Gastric Cancer Microbiome

Identifying a microbiome pattern in gastric cancer (GC) is hugely debatable due to the variation resulting from the diversity of the studied populations, clinical scenarios, and metagenomic approach. H. pylori remains the main microorganism impacting gastric carcinogenesis and seems necessary for the initial steps of the process. Nevertheless, an additional non-H. pylori microbiome pattern is also described, mainly at the final steps of the carcinogenesis. Unfortunately, most of the presented results are not reproducible, and there are no consensual candidates to share the H. pylori protagonists. Limitations to reach a consistent interpretation of metagenomic data include contamination along every step of the process, which might cause relevant misinterpretations. In addition, the functional consequences of an altered microbiome might be addressed. Aiming to minimize methodological bias and limitations due to small sample size and the lack of standardization of bioinformatics assessment and interpretation, we carried out a comprehensive analysis of the publicly available metagenomic data from various conditions relevant to gastric carcinogenesis. Mainly, instead of just analyzing the results of each available publication, a new approach was launched, allowing the comprehensive analysis of the total sample amount, aiming to produce a reliable interpretation due to using a significant number of samples, from different origins, in a standard protocol. Among the main results, Helicobacter and Prevotella figured in the “top 6” genera of every group. Helicobacter was the first one in chronic gastritis (CG), gastric cancer (GC), and adjacent (ADJ) groups, while Prevotella was the leader among healthy control (HC) samples. Groups of bacteria are differently abundant in each clinical situation, and bacterial metabolic pathways also diverge along the carcinogenesis cascade. This information may support future microbiome interventions aiming to face the carcinogenesis process and/or reduce GC risk.

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Induction and prevention of gastric cancer with combined Helicobacter pylori and capsaicin administration and DFMO treatment, respectively

10.21203/rs.2.21633/v1 ◽

2020 ◽

Author(s):

Faisal Aziz ◽

Mingxia Xin ◽

Yunfeng Gao ◽

Josh Monts ◽

Kjersten Monson ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Mouse Models ◽

Chronic Gastritis ◽

Molecular Mechanisms ◽

Gastric Carcinogenesis ◽

Lifestyle Changes ◽

Host Susceptibility ◽

Anti Inflammatory ◽

H Pylori

Abstract Background: Gastric cancer risk evolves over time due to environmental, dietary, and lifestyle changes including Helicobacter pylori (H. pylori) infection and consumption of hot peppers (i.e. capsaicin). H. pylori infection promotes gastric mucosal injury in the early phase of capsaicin exposure. In addition, capsaicin consumption is reported to suppress immune function and increase host susceptibility to microbial infection. This relationship suggests a need to investigate the mechanism of how both H. pylori infection and capsaicin contribute to gastric inflammation and lead to gastric cancer. No previous experimental animal models have been developed to study this dual association. Here we developed a series of mouse models that progress from chronic gastritis to gastric cancer. C57-Balb/c mice were infected with the H. pylori (SS1) strain and then fed capsaicin (0.05% or 0.2g/kg/day) or not. Consequently, we investigated the association between H. pylori infection and capsaicin consumption during the initiation of gastric inflammation and the later development of gastric cancer. Tumor size and phenotype were analyzed to determine the molecular mechanism driving the shift from gastritis to stomach cancer. Gastric carcinogenesis was also prevented in these models using the ornithine decarboxylase inhibitor DFMO (2-difluoromethylornithine). Results: This study provides evidence showing that a combination of H. pylori infection and capsaicin consumption leads to gastric carcinogenesis. The transition from chronic gastritis to gastric cancer is mediated through interleukin-6 (IL-6) stimulation with an incidence rate of 50%. However, this progression can be prevented by treating with anti-inflammatory agents. In particular, we used DFMO to prevent gastric tumorigenesis by reducing inflammation and promoting recovery of disease-free stasis. The anti-inflammatory role of DFMO highlights the injurious effect of inflammation in gastric cancer development and the need to reduce gastric inflammation for cancer prevention. Conclusions: Overall, these mouse models provide reliable systems for analyzing the molecular mechanisms and synergistic effects of H. pylori and capsaicin on human cancer etiology. Accordingly, preventive measures like reduced capsaicin consumption, H. pylori clearance, and DFMO treatment can lessen gastric cancer incidence. Lastly, anti-inflammatory agents like DFMO can play important roles in prevention of inflammation-associated gastric cancer.

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Filtering high-dimensional methylation marks with extremely small sample size: an application to gastric cancer data

10.21203/rs.3.rs-284773/v1 ◽

2021 ◽

Author(s):

Xin Chen ◽

Qingrun Zhang ◽

Thierry Chekouo

Keyword(s):

Gastric Cancer ◽

Dna Methylation ◽

Sample Size ◽

Small Sample Size ◽

Small Sample ◽

Differential Methylation ◽

High Dimensional ◽

Cancer Data ◽

Cancer Pathogenesis ◽

A Genome

Abstract Background: DNA methylations in critical regions are highly involved in cancer pathogenesis and drug response. However, to identify causal methylations out of a large number of potential polymorphic DNA methylation sites is challenging. This high-dimensional data brings two obstacles: first, many established statistical models are not scalable to so many features; second, multiple-test and overfitting become serious. To this end, a method to quickly filter candidate sites to narrow down targets for downstream analyses is urgently needed. Methods: BACkPAy is a pre-screening Bayesian approach to detect biological meaningful clusters of potential differential methylation levels with small sample size. BACkPAy prioritizes potentially important biomarkers by the Bayesian false discovery rate (FDR) approach. It filters non-informative sites (i.e. non-differential) with flat methylation pattern levels accross experimental conditions. In this work, we applied BACkPAy to a genome-wide methylation dataset with 3 tissue types and each type contains 3 gastric cancer samples. We also applied LIMMA (Linear Models for Microarray and RNA-Seq Data) to compare its results with what we achieved by BACkPAy. Then, Cox proportional hazards regression models were utilized to visualize prognostics significant markers with The Cancer Genome Atlas (TCGA) data for survival analysis. Results: Using BACkPAy, we identified 8 biological meaningful clusters/groups of differential probes from the DNA methylation dataset. Using TCGA data, we also identified five prognostic genes (i.e. predictive to the progression of gastric cancer) that contain some differential methylation probes, whereas no significant results was identified using the Benjamin-Hochberg FDR in LIMMA. Conclusions: We showed the importance of using BACkPAy for the analysis of DNA methylation data with extremely small sample size in gastric cancer. We revealed that RDH13, CLDN11, TMTC1, UCHL1 and FOXP2 can serve as predictive biomarkers for gastric cancer treatment and the promoter methylation level of these five genes in serum could have prognostic and diagnostic functions in gastric cancer patients.

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The role of the gastric bacterial microbiome in gastric cancer: Helicobacter pylori and beyond

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284819894062 ◽

2019 ◽

Vol 12 ◽

pp. 175628481989406 ◽

Cited By ~ 8

Author(s):

Christian Schulz ◽

Kerstin Schütte ◽

Julia Mayerle ◽

Peter Malfertheiner

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Bacterial Pathogen ◽

Gastric Carcinogenesis ◽

Nucleotide Sequencing ◽

Wide Field ◽

Current State ◽

Organ Systems ◽

Bacterial Microbiome ◽

H Pylori

A link between chronic inflammation and carcinogenesis has been depicted in many organ systems. Helicobacter pylori is the most prevalent bacterial pathogen, induces chronic gastritis and is associated with more than 90% of cases of gastric cancer (GC). However, the introduction of nucleotide sequencing techniques and the development of biocomputional tools have surpassed traditional culturing techniques and opened a wide field for studying the mucosal and luminal composition of the bacterial gastric microbiota beyond H. pylori. In studies applying animal models, a potential role in gastric carcinogenesis for additional bacteria besides H. pylori has been demonstrated. At different steps of gastric carcinogenesis, changes in bacterial communities occur. Whether these microbial changes are a driver of malignant disease or a consequence of the histologic progression along the precancerous cascade, is not clear at present. It is hypothesized that atrophy, as a consequence of chronic gastric inflammation, alters the gastric niche for commensals that might further urge the development of H. pylori-induced GC. Here, we review the current state of knowledge on gastric bacteria other than H. pylori and on their synergism with H. pylori in gastric carcinogenesis.

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Cross-sectional study of human coding- and non-coding RNAs in progressive stages of Helicobacter pylori infection

Scientific Data ◽

10.1038/s41597-020-00636-6 ◽

2020 ◽

Vol 7 (1) ◽

Author(s):

Sergio Lario ◽

María J. Ramírez-Lázaro ◽

Aintzane González-Lahera ◽

José L. Lavín ◽

Maria Vila-Casadesús ◽

...

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Expression Profiles ◽

Gastric Carcinogenesis ◽

Individual Response ◽

Peptic Ulcers ◽

Gastric Diseases ◽

Sequence Of Events ◽

Non Coding Rnas ◽

H Pylori

Abstract Helicobacter pylori infects 4.4 billion individuals worldwide and is considered the most important etiologic agent for peptic ulcers and gastric cancer. Individual response to H. pylori infection is complex and depends on complex interactions between host and environmental factors. The pathway towards gastric cancer is a sequence of events known as Correa’s model of gastric carcinogenesis, a stepwise inflammatory process from normal mucosa to chronic-active gastritis, atrophy, metaplasia and gastric adenocarcinoma. This study examines gastric clinical specimens representing different steps of the Correa pathway with the aim of identifying the expression profiles of coding- and non-coding RNAs that may have a role in Correa’s model of gastric carcinogenesis. We screened for differentially expressed genes in gastric biopsies by employing RNAseq, microarrays and qRT-PCR. Here we provide a detailed description of the experiments, methods and results generated. The datasets may help other scientists and clinicians to find new clues to the pathogenesis of H. pylori and the mechanisms of progression of the infection to more severe gastric diseases. Data is available via ArrayExpress.

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The Role of PPARγinHelicobacter pyloriInfection and Gastric Carcinogenesis

PPAR Research ◽

10.1155/2012/687570 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6 ◽

Cited By ~ 5

Author(s):

Jong-Min Lee ◽

Sung Soo Kim ◽

Young-Seok Cho

Keyword(s):

Gastric Cancer ◽

Cell Proliferation ◽

Current Knowledge ◽

Mucosal Injury ◽

Gastric Carcinogenesis ◽

Etiologic Factor ◽

Peroxisome Proliferator ◽

Peroxisome Proliferator Activated Receptor ◽

H Pylori

Peroxisome proliferator-activated receptorγ(PPARγ) is a nuclear receptor that is important in many physiological and pathological processes, such as lipid metabolism, insulin sensitivity, inflammation, cell proliferation, and carcinogenesis. Several studies have shown that PPARγplays an important role in gastric mucosal injury due toHelicobacter pylori(H. pylori). AsH. pyloriinfection is the main etiologic factor in chronic gastritis and gastric cancer, understanding of the potential roles of PPARγinH. pyloriinfection may lead to the development of a therapeutic target. In this paper, the authors discuss the current knowledge on the role of PPARγinH. pyloriinfection and its related gastric carcinogenesis.

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Survival of patients with HER2-positive gastric cancer with introduction of trastuzumab.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.128 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 128-128

Author(s):

Kohei Shitara ◽

Yasushi Yatabe ◽

Masato Sugano ◽

Keitaro Matsuo ◽

Chihiro Kondo ◽

...

Keyword(s):

Gastric Cancer ◽

Small Sample Size ◽

Small Sample ◽

Her2 Status ◽

First Line ◽

Her2 Positive ◽

Line Therapy ◽

The Impact ◽

Time Varying Covariates ◽

Line Chemotherapy

128 Background: ToGA study showed that trastuzumab given in combination with first-line chemotherapy (fluoropyrimidine plus cisplatin) improved the overall survival of HER2-positive patients with advanced gastric cancer (AGC). Meanwhile, the prognostic value of HER2 or the efficacy of trastuzumab in second- or further-line chemotherapy remains controversial. Methods: We retrospectively analyzed 567 patients with AGC who initiated systemic chemotherapy before March 2011. Among them, 287 were evaluated for their HER2 status. HER2 positivity was defined as IHC 3+ or IHC 2+ with amplification by FISH. Treatment outcomes were compared between patients with HER2-positive and HER2-negative AGC. To evaluate the impact of exposure to trastuzumab in any line of chemotherapy, we applied time-varying covariates (TVC) analysis to avoid possible lead-time bias. Results: The median survival time (MST) of HER2-evaluated patients (n=287) tended to be better than that of HER2-non-evaluated patients (n=280, 14.5 vs. 13.2 months; P=0.03). Among the HER2-evaluated patients, 47 (16.3%) were HER2-positive and had longer survival than HER2-negative patients (24.1 vs. 13.4 months; P=0.05). Among the HER2-positive patients, 35 received trastuzumab; 15 patients received it as first-line therapy and 20 received it as second- or further-line therapy. The MST of HER2-positive patients with trastuzumab treatment was significantly longer than that of HER2-positive patients without trastuzumab (26.6 vs. 13.5 months; P=0.015). HER2-negative patients and HER2-positive patients without trastuzumab had similar survival durations. According to multivariate analysis with TVCs, exposure to trastuzumab was independently associated with better prognosis (HR 0.54, P=0.04). Conclusions: Although the retrospective nature and small sample size are major limitations of this study, recent HER2-positive AGC patients showed a better prognosis than HER2-negative patients, especially with the introduction of trastuzumab.

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Identification of Gene Signatures Used to Recognize Biological Characteristics of Gastric Cancer upon Gene Expression Data

Biomarker Insights ◽

10.4137/bmi.s13059 ◽

2014 ◽

Vol 9 ◽

pp. BMI.S13059 ◽

Cited By ~ 3

Author(s):

Zhi Yan ◽

Brian T. Luke ◽

Shirley X. Tsang ◽

Rui Xing ◽

Yuanming Pan ◽

...

Keyword(s):

Gene Expression ◽

Gastric Cancer ◽

Information Gain ◽

Small Sample Size ◽

High Sensitivity ◽

Small Sample ◽

Machine Learning Algorithms ◽

Biological Characteristics ◽

Gene Signatures ◽

Mining Model

High-throughput gene expression microarrays can be examined by machine-learning algorithms to identify gene signatures that recognize the biological characteristics of specific human diseases, including cancer, with high sensitivity and specificity. A previous study compared 20 gastric cancer (GC) samples against 20 normal tissue (NT) samples and identified 1,519 differentially expressed genes (DEGs). In this study, Classification Information Index (CII), Information Gain Index (IGI), and RELIEF algorithms are used to mine the previously reported gene expression profiling data. In all, 29 of these genes are identified by all three algorithms and are treated as GC candidate biomarkers. Three biomarkers, COL1A2, ATP4B, and HADHSC, are selected and further examined using quantitative real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry (IHC) staining in two independent sets of GC and normal adjacent tissue (NAT) samples. Our study shows that COL1A2 and HADHSC are the two best biomarkers from the microarray data, distinguishing all GC from the NT, whereas ATP4B is diagnostically significant in lab tests because of its wider range of fold-changes in expression. Herein, a data-mining model applicable for small sample sizes is presented and discussed. Our result suggested that this mining model may be useful in small sample-size studies to identify putative biomarkers and potential biological features of GC.

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Hydrogen Metabolism inHelicobacter pyloriPlays a Role in Gastric Carcinogenesis through Facilitating CagA Translocation

mBio ◽

10.1128/mbio.01022-16 ◽

2016 ◽

Vol 7 (4) ◽

Cited By ~ 14

Author(s):

Ge Wang ◽

Judith Romero-Gallo ◽

Stéphane L. Benoit ◽

M. Blanca Piazuelo ◽

Ricardo L. Dominguez ◽

...

Keyword(s):

Gastric Cancer ◽

Cancer Risk ◽

Respiratory Chain ◽

Molecular Hydrogen ◽

Gastric Carcinogenesis ◽

Hydrogenase Activity ◽

Hydrogen Metabolism ◽

Gastric Cancer Risk ◽

Ags Cells ◽

H Pylori

ABSTRACTA known virulence factor ofHelicobacter pylorithat augments gastric cancer risk is the CagA cytotoxin. A carcinogenic derivative strain, 7.13, that has a greater ability to translocate CagA exhibits much higher hydrogenase activity than its parent noncarcinogenic strain, B128. A Δhydmutant strain with deletion of hydrogenase genes was ineffective in CagA translocation into human gastric epithelial AGS cells, while no significant attenuation of cell adhesion was observed. The quinone reductase inhibitor 2-n-heptyl-4-hydroxyquinoline-N-oxide (HQNO) was used to specifically inhibit the H2-utilizing respiratory chain of outer membrane-permeabilized bacterial cells; that level of inhibitor also greatly attenuated CagA translocation into AGS cells, indicating the H2-generated transmembrane potential is a contributor to toxin translocation. The Δhydstrain showed a decreased frequency of DNA transformation, suggesting thatH. pylorihydrogenase is also involved in energizing the DNA uptake apparatus. In a gerbil model of infection, the ability of the Δhydstrain to induce inflammation was significantly attenuated (at 12 weeks postinoculation), while all of the gerbils infected with the parent strain (7.13) exhibited a high level of inflammation. Gastric cancer developed in 50% of gerbils infected with the wild-type strain 7.13 but in none of the animals infected with the Δhydstrain. By examining the hydrogenase activities from well-defined clinicalH. pyloriisolates, we observed that strains isolated from cancer patients (n= 6) have a significantly higher hydrogenase (H2/O2) activity than the strains isolated from gastritis patients (n= 6), further supporting an association betweenH. pylorihydrogenase activity and gastric carcinogenesis in humans.IMPORTANCEHydrogen-utilizing hydrogenases are known to be important for some respiratory pathogens to colonize hosts. Here a gastric cancer connection is made via a pathogen’s (H. pylori) use of molecular hydrogen, a host microbiome-produced gas. Delivery of the known carcinogenic factor CagA into host cells is augmented by the H2-utilizing respiratory chain of the bacterium. The role of hydrogenase in carcinogenesis is demonstrated in an animal model, whereby inflammation markers and cancer development were attenuated in the hydrogenase-null strain. Hydrogenase activity comparisons of clinical strains of the pathogen also support a connection between hydrogen metabolism and gastric cancer risk. While molecular hydrogen use is acknowledged to be an alternative high-energy substrate for some pathogens, this work extends the roles of H2oxidation to include transport of a carcinogenic toxin. The work provides a new avenue for exploratory treatment of some cancers via microflora alterations.

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Effect of Helicobacter pylori Eradication on Epigenetic Changes in Gastric Cancer-related Genes

The Korean Journal of Helicobacter and Upper Gastrointestinal Research ◽

10.7704/kjhugr.2021.0042 ◽

2021 ◽

Vol 21 (4) ◽

pp. 256-266

Author(s):

Ji Min Choi ◽

Sang Gyun Kim

Keyword(s):

Gastric Cancer ◽

Helicobacter Pylori ◽

Gastric Mucosa ◽

Gastric Carcinogenesis ◽

Point Of View ◽

Epigenetic Changes ◽

Epigenetic Alterations ◽

Helicobacter Pylori Eradication ◽

Gastric Cancer Prevention ◽

H Pylori

It is known that gastric carcinogenesis results from the progressive changes from chronic gastritis to gastric atrophy, intestinal metaplasia, dysplasia, and invasive carcinoma. Several genetic and epigenetic alterations are involved in this process, and Helicobacter pylori (H. pylori) infection is believed to induce the initiation and progression of these steps. From an epigenetic point of view, H. pylori induces hypermethylation of genes involved in the development of gastric cancer and regulates the expression of various microRNAs (miRNAs). These H. pylori-related epigenetic changes are accumulated not only at the site of neoplasm but also in the adjacent non-cancerous gastric mucosa. Thereby, a state vulnerable to gastric cancer known as an epigenetic field defect is formed. H. pylori eradication can have an effective chemopreventive effect in gastric carcinogenesis. However, the molecular biological changes that occur in the stomach environment during H. pylori eradication have not yet been established. Several studies have reported that H. pylori eradication can restore infection-related changes, especially epigenetic alterations in gastric cancer-related genes, but some studies have shown otherwise. Simply put, it appears that the recovery of methylated gastric cancer-related genes and miRNAs during H. pylori eradication may vary among genes and may also differ depending on the histological subtype of the gastric mucosa. In this review, we will discuss the potential mechanism of gastric cancer prevention by H. pylori eradication, mainly from an epigenetic perspective.

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Helicobacter pylori and Respiratory Diseases: 2021 Update

Microorganisms ◽

10.3390/microorganisms9102033 ◽

2021 ◽

Vol 9 (10) ◽

pp. 2033

Author(s):

Marilena Durazzo ◽

Alessandro Adriani ◽

Sharmila Fagoonee ◽

Giorgio Maria Saracco ◽

Rinaldo Pellicano

Keyword(s):

Helicobacter Pylori ◽

Respiratory Diseases ◽

Small Sample Size ◽

Small Sample ◽

Deficiency Anemia ◽

Chronic Obstructive ◽

Case Control Studies ◽

Gastric Diseases ◽

Medline Search ◽

H Pylori

Helicobacter pylori (H. pylori) is a Gram-negative bacterium involved in the development of gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosa-associated lymphoid tissue. Unexplained iron deficiency anemia, idiopathic thrombocytopenic purpura and vitamin B12 deficiency have also been related to H. pylori infection, whereas for other extra-gastric diseases, the debate is still open. In this review, we evaluate and discuss the potential involvement of H. pylori infection in the pathogenesis of several respiratory diseases. A MEDLINE search of all studies published in English from 1965 to 2021 was carried out. Controversial findings have been reported in patients with bronchial asthma, chronic obstructive pulmonary disease, bronchiectasis, lung cancer, tuberculosis, cystic fibrosis, and sarcoidosis. Most of the available literature is concerned with case-control studies based on seroprevalence, with a small sample size and low consideration of confounders, which represents a potential issue. So far, there is no clear evidence of a causal association between H. pylori infection and respiratory diseases, and larger studies with appropriate epidemiological design are required.

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