1 4114 115 MECHANISMS FOR THE INDUCTION OF GASTRIC CANCER BY HELICOBACTER PYLORI INFECTION: ABERRANT DNA METHYLATION PATHWAY. MULTIPLE PATHOGENIC MECHANISMS BY WHICH HELICOBACTER PYLORI INFECTION INDUCES GASTRIC CANCER HAVE BEEN ESTABLISHED IN THE LAST TWO DECADES. IN PARTICULAR, ABERRANT DNA METHYLATION IS INDUCED IN MULTIPLE DRIVER GENES, WHICH INACTIVATES THEM. METHYLATION PROFILES IN GASTRIC CANCER ARE ASSOCIATED WITH SPECIFIC SUBTYPES, SUCH AS MICROSATELLITE INSTABILITY. RECENT COMPREHENSIVE AND INTEGRATED ANALYSES SHOWED THAT MANY CANCER-RELATED PATHWAYS ARE MORE FREQUENTLY ALTERED BY ABERRANT DNA METHYLATION THAN BY MUTATIONS. ABERRANT DNA METHYLATION CAN EVEN BE PRESENT IN NONCANCEROUS GASTRIC MUCOSAE, PRODUCING AN "EPIGENETIC FIELD FOR CANCERIZATION." MECHANISTICALLY, H. PYLORI-INDUCED CHRONIC INFLAMMATION, BUT NOT H. PYLORI ITSELF, PLAYS A DIRECT ROLE IN THE INDUCTION OF ABERRANT DNA METHYLATION. THE EXPRESSION OF THREE INFLAMMATION-RELATED GENES, IL1B, NOS2, AND TNF, IS HIGHLY ASSOCIATED WITH THE INDUCTION OF ABERRANT DNA METHYLATION. IMPORTANTLY, THE DEGREE OF ACCUMULATED ABERRANT DNA METHYLATION IS STRONGLY CORRELATED WITH GASTRIC CANCER RISK. A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THE UTILITY OF EPIGENETIC CANCER RISK DIAGNOSIS FOR METACHRONOUS GASTRIC CANCER. SUPPRESSION OF ABERRANT DNA METHYLATION BY A DEMETHYLATING AGENT WAS SHOWN TO INHIBIT GASTRIC CANCER DEVELOPMENT IN AN ANIMAL MODEL. INDUCTION OF ABERRANT DNA METHYLATION IS THE MAJOR PATHWAY BY WHICH H. PYLORI INFECTION INDUCES GASTRIC CANCER, AND THIS CAN BE UTILIZED FOR TRANSLATIONAL OPPORTUNITIES. 2017 2 4994 48 PERFORMANCE OF DNA METHYLATION ON THE MOLECULAR PATHOGENESIS OF HELICOBACTER PYLORI IN GASTRIC CANCER; TARGETED THERAPY APPROACH. GASTRIC CANCER (GC) IS A SIGNIFICANT CAUSE OF CANCER MORTALITY WHICH HAS LED TO FOCUSED EXPLORATION OF THE PATHOLOGY OF GC. THE ADVENT OF GENOME-WIDE ANALYSIS METHODS HAS MADE IT POSSIBLE TO UNCOVER GENETIC AND EPIGENETIC FLUCTUATION SUCH AS ABNORMAL DNA METHYLATION IN GENE PROMOTER REGIONS THAT IS EXPECTED TO PLAY A KEY ROLE IN GC. THE STUDY OF GASTRIC MALIGNANCIES REQUIRES AN ETIOLOGICAL PERSPECTIVE, AND HELICOBACTER PYLORI (H. PYLORI) WAS IDENTIFIED TO PLAY A ROLE IN GC. H. PYLORI INFECTION CAUSES CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM CAUSING ABNORMAL POLYCLONAL METHYLATION, WHICH MIGHT RAISE THE RISK OF GC. IN THE LAST TWO DECADES, VARIOUS PATHOGENIC FACTORS BY WHICH H. PYLORI INFECTION CAUSES GC HAVE BEEN DISCOVERED. ABNORMAL DNA METHYLATION IS TRIGGERED IN SEVERAL GENES, RENDERING THEM INACTIVE. IN GC, METHYLATION PATTERNS ARE LINKED TO CERTAIN SUBTYPES INCLUDING MICROSATELLITE INSTABILITY. MULTIPLE CANCER-RELATED PROCESSES ARE MORE USUALLY CHANGED BY ABNORMAL DNA METHYLATION THAN THROUGH MUTATIONS, ACCORDING TO CURRENT GENERAL AND COMBINED INVESTIGATIONS. FURTHERMORE, THE AMOUNT OF ACQUIRED ABNORMAL DNA METHYLATION IS HEAVILY LINKED TO THE CHANCES OF DEVELOPING GC. THEREFORE, WE INVESTIGATED ABNORMAL DNA METHYLATION IN GC AND THE LINK BETWEEN METHYLATION AND H. PYLORI INFECTION. 2022 3 1540 39 DNA METHYLATION IN GASTRIC CANCER, RELATED TO HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS. GASTRIC CANCER IS A LEADING CAUSE OF CANCER DEATH WORLDWIDE, AND SIGNIFICANT EFFORT HAS BEEN FOCUSED ON CLARIFYING THE PATHOLOGY OF GASTRIC CANCER. IN PARTICULAR, THE DEVELOPMENT OF GENOME-WIDE ANALYSIS TOOLS HAS ENABLED THE DETECTION OF GENETIC AND EPIGENETIC ALTERATIONS IN GASTRIC CANCER; FOR EXAMPLE, ABERRANT DNA METHYLATION IN GENE PROMOTER REGIONS IS THOUGHT TO PLAY A CRUCIAL ROLE IN GASTRIC CARCINOGENESIS. THE ETIOLOGICAL VIEWPOINT IS ALSO ESSENTIAL FOR THE STUDY OF GASTRIC CANCERS, AND TWO DISTINCT PATHOGENS, HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV), ARE KNOWN TO PARTICIPATE IN GASTRIC CARCINOGENESIS. CHRONIC INFLAMMATION OF THE GASTRIC EPITHELIUM DUE TO H. PYLORI INFECTION INDUCES ABERRANT POLYCLONAL METHYLATION THAT MAY LEAD TO AN INCREASED RISK OF GASTRIC CANCER. IN ADDITION, EBV INFECTION IS KNOWN TO CAUSE EXTENSIVE METHYLATION, AND EBV-POSITIVE GASTRIC CANCERS DISPLAY A HIGH METHYLATION EPIGENOTYPE, IN WHICH ABERRANT METHYLATION EXTENDS TO NOT ONLY POLYCOMB REPRESSIVE COMPLEX (PRC)-TARGET GENES IN EMBRYONIC STEM CELLS BUT ALSO NON-PRC-TARGET GENES. HERE, WE REVIEW ABERRANT DNA METHYLATION IN GASTRIC CANCER AND THE ASSOCIATION BETWEEN METHYLATION AND INFECTION WITH H. PYLORI AND EBV. 2014 4 3220 44 HELICOBACTER PYLORI AND MICRORNAS: RELATION WITH INNATE IMMUNITY AND PROGRESSION OF PRENEOPLASTIC CONDITIONS. THE ACCEPTED PARADIGM FOR INTESTINAL-TYPE GASTRIC CANCER PATHOGENESIS IS A MULTISTEP PROGRESSION FROM CHRONIC GASTRITIS INDUCED BY HELICOBACTER PYLORI (H. PYLORI) TO GASTRIC ATROPHY, INTESTINAL METAPLASIA, DYSPLASIA AND ULTIMATELY GASTRIC CANCER. THE GENETIC AND MOLECULAR MECHANISMS UNDERLYING DISEASE PROGRESSION ARE STILL NOT COMPLETELY UNDERSTOOD AS ONLY A FRACTION OF COLONIZED INDIVIDUALS EVER DEVELOP NEOPLASIA SUGGESTING THAT BACTERIAL, HOST AND ENVIRONMENTAL FACTORS ARE INVOLVED. MICRORNAS ARE NONCODING RNAS THAT MAY INFLUENCE H. PYLORI-RELATED PATHOLOGY THROUGH THE REGULATION OF THE TRANSCRIPTION AND EXPRESSION OF VARIOUS GENES, PLAYING AN IMPORTANT ROLE IN INFLAMMATION, CELL PROLIFERATION, APOPTOSIS AND DIFFERENTIATION. INDEED, H. PYLORI HAVE BEEN SHOWN TO MODIFY MICRORNA EXPRESSION IN THE GASTRIC MUCOSA AND MICRORNAS ARE INVOLVED IN THE IMMUNE HOST RESPONSE TO THE BACTERIA AND IN THE REGULATION OF THE INFLAMMATORY RESPONSE. MICRORNAS HAVE A KEY ROLE IN THE REGULATION OF INFLAMMATORY PATHWAYS AND H. PYLORI MAY INFLUENCE INFLAMMATION-MEDIATED GASTRIC CARCINOGENESIS POSSIBLY THROUGH DNA METHYLATION AND EPIGENETIC SILENCING OF TUMOR SUPPRESSOR MICRORNAS. FURTHERMORE, MICRORNAS INFLUENCED BY H. PYLORI ALSO HAVE BEEN FOUND TO BE INVOLVED IN CELL CYCLE REGULATION, APOPTOSIS AND EPITHELIAL-MESENCHYMAL TRANSITION. ALTOGETHER, MICRORNAS SEEM TO HAVE AN IMPORTANT ROLE IN THE PROGRESSION FROM GASTRITIS TO PRENEOPLASTIC CONDITIONS AND NEOPLASTIC LESIONS AND SINCE EACH MICRORNA CAN CONTROL THE EXPRESSION OF HUNDREDS TO THOUSANDS OF GENES, KNOWLEDGE OF MICRORNAS TARGET GENES AND THEIR FUNCTIONS ARE OF PARAMOUNT IMPORTANCE. IN THIS ARTICLE WE PRESENT A COMPREHENSIVE REVIEW ABOUT THE ROLE OF MICRORNAS IN H. PYLORI GASTRIC CARCINOGENESIS, IDENTIFYING THE MICRORNAS DOWNREGULATED AND UPREGULATED IN THE INFECTION AND CLARIFYING THEIR BIOLOGICAL ROLE IN THE LINK BETWEEN IMMUNE HOST RESPONSE, INFLAMMATION, DNA METHYLATION AND GASTRIC CARCINOGENESIS. 2015 5 762 35 CAUSAL ROLE OF HELICOBACTER PYLORI INFECTION AND ERADICATION THERAPY IN GASTRIC CARCINOGENESIS. MANY EPIDEMIOLOGICAL REPORTS INDICATE THAT HELICOBACTER PYLORI (H PYLORI) INFECTION PLAYS AN IMPORTANT ROLE IN GASTRIC CARCINOGENESIS. SEVERAL GENETIC AND EPIGENETIC ALTERATIONS CONTRIBUTE TO THE INITIATION, PROMOTION, AND PROGRESSION OF THE CANCER CELLS IN A MULTI-STEP MANNER. H PYLORI IS KNOWN TO INDUCE CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA. ITS PRODUCTS, INCLUDING SUPEROXIDES, PARTICIPATE IN THE DNA DAMAGE FOLLOWED BY INITIATION, AND THE INFLAMMATION-DERIVED CYTOKINES AND GROWTH FACTORS CONTRIBUTE TO THE PROMOTION OF GASTRIC CARCINOGENESIS. BY ERADICATING H PYLORI, GASTRIC INFLAMMATION CAN BE CURED; THE THERAPY DIMINISHES THE LEVELS NOT ONLY OF INFLAMMATORY CELL INFILTRATION, BUT ALSO ATROPHY/INTESTINAL METAPLASIA IN PART. A RANDOMIZED CONTROLLED TRIAL REVEALED THAT THE ERADICATION THERAPY DIMINISHED THE GASTRIC CANCER PREVALENCE IN CASES WITHOUT PRE-CANCEROUS CONDITIONS. IN ADDITION, RECENT EPIDEMIOLOGICAL STUDIES FROM JAPANESE GROUPS DEMONSTRATED THAT THE DEVELOPMENT OF GASTRIC CANCER, ESPECIALLY OF THE INTESTINAL TYPE, WAS DECREASED BY SUCCESSFUL ERADICATION THERAPY, ALTHOUGH THESE WERE DESIGNED IN A NON-RANDOMIZED MANNER. HOWEVER, IT SHOULD BE MENTIONED THAT ENDOSCOPIC DETECTION IS THE ONLY WAY TO EVALUATE THE DEGREE OF GASTRIC CARCINOGENESIS. WE HAVE REPORTED THAT THE ENDOSCOPIC AND HISTOLOGICAL MORPHOLOGIES COULD BE MODIFIED BY ERADICATION THERAPY AND IT MIGHT CONTRIBUTE TO THE PREVALENCE OF GASTRIC CANCER DEVELOPMENT. CONSIDERING THE BIOLOGICAL NATURE OF CANCER CELL PROLIFERATION, IT IS CONSIDERED THAT A SUFFICIENTLY LONG-TERM FOLLOW-UP WOULD BE ESSENTIAL TO DISCUSS THE ANTICANCER EFFECT OF ERADICATION THERAPY. 2006 6 6841 39 [MECHANISMS OF H. PYLORI INFECTION-INDUCED GASTRIC CARCINOGENESIS]. MANY EPIDEMIOLOGICAL STUDIES HAVE DEMONSTRATED A STRONG ASSOCIATION BETWEEN H. PYLORI (HELICOBACTER PYLORI) INFECTION AND HUMAN GASTRIC CANCER DEVELOPMENT. THE PRECISE MECHANISMS ACCOUNTING FOR GASTRIC CANCER DEVELOPMENT INDUCED BY H. PYLORI INFECTION ARE STILL NOT COMPLETELY UNDERSTOOD. HOWEVER, IT SHOULD BE REASONABLE TO ASSUME THAT THERE ARE TWO DISTINCT MOLECULAR PATHWAYS FOR GASTRIC CARCINOGENESIS BY H. PYLORI INFECTION; THE DIRECT ACTION OF THE BACTERIA ITSELF ON GASTRIC EPITHELIAL CELLS, AND THE ACCUMULATION OF GENETIC CHANGES CAUSED BY PROLONGED BACTERIAL INFECTION AND CHRONIC INFLAMMATION. AS A DIRECT ACTION OF H. PYLORI, BACTERIAL PROTEINS SUCH AS CAGA COULD BE DELIVERED INTO GASTRIC EPITHELIAL CELLS VIA THE TYPE IV SECRETION APPARATUS AND MODIFY THE HOST CELL FUNCTIONS RELATED TO CELL PROLIFERATION. IN ADDITION TO THE DIRECT BACTERIAL ACTION, H. PYLORI INFECTION AND THE RESULTANT INFLAMMATORY RESPONSE CAUSE VARIOUS GENETIC AND EPIGENETIC CHANGES IN TUMOR-RELATED GENES OF THE GASTRIC EPITHELIAL CELLS. NOTABLY, EXPRESSION OF AID (ACTIVATION-INDUCED CYTIDINE DEAMINASE), A DNA EDITING ENZYME THAT UNDERGOES SOMATIC HYPERMUTATION ON HUMAN GENES, IS INDUCED IN RESPONSE TO H. PYLORI INFECTION AND PROINFLAMMATORY CYTOKINE STIMULATION IN HUMAN GASTRIC EPITHELIAL CELLS. AS A RESULT, THE ACCUMULATION OF GENETIC ALTERATIONS WOULD PERSIST UNTIL THE CLINICAL STAGE OF ATROPHIC GASTRITIS AND EVENTUALLY TRIGGER THE MALIGNANT TRANSFORMATION OF GASTRIC CELLS. 2010 7 2122 53 EPIGENETIC IMPACT OF INFECTION ON CARCINOGENESIS: MECHANISMS AND APPLICATIONS. VIRAL AND BACTERIAL INFECTIONS ARE INVOLVED IN THE DEVELOPMENT OF HUMAN CANCERS, SUCH AS LIVER, NASOPHARYNGEAL, CERVICAL, HEAD AND NECK, AND GASTRIC CANCERS. ABERRANT DNA METHYLATION IS FREQUENTLY PRESENT IN THESE CANCERS, AND SOME OF THE ABERRANTLY METHYLATED GENES ARE CAUSALLY INVOLVED IN CANCER DEVELOPMENT AND PROGRESSION. NOTABLY, ABERRANT DNA METHYLATION CAN BE PRESENT EVEN IN NON-CANCEROUS OR PRECANCEROUS TISSUES, AND ITS LEVELS CORRELATE WITH THE RISK OF CANCER DEVELOPMENT, PRODUCING A SO-CALLED 'EPIGENETIC FIELD FOR CANCERIZATION'. MECHANISTICALLY, MOST VIRAL OR BACTERIAL INFECTIONS INDUCE DNA METHYLATION INDIRECTLY VIA CHRONIC INFLAMMATION, BUT RECENT STUDIES HAVE INDICATED THAT SOME VIRUSES HAVE DIRECT EFFECTS ON THE EPIGENETIC MACHINERY OF HOST CELLS. FROM A TRANSLATIONAL VIEWPOINT, A RECENT MULTICENTER PROSPECTIVE COHORT STUDY DEMONSTRATED THAT ASSESSMENT OF THE EXTENT OF ALTERATIONS IN DNA METHYLATION IN NON-CANCEROUS TISSUES CAN BE USED TO PREDICT CANCER RISK. FURTHERMORE, SUPPRESSION OF ABERRANT DNA METHYLATION WAS SHOWN TO BE A USEFUL STRATEGY FOR CANCER PREVENTION IN AN ANIMAL MODEL. HERE, WE REVIEW THE INVOLVEMENT OF ABERRANT DNA METHYLATION IN VARIOUS TYPES OF INFECTION-ASSOCIATED CANCERS, ALONG WITH INDIVIDUAL INDUCTION MECHANISMS, AND WE DISCUSS THE APPLICATION OF THESE FINDINGS FOR CANCER PREVENTION, DIAGNOSIS, AND THERAPY. 2016 8 342 39 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS. 2007 9 5276 46 PROMOTER METHYLATION OF TUMOR-RELATED GENES IN GASTRIC CARCINOGENESIS. ABERRANT PROMOTER METHYLATION AND SUBSEQUENT SILENCING OF CANCER-RELATED GENES HAS BEEN RECOGNIZED AS AN IMPORTANT PATHWAY INVOLVED IN GASTRIC CARCINOGENESIS. IN FACT, SEVERAL FACTORS ARE BELIEVED TO CONTRIBUTE TO ITS INDUCTION IN GASTRIC EPITHELIA, INCLUDING AGING, DIET, CHRONIC INFLAMMATION AND INFECTION OF HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV). HOWEVER, THE UNDERLING MECHANISMS ARE NOT COMPLETELY IDENTIFIED, DESPITE THE BELIEF THAT INCREASED EXPRESSION OR ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), OR DECREASED DEMETHYLATION ACTIVITY MAY CONTRIBUTE TO THE EXCESSIVE METHYLATION. A GREAT NUMBER OF GENES WITH PROMOTER METHYLATION HAVE BEEN OBSERVED IN GASTRIC CANCER (GC), AMONG WHICH P16INK4A (P16), MUT L HOMOLOGUE 1 (MLH1), EPITHELIAL-CADHERIN (E-CADHERIN), RUNT-RELATED TRANSCRIPTION FACTOR 3 (RUNX3), ADENOMATOUS POLYPOSIS COLI (APC), O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT), RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) AND DEATH-ASSOCIATED PROTEIN KINASE (DAPK) HAVE BEEN EXTENSIVELY STUDIED. UNLIKE THE DISTINCT METHYLATION CHARACTERIZATION IN SINGLE GENES, METHYLATION ANALYSIS OF MULTIPLE GENES MAY PROVIDE MORE INFORMATION IN RISK PREDICTION, EARLY DETECTION, PROGNOSIS ASSESSMENT AND CHEMOTHERAPY CHOICE FOR GC. SPECIFICALLY, PARTICULAR MONITORING AND SCREENING SHOULD BE PERFORMED ON THOSE OVER 45 YEARS OLD, WITH PRECANCEROUS GASTRIC DISEASE OR INFECTION OF H. PYLORI OR EBV. AS AN ALTERNATIVE TO TUMOR TISSUES, METHYLATION DETECTION IN PATIENT SERA OR GASTRIC WASHES MAY ALSO BE USED IN RISK PREDICTION AND EARLY DETECTION. HOWEVER, WHAT STILL POSES A GREAT CHALLENGE AS WELL AS A PUZZLE IS THE DETERMINATION OF THE VERY GENES THAT SHOULD BE USED IN METHYLATION ANALYSIS. BECAUSE EPIGENETIC ALTERATIONS ARE NORMALLY REVERSIBLE, DRUGS OR CHEMICAL COMPOUNDS WITH DEMETHYLATING ACTIVITY, SUCH AS 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) COULD BE USED IN THE TREATMENT OF PATIENTS WITH MULTIPLE GENE METHYLATION. IN VIEW OF THE ADVERSE EFFECTS OF 5-AZA-DC, DNMT-TARGETED STRATEGY HAS BEEN PROPOSED AND MAY PROVE TO BE MORE EFFECTIVE THAN DEMETHYLATING AGENTS. 2012 10 2852 27 FROM GASTRIC INFLAMMATION TO GASTRIC CANCER. THE MAJORITY OF GASTRIC ADENOCARCINOMAS ARE RELATED TO CHRONIC INFLAMMATION INDUCED BY HELICOBACTER PYLORI INFECTION. FOR INTESTINAL-TYPE GASTRIC CANCER, A MULTISTEP PROCESS OF MUCOSAL ALTERATIONS LEADING FROM GASTRITIS VIA GLANDULAR ATROPHY, INTESTINAL METAPLASIA AND DYSPLASIA TO INVASIVE CARCINOMA IS WELL RECOGNIZED. ONGOING CLINICAL STUDIES FOCUS ON A 'POINT OF NO RETURN'. IT IS DEFINED AS A SITUATION WHEN CERTAIN ALTERATIONS ARE NO LONGER REVERSIBLE BY H. PYLORI ERADICATION AND PROGRESSION TO GASTRIC CANCER MAY CONTINUE. H. PYLORI AFFECTS THE MUCOSAL AS WELL AS THE SYSTEMIC IMMUNE RESPONSE BY SECRETION OF CYTOKINES AND THE RECRUITMENT OF DISTINCT INFLAMMATORY CELLS. THE IMMUNE RESPONSE IS CHARACTERIZED BY A BALANCE BETWEEN A TH1-DOMINATED RESPONSE AND THE RECRUITMENT OF ANTIGEN-SPECIFIC REGULATORY T CELLS THAT ALLOW THE BACTERIA TO PERSIST IN HUMAN GASTRIC MUCOSA. BESIDES IMMUNE-MEDIATED EFFECTS, H. PYLORI INDUCES CELLULAR ALTERATIONS AS WELL AS GENETIC ALTERATIONS IN GENES THAT ARE ESSENTIAL FOR THE EPIGENETIC INTEGRITY AND MUCOSAL HOMEOSTASIS. THESE GENETIC ALTERATIONS DURING GASTRIC CANCER DEVELOPMENT ARE IN FOCUS OF INTENSIVE RESEARCH AND SHOULD ULTIMATELY ALLOW THE IDENTIFICATION OF RISK FACTORS INVOLVED IN GASTRIC CARCINOGENESIS. THE DETECTION OF INDIVIDUALS AT HIGH RISK FOR GASTRIC CANCER WOULD HELP TO DESIGN APPROPRIATE STRATEGIES FOR PREVENTION AND SURVEILLANCE. 2010 11 6369 37 THE ROLE OF MICRORNAS IN HELICOBACTER PYLORI PATHOGENESIS AND GASTRIC CARCINOGENESIS. GASTRIC CARCINOGENESIS IS A MULTISTEP PROCESS ORCHESTRATED BY ABERRANCIES IN THE GENETIC AND EPIGENETIC REGULATION OF ONCOGENES AND TUMOR SUPPRESSOR GENES. CHRONIC INFECTION WITH HELICOBACTER PYLORI IS THE STRONGEST KNOWN RISK FACTOR FOR THE DEVELOPMENT OF GASTRIC CANCER. H. PYLORI EXPRESSES A SPECTRUM OF VIRULENCE FACTORS THAT DYSREGULATE HOST INTRACELLULAR SIGNALING PATHWAYS THAT LOWER THE THRESHOLD FOR NEOPLASTIC TRANSFORMATION. IN ADDITION TO BACTERIAL DETERMINANTS, NUMEROUS HOST AND ENVIRONMENTAL FACTORS INCREASE THE RISK OF GASTRIC CARCINOGENESIS. RECENT DISCOVERIES HAVE SHED NEW LIGHT ON THE INVOLVEMENT OF MICRORNAS (MIRNAS) IN GASTRIC CARCINOGENESIS. MIRNAS REPRESENT AN ABUNDANT CLASS OF SMALL, NON-CODING RNAS INVOLVED IN GLOBAL POST-TRANSCRIPTIONAL REGULATION AND, CONSEQUENTLY, PLAY AN INTEGRAL ROLE AT MULTIPLE STEPS IN CARCINOGENESIS, INCLUDING CELL CYCLE PROGRESSION, PROLIFERATION, APOPTOSIS, INVASION, AND METASTASIS. EXPRESSION LEVELS OF MIRNAS ARE FREQUENTLY ALTERED IN MALIGNANCIES, WHERE THEY FUNCTION AS EITHER ONCOGENIC MIRNAS OR TUMOR SUPPRESSOR MIRNAS. THIS REVIEW FOCUSES ON MIRNAS DYSREGULATED BY H. PYLORI AND POTENTIAL ETIOLOGIC ROLES THEY PLAY IN H. PYLORI-MEDIATED GASTRIC CARCINOGENESIS. 2011 12 3659 49 INDUCTION OF EPIGENETIC ALTERATIONS BY CHRONIC INFLAMMATION AND ITS SIGNIFICANCE ON CARCINOGENESIS. CHRONIC INFLAMMATION IS DEEPLY INVOLVED IN DEVELOPMENT OF HUMAN CANCERS, SUCH AS GASTRIC AND LIVER CANCERS. INDUCTION OF CELL PROLIFERATION, PRODUCTION OF REACTIVE OXYGEN SPECIES, AND DIRECT STIMULATION OF EPITHELIAL CELLS BY INFLAMMATION-INDUCING FACTORS HAVE BEEN CONSIDERED AS MECHANISMS INVOLVED. INFLAMMATION-RELATED CANCERS ARE KNOWN FOR THEIR MULTIPLE OCCURRENCES, AND ABERRANT DNA METHYLATION IS KNOWN TO BE PRESENT EVEN IN NONCANCEROUS TISSUES. IMPORTANTLY, FOR SOME CANCERS, THE DEGREE OF ACCUMULATION HAS BEEN DEMONSTRATED TO BE CORRELATED WITH RISK OF DEVELOPING CANCERS. THIS INDICATES THAT INFLAMMATION INDUCES ABERRANT EPIGENETIC ALTERATIONS IN A TISSUE EARLY IN THE PROCESS OF CARCINOGENESIS, AND ACCUMULATION OF SUCH ALTERATIONS FORMS "AN EPIGENETIC FIELD FOR CANCERIZATION." THIS ALSO SUGGESTS THAT INHIBITION OF INDUCTION OF EPIGENETIC ALTERATIONS AND REMOVAL OF THE ACCUMULATED ALTERATIONS ARE NOVEL APPROACHES TO CANCER PREVENTION. DISTURBANCES IN CYTOKINE AND CHEMOKINE SIGNALS AND INDUCTION OF CELL PROLIFERATIONS ARE IMPORTANT MECHANISMS OF HOW INFLAMMATION INDUCES ABERRANT DNA METHYLATION. ABERRANT DNA METHYLATION IS INDUCED IN SPECIFIC GENES, AND GENE EXPRESSION LEVELS, THE PRESENCE OF RNA POLYMERASE II (ACTIVE OR STALLED), AND TRIMETHYLATION OF H3K4 ARE INVOLVED IN THE SPECIFICITY. EXPRESSION OF DNA METHYLTRANSFERASES (DNMTS) IS NOT NECESSARILY INDUCED BY INFLAMMATION, AND LOCAL IMBALANCE BETWEEN DNMTS AND FACTORS THAT PROTECT GENES FROM DNA METHYLATION SEEMS TO BE IMPORTANT. 2010 13 4725 28 NORMAL GASTRIC TISSUE HELICOBACTER PYLORI INFECTION IS ASSOCIATED WITH EPIGENETIC AGE ACCELERATION, INCREASED MITOTIC TICK RATE, TISSUE CELL COMPOSITION, AND NATURAL KILLER CELL METHYLATION ALTERATIONS. BACKGROUND: GASTRIC ADENOCARCINOMAS ARE A LEADING CAUSE OF GLOBAL MORTALITY, ASSOCIATED WITH CHRONIC INFECTION WITH HELICOBACTER PYLORI . THE MECHANISMS BY WHICH INFECTION WITH H. PYLORI CONTRIBUTES TO CARCINOGENESIS ARE NOT WELL UNDERSTOOD. RECENT STUDIES FROM SUBJECTS WITH AND WITHOUT GASTRIC CANCER HAVE IDENTIFIED SIGNIFICANT DNA METHYLATION ALTERATIONS IN NORMAL GASTRIC MUCOSA ASSOCIATED WITH H. PYLORI INFECTION AND GASTRIC CANCER RISK. HERE WE FURTHER INVESTIGATED DNA METHYLATION ALTERATIONS IN NORMAL GASTRIC MUCOSA IN GASTRIC CANCER CASES (N = 42) AND CONTROL SUBJECTS (N = 42) WITH H. PYLORI INFECTION DATA. WE ASSESSED TISSUE CELL TYPE COMPOSITION, DNA METHYLATION ALTERATIONS WITHIN CELL POPULATIONS, EPIGENETIC AGING, AND REPETITIVE ELEMENT METHYLATION. RESULTS: IN NORMAL GASTRIC MUCOSA OF BOTH GASTRIC CANCER CASES AND CONTROL SUBJECTS, WE OBSERVED INCREASED EPIGENETIC AGE ACCELERATION ASSOCIATED WITH H. PYLORI INFECTION. WE ALSO OBSERVED AN INCREASED MITOTIC TICK RATE ASSOCIATED WITH H. PYLORI INFECTION IN BOTH GASTRIC CANCER CASES AND CONTROLS. SIGNIFICANT DIFFERENCES IN IMMUNE CELL POPULATIONS ASSOCIATED WITH H. PYLORI INFECTION IN NORMAL TISSUE FROM CANCER CASES AND CONTROLS WERE IDENTIFIED USING DNA METHYLATION CELL TYPE DECONVOLUTION. WE ALSO FOUND NATURAL KILLER CELL-SPECIFIC METHYLATION ALTERATIONS IN NORMAL MUCOSA FROM GASTRIC CANCER PATIENTS WITH H. PYLORI INFECTION. CONCLUSIONS: OUR FINDINGS FROM NORMAL GASTRIC MUCOSA PROVIDE INSIGHT INTO UNDERLYING CELLULAR COMPOSITION AND EPIGENETIC ASPECTS OF H. PYLORI ASSOCIATED GASTRIC CANCER ETIOLOGY. 2023 14 3686 32 INFLAMMATION-RELATED ABERRANT PATTERNS OF DNA METHYLATION: DETECTION AND ROLE IN EPIGENETIC DEREGULATION OF CANCER CELL TRANSCRIPTOME. IT IS NOW APPARENT THAT EPIGENETIC ABNORMALITIES, IN PARTICULAR ALTERED DNA METHYLATION, PLAY A CRUCIAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF HUMAN CANCERS. DNA HYPERMETHYLATION AT PROMOTER CPG ISLANDS IS NOW RECOGNIZED AS A THIRD MECHANISM BY WHICH INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS. ABERRANT CPG ISLAND HYPERMETHYLATION IS ALSO FREQUENTLY OBSERVED IN CHRONIC INFLAMMATION AND PRECANCEROUS LESIONS, WHICH SUGGESTS THAT IT IS AN EARLY EVENT IN TUMORIGENESIS THAT COULD SERVE AS A USEFUL TUMOR MARKER. A VARIETY OF SCREENING TECHNIQUES HAVE BEEN DEVELOPED FOR GENOME-WIDE SCREENING OF METHYLATION STATUS. OF THOSE, TRANSCRIPTOME ANALYSIS COUPLED WITH PHARMACOLOGICAL UNMASKING HAS EMERGED AS A POWERFUL TOOL FOR REVEALING DNA METHYLATION PATTERNS IN CANCER CELLS AND IDENTIFYING NEW TUMOR MARKER CANDIDATES. 2009 15 3067 39 GENOME-WIDE DNA METHYLATION PROFILES IN PRECANCEROUS CONDITIONS AND CANCERS. ALTERATIONS OF DNA METHYLATION, WHICH RESULT IN CHROMOSOMAL INSTABILITY AND SILENCING OF TUMOR-RELATED GENES, ARE AMONG THE MOST CONSISTENT EPIGENETIC CHANGES OBSERVED IN HUMAN CANCERS. ANALYSIS OF TISSUE SPECIMENS HAS REVEALED THAT DNA METHYLATION ALTERATIONS PARTICIPATE IN MULTISTAGE CARCINOGENESIS, EVEN FROM THE EARLY AND PRECANCEROUS STAGES, ESPECIALLY IN ASSOCIATION WITH CHRONIC INFLAMMATION AND/OR PERSISTENT VIRAL INFECTION, SUCH AS CHRONIC HEPATITIS OR LIVER CIRRHOSIS RESULTING FROM INFECTION WITH HEPATITIS B OR C VIRUS. DNA METHYLATION ALTERATIONS CAN ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY, BUT IS SIGNIFICANTLY CORRELATED WITH ACCUMULATION OF DNA HYPERMETHYLATION IN CPG ISLANDS OF TUMOR-RELATED GENES. ALTERATION OF DNA METHYLTRANSFERASE 3B SPLICING MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION IN PERICENTROMERIC SATELLITE REGIONS. GENOME-WIDE ANALYSIS OF DNA METHYLATION STATUS HAS REVEALED THAT THE DNA METHYLATION PROFILE AT THE PRECANCEROUS STAGE IS BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. DNA METHYLATION STATUS IS NOT SIMPLY ALTERED AT THE PRECANCEROUS STAGE; RATHER, DNA METHYLATION ALTERATIONS AT THE PRECANCEROUS STAGE MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. THEREFORE, GENOME-WIDE DNA METHYLATION PROFILING MAY PROVIDE OPTIMAL INDICATORS FOR CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION, AND THUS PROVIDE AN AVENUE FOR CANCER PREVENTION AND THERAPY ON AN INDIVIDUAL BASIS. 2010 16 3221 34 HELICOBACTER PYLORI AND THE MOLECULAR PATHOGENESIS OF INTESTINAL-TYPE GASTRIC CARCINOMA. GASTRIC CARCINOMA IS AN INFLAMMATION-RELATED CANCER CAUSED BY LONG-TERM INFECTION WITH THE HUMAN BACTERIAL PATHOGEN, HELICOBACTER PYLORI. THE PATTERN OF ACUTE-ON-CHRONIC INFLAMMATION CAUSES PROGRESSIVE MUCOSAL DAMAGE WHICH MAY RESULT IN ATROPHY WITH METAPLASTIC EPITHELIA AND EVENTUALLY GASTRIC CANCER. RECENTLY, IT HAS BEEN RECOGNIZED THAT H. PYLORI CAN ALSO CAUSE GENETIC INSTABILITY SUCH AS DOUBLE-STRANDED DNA BREAKS AND CAN PRODUCE GENE ACTIVATION AND SILENCING VIA EPIGENETIC PATHWAYS. AS GENETIC INSTABILITY IS THE HALLMARK OF CANCER, WE HIGHLIGHT RECENT PROGRESS IN UNDERSTANDING THE GASTRIC CARCINOGENESIS IN RELATION TO H. PYLORI-RELATED INFLAMMATION, H. PYLORI-INDUCED DOUBLE-STRANDED DNA BREAKAGE AND ABERRANT GENE EXPRESSION AS WELL AS THE MECHANISMS AND ROLE OF H. PYLORI-ASSOCIATED EPIGENETIC CHANGE IN GENE EXPRESSION. 2014 17 4960 34 PATHOGENESIS OF PRE-NEOPLASTIC LESIONS OF THE STOMACH: TARGETS FOR PREVENTION. GASTRIC ATROPHY AND INTESTINAL METAPLASIA ARE GENERALLY CONSIDERED TO BE PRECANCEROUS LESIONS OF THE STOMACH. CHRONIC HELICOBACTER PYLORI INFECTION IS ONE THE MOST IMPORTANT FACTORS IN THE DEVELOPMENT OF THESE PRE-MALIGNANT GASTRIC LESIONS. IN ADDITION TO BACTERIAL FACTORS, POLYMORPHISMS IN THE CYTOKINE GENES OF THE HOST THAT MODULATE INFLAMMATORY RESPONSES ARE FOUND TO HAVE A SYNERGISTIC EFFECT IN THE DEVELOPMENT OF GASTRIC CANCER AS WELL AS PRE-NEOPLASTIC LESIONS. RECENTLY, INAPPROPRIATE ACTIVATION OF THE INTESTINE-SPECIFIC TRANSCRIPTION FACTOR LIKE THE HOMEOBOX GENE COMPLEX CDX1 AND CDX2 ARE FOUND TO BE AN IMPORTANT CONTRIBUTING FACTOR IN THE INDUCTION OF INTESTINAL METAPLASIA IN THE STOMACH. ABERRANT EXPRESSION OF CYCLOOXYGENASE-2 AND EPIGENETIC CHANGES ARE ALSO FREQUENTLY DETECTED IN PRE-NEOPLASTIC GASTRIC LESIONS. ONE OF THE MOST IMPORTANT QUESTIONS RELATING TO THESE PRE-NEOPLASTIC GASTRIC LESIONS IS THAT WHETHER H. PYLORI ERADICATION COULD REVERSE THESE CHANGES. HOWEVER, MOST CONTROLLED STUDIES SHOWED NO OR JUST MODEST IMPROVEMENT IN INTESTINAL METAPLASIA AFTER H. PYLORI ERADICATION. FURTHER STUDIES SHOULD EVALUATE THE ROLE OF OTHER CHEMOPREVENTIVE AGENTS, PARTICULARLY CYCLOOXYGENASE-2 INHIBITOR, ON REGRESSION OF PRE-NEOPLASTIC LESIONS. 2004 18 3226 36 HELICOBACTER PYLORI INFECTION, ONCOGENIC PATHWAYS AND EPIGENETIC MECHANISMS IN GASTRIC CARCINOGENESIS. CHRONIC COLONIZATION OF THE HUMAN STOMACH BY HELICOBACTER PYLORI, A GRAM-NEGATIVE BACTERIUM, IS THE MAJOR CAUSE OF CHRONIC GASTRITIS, PEPTIC ULCERS AND GASTRIC CANCER. RECENT PROGRESS HAS ELUCIDATED IMPORTANT BACTERIAL AND HOST FACTORS THAT ARE RESPONSIBLE FOR H. PYLORI-INDUCED GASTRIC INFLAMMATION AND GASTRIC MALIGNANCY. H. PYLORI CYTOTOXIN-ASSOCIATED ANTIGEN A IS THE MAJOR ONCOGENIC FACTOR INJECTED INTO HOST CELLS FROM BACTERIA AND IT DISRUPTS EPITHELIAL CELL FUNCTIONS. TOGETHER WITH H. PYLORI CAG PATHOGENICITY ISLAND, IT CAUSES GENERAL INFLAMMATORY STRESS WITHIN GASTRIC MUCOSA AND ACTIVATES MULTIPLE ONCOGENIC PATHWAYS IN EPITHELIAL CELLS. A GROWING LIST OF THESE PATHWAYS INCLUDES NF-KAPPAB, ACTIVATOR PROTEIN-1, PI3K, SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3, WNT/BETA-CATENIN AND CYCLOOXYGENASE 2. H. PYLORI INDUCES EPIGENETIC ALTERATIONS, SUCH AS DNA METHYLATION AND HISTONE MODIFICATION, WHICH PLAY CRITICAL ROLES IN ONCOGENIC TRANSFORMATION. IN ADDITION, INVESTIGATIONS INTO GASTRIC STEM CELL OR PROGENITOR CELL BIOLOGY HAVE SHED LIGHT ON THE MECHANISMS THROUGH WHICH GASTRIC CANCER MAY ORIGINATE. CONTINUED INVESTIGATION IN THESE AREAS WILL YIELD NOVEL INSIGHTS AND HELP TO ELUCIDATE THE MECHANISMS OF BACTERIA-INDUCED CARCINOGENESIS. 2010 19 2377 42 EPIGENETIC REGULATION OF TUMOR SUPPRESSORS BY HELICOBACTER PYLORI ENHANCES EBV-INDUCED PROLIFERATION OF GASTRIC EPITHELIAL CELLS. HELICOBACTER PYLORI AND EPSTEIN-BARR VIRUS (EBV) ARE TWO WELL-KNOWN CONTRIBUTORS TO CANCER AND CAN ESTABLISH LIFELONG PERSISTENT INFECTION IN THE HOST. THIS LEADS TO CHRONIC INFLAMMATION, WHICH ALSO CONTRIBUTES TO DEVELOPMENT OF CANCER. ASSOCIATION WITH H. PYLORI INCREASES THE RISK OF GASTRIC CARCINOMA, AND COEXISTENCE WITH EBV ENHANCES PROLIFERATION OF INFECTED CELLS. FURTHER, H. PYLORI-EBV COINFECTION CAUSES CHRONIC INFLAMMATION IN PEDIATRIC PATIENTS. WE HAVE ESTABLISHED AN H. PYLORI-EBV COINFECTION MODEL SYSTEM USING HUMAN GASTRIC EPITHELIAL CELLS. WE SHOWED THAT H. PYLORI INFECTION CAN INCREASE THE ONCOGENIC PHENOTYPE OF EBV-INFECTED CELLS AND THAT THE CYTOTOXIN-ASSOCIATED GENE (CAGA) PROTEIN ENCODED BY H. PYLORI STIMULATED EBV-MEDIATED CELL PROLIFERATION IN THIS COINFECTION MODEL SYSTEM. THIS LED TO INCREASED EXPRESSION OF DNA METHYL TRANSFERASES (DNMTS), WHICH REPROGRAMMED CELLULAR TRANSCRIPTIONAL PROFILES, INCLUDING THOSE OF TUMOR SUPPRESSOR GENES (TSGS), THROUGH HYPERMETHYLATION. THESE FINDINGS PROVIDE NEW INSIGHTS INTO A MOLECULAR MECHANISM WHEREBY COOPERATIVITY BETWEEN TWO ONCOGENIC AGENTS LEADS TO ENHANCED ONCOGENIC ACTIVITY OF GASTRIC CANCER CELLS.IMPORTANCE WE HAVE STUDIED THE COOPERATIVITY BETWEEN H. PYLORI AND EBV, TWO KNOWN ONCOGENIC AGENTS. THIS LED TO AN ENHANCED ONCOGENIC PHENOTYPE IN GASTRIC EPITHELIAL CELLS. WE NOW DEMONSTRATE THAT EBV-DRIVEN EPIGENETIC MODIFICATIONS ARE ENHANCED IN THE PRESENCE OF H. PYLORI, MORE SPECIFICALLY, IN THE PRESENCE OF ITS CAGA SECRETORY ANTIGEN. THIS RESULTS IN INCREASED PROLIFERATION OF THE INFECTED GASTRIC CELLS. OUR FINDINGS NOW ELUCIDATE A MOLECULAR MECHANISM WHEREBY EXPRESSION OF CELLULAR DNA METHYL TRANSFERASES IS INDUCED INFLUENCING INFECTION BY EBV. HYPERMETHYLATION OF THE REGULATORY GENOMIC REGIONS OF TUMOR SUPPRESSOR GENES RESULTS IN THEIR SILENCING. THIS DRASTICALLY AFFECTS THE EXPRESSION OF CELL CYCLE, APOPTOSIS, AND DNA REPAIR GENES, WHICH DYSREGULATES THEIR ASSOCIATED PROCESSES, AND PROMOTION OF THE ONCOGENIC PHENOTYPE. 2018 20 2853 26 FROM HELICOBACTER PYLORI INFECTION TO GASTRIC CANCER: CURRENT EVIDENCE ON THE IMMUNE RESPONSE. GASTRIC CANCER (GC) IS THE RESULT OF A MULTIFACTORIAL PROCESS WHOSE MAIN COMPONENTS ARE INFECTION BY HELICOBACTER PYLORI (H. PYLORI), BACTERIAL VIRULENCE FACTORS, HOST IMMUNE RESPONSE AND ENVIRONMENTAL FACTORS. THE DEVELOPMENT OF THE NEOPLASTIC MICROENVIRONMENT ALSO DEPENDS ON GENETIC AND EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES, WHICH RESULTS IN DEREGULATION OF CELL SIGNALING PATHWAYS AND APOPTOSIS PROCESS. THIS REVIEW SUMMARIZES THE MAIN ASPECTS OF THE PATHOGENESIS OF GC AND THE IMMUNE RESPONSE INVOLVED IN CHRONIC INFLAMMATION GENERATED BY H. PYLORI. 2022