
December 2020

Suppression of Helicobacter pylori infection by daily cranberry intake: A double-blind, randomized, placebo-controlled trial.

J Gastroenterol Hepatol 2021 Apr 23;36(4):927-935. Epub 2020 Aug 23.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.

Background And Aim: Dietary strategies that contribute to reducing incidence of Helicobacter pylori infection without negative side effects are highly desirable owing to worldwide bacterial prevalence and carcinogenesis potential. The aim of this study was to determine dosage effect of daily cranberry consumption on H. pylori suppression over time in infected adults to assess the potential of this complementary management strategy in a region with high gastric cancer risk and high prevalence of H. pylori infection.

Methods: This double-blind, randomized, placebo-controlled trial on 522 H. pylori-positive adults evaluated dose-response effects of proanthocyanidin-standardized cranberry juice, cranberry powder, or their placebos on suppression of H. pylori at 2 and 8 weeks by C-urea breath testing and eradication at 45 days post-intervention.

Results: H. pylori-negative rates in placebo, low-proanthocyanidin, medium-proanthocyanidin, and high-proanthocyanidin cranberry juice groups at week 2 were 13.24%, 7.58%, 1.49%, and 13.85% and at week 8 were 7.35%, 7.58%, 4.48%, and 20.00%, respectively. Consumption of high-proanthocyanidin juice twice daily (44 mg proanthocyanidin/240-mL serving) for 8 weeks resulted in decreased H. pylori infection rate by 20% as compared with other dosages and placebo (P < 0.05). Percentage of H. pylori-negative participants increased from 2 to 8 weeks in subjects who consumed 44 mg proanthocyanidin/day juice once or twice daily, showing a statistically significant positive trend over time. Encapsulated cranberry powder doses were not significantly effective at either time point. Overall trial compliance was 94.25%. Cranberry juice and powder were well-tolerated.

Conclusions: Twice-daily consumption of proanthocyanidin-standardized cranberry juice may help potentiate suppression of H. pylori infection.

Trial Registration: ChiCTR1800017522, per WHO ICTRP.
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http://dx.doi.org/10.1111/jgh.15212DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8246812PMC
April 2021

Association Between Lifestyle Factors, Vitamin and Garlic Supplementation, and Gastric Cancer Outcomes: A Secondary Analysis of a Randomized Clinical Trial.

JAMA Netw Open 2020 06 1;3(6):e206628. Epub 2020 Jun 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education-Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

Importance: The associations of lifestyle factors with gastric cancer (GC) are still underexplored in populations in China. Long-term nutritional supplementation may prevent GC in high-risk populations, but the possible effect modification by lifestyle factors remains unknown.

Objective: To evaluate how lifestyle factors, including smoking, alcohol intake, and diet, may change the risk of GC incidence and mortality and whether the effects of vitamin and garlic supplementation on GC are associated with major lifestyle factors.

Design, Setting, And Participants: This is a secondary analysis of the Shandong Intervention Trial, a masked, randomized, placebo-controlled trial that aimed to assess the effect of vitamin and garlic supplementations and Helicobacter pylori treatment on GC in a factorial design with 22.3 years of follow-up. The study took place in Linqu County, Shandong province, China, a high-risk area for GC. Data were collected from Jully 1995 to December 2017. Overall, 3365 participants aged 35 to 64 years identified in 13 randomly selected villages who agreed to undergo gastroscopy were invited to participate in the trial and were included in the analysis. Data analysis was conducted from March to May 2019.

Interventions: Participants received vitamin and garlic supplementation for 7.3 years, H pylori treatment for 2 weeks (among participants with H pylori ), or placebo.

Main Outcomes And Measures: The primary outcomes were GC incidence and GC mortality (1995-2017). We also examined the progression of gastric lesions (1995-2003) as a secondary outcome.

Results: Of the 3365 participants (mean [SD] age, 47.1 [9.2] years; 1639 [48.7%] women), 1677 (49.8%) were randomized to receive active vitamin supplementation, with 1688 (50.2%) receiving placebo, and 1678 (49.9%) receiving active garlic supplementation, with 1687 (50.1%) receiving placebo. Overall, 151 GC cases (4.5%) and 94 GC deaths (2.8%) were identified. Smoking was associated with increased risk of GC incidence (odds ratio, 1.72; 95% CI, 1.003-2.93) and mortality (hazard ratio [HR], 2.01; 95% CI, 1.01-3.98). Smoking was not associated with changes to the effects of vitamin or garlic supplementation. The protective effect on GC mortality associated with garlic supplementation was observed only among those not drinking alcohol (never drank alcohol: HR, 0.33; 95% CI, 0.15-0.75; ever drank alcohol: HR, 0.92; 95% CI, 0.55-1.54; P for interaction = .03), and significant interactions were only seen among participants with H pylori (never drank alcohol: HR, 0.31; 95% CI, 0.12-0.78; ever drank alcohol: HR, 0.91; 95% CI, 0.52-1.60; P for interaction = .04). No significant interactions between vitamin supplementation and lifestyle factors were found.

Conclusions And Relevance: In this secondary analysis of a randomized clinical trial, smoking was associated with an increased risk of GC incidence and mortality. Not drinking alcohol was associated with a stronger beneficial effect of garlic supplementation on GC prevention. Our findings provide new insights into lifestyle intervention for GC prevention, suggesting that mass GC prevention strategies may need to be tailored to specific population subgroups to maximize the potential beneficial effect.

Trial Registration: ClinicalTrials.gov Identifier: NCT00339768.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.6628DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7320300PMC
June 2020

Telomere Length of Circulating Cell-Free DNA and Gastric Cancer in a Chinese Population at High-Risk.

Front Oncol 2019 17;9:1434. Epub 2019 Dec 17.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

Telomeres have long been found to be involved in cancer development, while little was known about the dynamic changes of telomere length in carcinogenesis process. The present study longitudinally investigated telomere alterations of cell-free DNA (cfDNA) in 86 gastric cancer (GC) subjects recruited through a 16-year prospective cohort with 2-4 serums collected before each GC-diagnosis from baseline and three follow-up time-points (a total of 276 samples). As the control, 86 individual-matched cancer-free subjects were enrolled with 276 serums from the matched calendar year. In the 73 pairs of baseline serums from GC and control subjects, shortened telomeres showed increased subsequent GC risk [odds ratio (OR) = 9.17, 95% CI: 2.72-31.25 for 1 unit shortening]. In each baseline gastric lesion category, higher risks of GC progression were also found with shortened cfDNA telomeres; ORs per 1 unit shortening were 6.99 (95% CI: 1.63-30.30) for mild gastric lesions, 6.06 (95% CI: 1.89-19.61) for intestinal metaplasia and 15.63 (95% CI: 1.91-125.00) for dysplasia. With all measurements from baseline and follow-up time-points, shortened telomeres also showed significant association with GC risk (OR = 7.37, 95% CI: 2.06-26.32 for 1 unit shortening). In temporal trend analysis, shortened telomeres were found in GC subjects compared to corresponding controls more than 3 years ahead of GC-diagnosis (most < 0.05), while no significant difference was found between two groups within 3 years approaching to GC-diagnosis. Our findings suggest that telomere shortening may be associated with gastric carcinogenesis, which supports further etiological study and potential biomarker for risk stratification.
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http://dx.doi.org/10.3389/fonc.2019.01434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928050PMC
December 2019

Effect of on gastrointestinal microbiota: a population-based study in Linqu, a high-risk area of gastric cancer.

Gut 2020 09 19;69(9):1598-1607. Epub 2019 Dec 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China

Objective: Gastrointestinal microbiota may be involved in associated gastric cancer development. The aim of this study was to explore the possible microbial mechanisms in gastric carcinogenesis and potential dysbiosis arising from 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- treatment, relative to 49 negative subjects.

Results: In 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 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 and , , , , were found only in advanced gastric lesion patients, and were absent in normal/superficial gastritis group. Changes in faecal microbiota included increased after successful eradication and more upregulated drug-resistant functional orthologs after failed treatment.

Conclusion: infection contributes significantly to gastric microbial dysbiosis that may be involved in carcinogenesis. Successful eradication potentially restores gastric microbiota to a similar status as found in uninfected individuals, and shows beneficial effects on gut microbiota.
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http://dx.doi.org/10.1136/gutjnl-2019-319696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7456744PMC
September 2020

Effects of treatment and vitamin and garlic supplementation on gastric cancer incidence and mortality: follow-up of a randomized intervention trial.

BMJ 2019 Sep 11;366:l5016. Epub 2019 Sep 11.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Haidian District, Beijing 100142, China.

Objective: To assess the effects of 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 were randomly assigned to treatment, vitamin supplementation, garlic supplementation, or their placebos in a 2×2×2 factorial design, and 1107 seronegative participants were randomly assigned to vitamin supplementation, garlic supplementation, or their placebos in a 2×2 factorial design.

Interventions: 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 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 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 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: 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. treatment and vitamin supplementation were also associated with a statistically significantly reduced incidence of gastric cancer.

Trial Registration: ClinicalTrials.gov NCT00339768.
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http://dx.doi.org/10.1136/bmj.l5016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737461PMC
September 2019

Whole Genome Messenger RNA Profiling Identifies a Novel Signature to Predict Gastric Cancer Survival.

Clin Transl Gastroenterol 2019 01;10(1):e00004

Key Laboratory of Carcinogenesis and Translational Research, Ministry of Education/Beijing, Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

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.
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http://dx.doi.org/10.14309/ctg.0000000000000004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6369880PMC
January 2019

Methylation and Expression of Nonclustered Protocadherins Encoding Genes and Risk of Precancerous Gastric Lesions in a High-Risk Population.

Cancer Prev Res (Phila) 2018 11 13;11(11):717-726. Epub 2018 Sep 13.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, People's Republic of China.

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 () infection in prior genome-wide methylation analysis. To further investigate the methylation and expression of nonclustered PCDHs encoding genes in -related gastric carcinogenesis process, four candidate genes including and 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 positive subjects than the negative group (all < 0.001). Elevated methylation levels of and were observed with the increasing severity of gastric lesions (both < 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 and 7 was further supported when we explored the methylation and mRNA expression in The Cancer Genome Atlas database (all < 0.001). Our study found elevated promoter methylation and decreased expression of and in advanced gastric lesions, suggesting that elevated and methylation may be an early event in gastric carcinogenesis. .
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http://dx.doi.org/10.1158/1940-6207.CAPR-18-0119DOI Listing
November 2018

Validation of a Blood Biomarker for Identification of Individuals at High Risk for Gastric Cancer.

Cancer Epidemiol Biomarkers Prev 2018 12 29;27(12):1472-1479. Epub 2018 Aug 29.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China.

Background: is the leading cause of gastric cancer, yet the majority of infected individuals will not develop neoplasia. Previously, we developed and replicated serologic 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. 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 , 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, = 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.
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http://dx.doi.org/10.1158/1055-9965.EPI-18-0582DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6279536PMC
December 2018

Association Between Gut Microbiota and -Related Gastric Lesions in a High-Risk Population of Gastric Cancer.

Front Cell Infect Microbiol 2018 19;8:202. Epub 2018 Jun 19.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

Eradication of 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 -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 , and 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 infection compared with negative subjects. As for the differential bacteria, the average relative abundance of was found to significantly decrease from negative (66.16%) to past infection group (33.01%, = 0.007), as well as from normal (76.49%) to gastritis (56.04%) and metaplasia subjects (46.83%, = 0.027). For and , the average relative abundances showed elevated trends in the past infection group (47.11, 20.53%) compared to negative group (23.44, 9.05%, = 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%, = 0.016 and 0.294, respectively) or metaplasia subjects (32.33, 20.07%, both < 0.05). These findings suggest that the alterations of fecal microbiota, especially the dominant phyla of and , may be involved in the process of -related gastric lesion progression and provide hints for future evaluation of microbial changes after eradication.
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http://dx.doi.org/10.3389/fcimb.2018.00202DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6018392PMC
July 2019

Cut-off optimization for C-urea breath test in a community-based trial by mathematic, histology and serology approach.

Sci Rep 2017 05 18;7(1):2072. Epub 2017 May 18.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, China.

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 C-urea breath test (C-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 C-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 (r = 0.217, P < 0.001). A mathematical approach such as FMM might be an alternative measure in optimizing the cut-off point for C-UBT in community-based studies, and a second method to determine H.pylori status for subjects with borderline value of C-UBT was necessary and recommended.
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http://dx.doi.org/10.1038/s41598-017-02180-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5437005PMC
May 2017

Fruit and vegetable consumption, Helicobacter pylori antibodies, and gastric cancer risk: A pooled analysis of prospective studies in China, Japan, and Korea.

Int J Cancer 2017 Feb 31;140(3):591-599. Epub 2016 Oct 31.

Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center and Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN.

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.
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http://dx.doi.org/10.1002/ijc.30477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5531280PMC
February 2017

Genome-wide DNA methylation profiles altered by Helicobacter pylori in gastric mucosa and blood leukocyte DNA.

Oncotarget 2016 Jun;7(24):37132-37144

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

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.
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http://dx.doi.org/10.18632/oncotarget.9469DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5095064PMC
June 2016

Alterations of Cyclooxygenase-2 Methylation Levels Before and After Intervention Trial to Prevent Gastric Cancer in a Chinese Population.

Cancer Prev Res (Phila) 2016 06 28;9(6):484-90. Epub 2016 Mar 28.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Beijing, China. Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.

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.
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http://dx.doi.org/10.1158/1940-6207.CAPR-15-0389DOI Listing
June 2016

Hypomethylation of repetitive elements in blood leukocyte DNA and risk of gastric lesions in a Chinese population.

Cancer Epidemiol 2016 Apr 1;41:122-8. Epub 2016 Mar 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.canep.2016.02.004DOI Listing
April 2016

Methylation status of COX-2 in blood leukocyte DNA and risk of gastric cancer in a high-risk Chinese population.

BMC Cancer 2015 Dec 16;15:979. Epub 2015 Dec 16.

Key Laboratory of Carcinogenesis and Translation Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, P.R. China.

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.
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http://dx.doi.org/10.1186/s12885-015-1962-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4682260PMC
December 2015

Helicobacter pylori, cyclooxygenase-2 and evolution of gastric lesions: results from an intervention trial in China.

Carcinogenesis 2015 Dec 7;36(12):1572-9. Epub 2015 Oct 7.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China.

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.
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http://dx.doi.org/10.1093/carcin/bgv147DOI Listing
December 2015

Association of genetic polymorphisms of interleukins with gastric cancer and precancerous gastric lesions in a high-risk Chinese population.

Tumour Biol 2016 Feb 10;37(2):2233-42. Epub 2015 Sep 10.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing, 100142, People's Republic of China.

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)-1β, 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.
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http://dx.doi.org/10.1007/s13277-015-4022-xDOI Listing
February 2016

A large randomised controlled intervention trial to prevent gastric cancer by eradication of Helicobacter pylori in Linqu County, China: baseline results and factors affecting the eradication.

Gut 2016 Jan 18;65(1):9-18. Epub 2015 May 18.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.

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.
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http://dx.doi.org/10.1136/gutjnl-2015-309197DOI Listing
January 2016

NOD1 and NOD2 Genetic Variants in Association with Risk of Gastric Cancer and Its Precursors in a Chinese Population.

PLoS One 2015 1;10(5):e0124949. Epub 2015 May 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, 52 Fu-cheng Road, Hai-dian District, Beijing 100142, China.

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.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124949PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416772PMC
January 2016

Toll-like receptor 1 and 10 polymorphisms, Helicobacter pylori susceptibility and risk of gastric lesions in a high-risk Chinese population.

Infect Genet Evol 2015 Apr 14;31:263-9. Epub 2015 Feb 14.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China. Electronic address:

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.
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http://dx.doi.org/10.1016/j.meegid.2015.02.005DOI Listing
April 2015

RE: Effects of Helicobacter pylori treatment on gastric cancer incidence and mortality in subgroups. Response.

J Natl Cancer Inst 2014 Nov 7;106(11). Epub 2014 Nov 7.

Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD (MHG, WQL); Key Laboratory of Carcinogenesis and Translational Research, Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China (WCY, WQL); Department of Dermatology, Brown University Warren Alpert Medical School, Providence, RI (WQL); Department of Epidemiology, School of Public Health, Brown University, Providence, RI (WQL).

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http://dx.doi.org/10.1093/jnci/dju348DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4271035PMC
November 2014

Methylation status of blood leukocyte DNA and risk of gastric cancer in a high-risk Chinese population.

Cancer Epidemiol Biomarkers Prev 2014 Oct 1;23(10):2019-26. Epub 2014 Aug 1.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-13-0994DOI Listing
October 2014

Effects of Helicobacter pylori treatment on gastric cancer incidence and mortality in subgroups.

J Natl Cancer Inst 2014 Jul 12;106(7). Epub 2014 Jun 12.

Affiliations of authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD (W-QL, JFF, MHG); Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital and Institute, Beijing, China (W-QL, J-LM, LZ, J-YL, LS, K-FP, W-CY); RTI International, Rockville, MD (LMB); Linqu County Public Health Bureau, Shandong, China (W-DL, Z-XH); Westat, Rockville, MD (SC-M); Information Management Services, Rockville, MD (DP); International Epidemiology Institute, Rockville, MD (WJB); Department of Medicine (Epidemiology), Vanderbilt University, Nashville, TN (WJB).

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.
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http://dx.doi.org/10.1093/jnci/dju116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067110PMC
July 2014

[Serological assessment of Helicobacter pylori-specific antibodies and their association with gastric lesions in a high-risk population].

Zhonghua Zhong Liu Za Zhi 2013 Jul;35(7):547-51

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing 100142, China.

Objective: To determine the distributions of six Helicobacter pylori (Hp)-specific antibodies in a high-risk population of gastric cancer (GC) and explore the relationship between Hp virulence factors and precancerous gastric lesions.

Methods: Based on the two intervention trials conducted in Linqu County, the seropositivities for CagA, VacA, GroEL, UreA, HcpC and GGT were assessed by recombinant immunoassay (recomLine) in 623 participants with H. pylori infection determined by (13)C-urea breath test ((13)C-UBT) and/or enzyme linked immunosorbent assay (ELISA).

Results: In a total of 623 participants were detected by recomLine analysis, of which 594 were Hp-positive. The seropositivities rates of CagA, VacA, GroEL, UreA, HcpC and GGT were 84.0%, 38.2%, 66.7%, 17.7%, 58.8% and 42.8%, respectively. A total of 523 participants were determined as type I infection of Hp, accounting for 88.1%. Compared with superficial gastritis (SG), the infection rate of Hp type I was higher in the chronic atrophic gastritis (CAG) (P = 0.001).

Conclusions: The results of this population-based study suggest that the virulence factors of Hp may be related to the development of GC in a Chinese high-risk population. The recomLine analysis may serve as a tool for identification of Hp strains and prediction of high-risk population of GC.
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July 2013

Helicobacter pylori antibody responses and evolution of precancerous gastric lesions in a Chinese population.

Int J Cancer 2014 May 7;134(9):2118-25. Epub 2013 Nov 7.

Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Cancer Epidemiology, Peking University Cancer Hospital & Institute, Beijing, China.

Helicobacter pylori-specific proteins are involved in gastric carcinogenesis. To investigate the seroprevalence of six H. pylori-specific antibodies in patients with different gastric histology, and the impact of seropositivities on the evolution of precancerous gastric lesions, a follow-up study was conducted in Linqu County, China. The seropositivities for CagA, VacA, GroEL, UreA, HcpC and gGT were assessed by recomLine analysis in 573 H. pylori-positive subjects and correlated with evolution of precancerous gastric lesions. We found that the score of H. pylori recomLine test was significantly increased in subjects with chronic atrophic gastritis (CAG, p < 0.0001) or intestinal metaplasia (IM, p = 0.0125), and CagA was an independent predictor of advanced gastric lesions, adjusted odds ratios (ORs) were 2.54 (95% CI = 1.42-4.55) for IM and 2.38 (95% CI = 1.05-5.37) for dysplasia (DYS). Moreover, seropositivities for CagA and GroEL were identified as independent predictors for progression of gastric lesions in a longitudinal study, and ORs were 2.89 (95% CI = 1.27-6.59) and 2.20 (95% CI = 1.33-3.64), respectively. Furthermore, the risk of progression was more pronounced in subjects with more than three positive antigens (p(for) trend = 0.0003). This population-based study revealed that seropositivities for CagA and GroEL might be potential markers to identify patients infected with high-risk H. pylori strains, which are related to the development of GC in a Chinese high-risk population, and recomLine test might serve as a tool for risk stratification.
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http://dx.doi.org/10.1002/ijc.28560DOI Listing
May 2014
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