1 3231 100 HELICOBACTER PYLORI-INDUCED MODULATION OF THE PROMOTER METHYLATION OF WNT ANTAGONIST GENES IN GASTRIC CARCINOGENESIS. BACKGROUND: THIS STUDY AIMED TO INVESTIGATE THE CHANGES IN THE PROMOTER METHYLATION AND GENE EXPRESSION OF MULTIPLE WNT ANTAGONISTS BETWEEN THE CHRONIC INFECTION AND ERADICATION OF HELICOBACTER PYLORI (H. PYLORI) IN GASTRIC CARCINOGENESIS. METHODS: THE LEVELS OF METHYLATION AND CORRESPONDING MRNA EXPRESSION OF SEVEN WNT ANTAGONIST GENES (SFRP1, -2, -5, DKK1, -2, -3, WIF1) WERE COMPARED AMONG THE PATIENTS WITH H. PYLORI-POSITIVE GASTRIC CANCERS (GCS), AND H. PYLORI-POSITIVE AND H. PYLORI-NEGATIVE CONTROLS, BY QUANTITATIVE METHYLIGHT ASSAY AND REAL-TIME REVERSE TRANSCRIPTION (RT)-POLYMERASE CHAIN REACTION (PCR), RESPECTIVELY. THE CHANGES OF THE METHYLATION AND EXPRESSION LEVELS OF THE GENES WERE ALSO COMPARED BETWEEN THE H. PYLORI ERADICATION AND H. PYLORI-PERSISTENT GROUPS 1 YEAR AFTER ENDOSCOPIC RESECTION OF GCS. RESULTS: THE METHYLATION LEVELS OF SFRP AND DKK FAMILY GENES WERE SIGNIFICANTLY INCREASED IN THE PATIENTS WITH H. PYLORI-POSITIVE GCS AND FOLLOWED BY H. PYLORI-POSITIVE CONTROLS COMPARED WITH H. PYLORI-NEGATIVE CONTROLS (P < 0.001). SFRP1, -2, AND DKK3 GENE EXPRESSION WAS STEPWISE DOWNREGULATED FROM H. PYLORI-NEGATIVE CONTROLS, H. PYLORI-POSITIVE CONTROLS, AND TO H. PYLORI-POSITIVE GCS (P < 0.05). AMONG THE WNT ANTAGONISTS, ONLY THE DEGREES OF METHYLATION AND DOWNREGULATION OF DKK3 WERE SIGNIFICANTLY REDUCED AFTER H. PYLORI ERADICATION (P < 0.05). CONCLUSION: EPIGENETIC SILENCING OF SFRP AND DKK FAMILY GENES MAY FACILITATE THE FORMATION OF AN EPIGENETIC FIELD DURING H. PYLORI-ASSOCIATED GASTRIC CARCINOGENESIS. THE EPIGENETIC FIELD MAY NOT BE REVERSED EVEN AFTER H. PYLORI ERADICATION EXCEPT BY DKK3 METHYLATION.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
2 3227  36 HELICOBACTER PYLORI INFECTION-INDUCED H3SER10 PHOSPHORYLATION IN STEPWISE GASTRIC CARCINOGENESIS AND ITS CLINICAL IMPLICATIONS. BACKGROUND: OUR PREVIOUS WORKS HAVE DEMONSTRATED THAT HELICOBACTER PYLORI (HP) INFECTION CAN ALTER HISTONE H3 SERINE 10 PHOSPHORYLATION STATUS IN GASTRIC EPITHELIAL CELLS. HOWEVER, WHETHER HELICOBACTER PYLORI-INDUCED HISTONE H3 SERINE 10 PHOSPHORYLATION PARTICIPATES IN GASTRIC CARCINOGENESIS IS UNKNOWN. WE INVESTIGATE THE EXPRESSION OF HISTONE H3 SERINE 10 PHOSPHORYLATION IN VARIOUS STAGES OF GASTRIC DISEASE AND EXPLORE ITS CLINICAL IMPLICATION. MATERIALS AND METHODS: STOMACH BIOPSY SAMPLES FROM 129 PATIENTS WERE COLLECTED AND STAINED WITH HISTONE H3 SERINE 10 PHOSPHORYLATION, KI67, AND HELICOBACTER PYLORI BY IMMUNOHISTOCHEMISTRY STAINING, EXPRESSED AS LABELING INDEX. THEY WERE CATEGORIZED INTO NONATROPHIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS, INTESTINAL METAPLASIA, LOW-GRADE INTRAEPITHELIAL NEOPLASIA, HIGH-GRADE INTRAEPITHELIAL NEOPLASIA, AND INTESTINAL-TYPE GASTRIC CANCER GROUPS. HELICOBACTER PYLORI INFECTION WAS DETERMINED BY EITHER (13) C-UREA BREATH TEST OR IMMUNOHISTOCHEMISTRY STAINING. RESULTS: IN HELICOBACTER PYLORI-NEGATIVE PATIENTS, LABELING INDEX OF HISTONE H3 SERINE 10 PHOSPHORYLATION WAS GRADUALLY INCREASED IN NONATROPHIC GASTRITIS, CHRONIC ATROPHIC GASTRITIS, INTESTINAL METAPLASIA GROUPS, PEAKED AT LOW-GRADE INTRAEPITHELIAL NEOPLASIA, AND DECLINED IN HIGH-GRADE INTRAEPITHELIAL NEOPLASIA AND GASTRIC CANCER GROUPS. IN HELICOBACTER PYLORI-INFECTED PATIENTS, LABELING INDEX OF HISTONE H3 SERINE 10 PHOSPHORYLATION FOLLOWED THE SIMILAR PATTERN AS ABOVE, WITH INCREASED EXPRESSION OVER THE CORRESPONDING HELICOBACTER PYLORI-NEGATIVE CONTROLS EXCEPT IN NONATROPHIC GASTRITIS PATIENT WHOSE LABELING INDEX WAS DECREASED WHEN COMPARED WITH HELICOBACTER PYLORI-NEGATIVE CONTROL. LABELING INDEX OF KI67 IN HELICOBACTER PYLORI-NEGATIVE GROUPS WAS HIGHER IN GASTRIC CANCER THAN CHRONIC ATROPHIC GASTRITIS AND LOW-GRADE INTRAEPITHELIAL NEOPLASIA GROUPS, AND HIGHER IN INTESTINAL METAPLASIA GROUP COMPARED WITH CHRONIC ATROPHIC GASTRITIS GROUP. IN HELICOBACTER PYLORI-POSITIVE GROUPS, KI67 LABELING INDEX WAS INCREASED STEPWISE FROM NONATROPHIC GASTRITIS TO GASTRIC CANCER EXCEPT SLIGHTLY DECREASE IN CHRONIC ATROPHIC GASTRITIS GROUP. IN ADDITION, WE NOTED THAT HISTONE H3 SERINE 10 PHOSPHORYLATION STAINING IS ACCOMPANIED WITH ITS LOCATION CHANGES FROM GASTRIC GLAND BOTTOM EXPANDED TO WHOLE GLAND AS DISEASE STAGE PROGRESS. CONCLUSIONS: THESE RESULTS INDICATE THAT STEPWISE GASTRIC CARCINOGENESIS IS ASSOCIATED WITH ALTERED HISTONE H3 SERINE 10 PHOSPHORYLATION, HELICOBACTER PYLORI INFECTION ENHANCES HISTONE H3 SERINE 10 PHOSPHORYLATION EXPRESSION IN THESE PROCESSES; IT IS ALSO ACCOMPANIED WITH HISTONE H3 SERINE 10 PHOSPHORYLATION LOCATION CHANGE FROM GLAND BOTTOM STAINING EXPAND TO WHOLE GLAND EXPRESSION. THE RESULTS SUGGEST THAT EPIGENETIC DYSREGULATION MAY PLAY IMPORTANT ROLES IN HELICOBACTER PYLORI-INDUCED GASTRIC CANCER.	2018	

3 4725  29 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 1321  39 DEMONSTRATION AND CHARACTERIZATION OF MUTATIONS INDUCED BY HELICOBACTER PYLORI ORGANISMS IN GASTRIC EPITHELIAL CELLS. BACKGROUND: HELICOBACTER PYLORI GASTRITIS INCREASES GASTRIC CANCER RISK. MICROSATELLITE INSTABILITY-TYPE MUTATIONS ARE SECONDARY TO DEFICIENT DNA MISMATCH REPAIR. H. PYLORI GASTRITIS IS MORE FREQUENT IN PATIENTS WITH MICROSATELLITE INSTABILITY-POSITIVE GASTRIC CANCERS, AND H. PYLORI ORGANISMS INDEPENDENTLY OF INFLAMMATION CAN REDUCE DNA MISMATCH REPAIR PROTEIN LEVELS, RAISING THE HYPOTHESIS THAT H. PYLORI ORGANISMS MIGHT LEAD TO MUTAGENESIS DURING INFECTION. MATERIALS AND METHODS: MUTATIONS WERE DETECTED USING A GREEN FLUORESCENT PROTEIN REPORTER VECTOR (PEGFP-CA13). GASTRIC CANCER AGS CELLS TRANSFECTED WITH PEGFP-CA13 WERE COCULTURED WITH H. PYLORI OR ESCHERICHIA COLI. THE NUMBERS OF GREEN FLUORESCENT PROTEIN (GFP)-POSITIVE CELLS WERE DETERMINED, AND GFP, HMSH2, AND HMLH1 PROTEIN LEVELS WERE MEASURED BY WESTERN BLOT. THE EFFECT OF H. PYLORI ON CPG METHYLATION STATUS OF HMLH1 WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: GFP LEVELS AND GFP-POSITIVE CELL NUMBERS IN AGS CELLS COCULTURED WITH H. PYLORI SIGNIFICANTLY INCREASED, AS THE LEVELS OF HMLH1 AND HMSH2 DROPPED. H. PYLORI COCULTURES INDUCED LOW-LEVEL CPG METHYLATION OF THE HMLH1 PROMOTER. SEQUENCE ANALYSIS OF CELLS COCULTURED WITH H. PYLORI SHOWED AN INCREASED NUMBER OF FRAMESHIFT MUTATIONS AND POINT MUTATIONS AS COMPARED TO CELLS NOT COCULTURED WITH H. PYLORI (P = .03 AND P = .001, RESPECTIVELY). CONCLUSIONS: THIS IS THE FIRST REPORT SHOWING THAT H. PYLORI BACTERIA MAY LEAD TO ACCUMULATION OF GENOMIC MUTATIONS, INDEPENDENTLY OF UNDERLYING INFLAMMATION. THIS IS ASSOCIATED WITH REDUCED DNA MISMATCH REPAIR, AND IS AT LEAST IN PART ASSOCIATED WITH CPG METHYLATION OF THE HMLH1 PROMOTER. THESE DATA SUPPORT THE NOTION THAT H. PYLORI-INDUCED MUTATIONS AND EPIGENETIC ALTERATIONS IN GASTRIC EPITHELIAL CELLS DURING CHRONIC GASTRITIS MAY CONTRIBUTE TO AN INCREASED RISK OF GASTRIC CANCER ASSOCIATED WITH H. PYLORI INFECTION.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5 3134  38 GLOBAL DNA HYPOMETHYLATION IS AN EARLY EVENT IN HELICOBACTER PYLORI-RELATED GASTRIC CARCINOGENESIS. AIM: CANCER, PARTICULARLY GASTRIC CANCER (GC), IS PREVALENTLY AN EPIGENETIC PHENOMENON THAT IS DEPENDENT ON AN ALTERED DNA METHYLATION PATTERN. IN GASTRIC CARCINOGENESIS, MANY GENES SHOW ABERRANT METHYLATION; HOWEVER, NONE OF THEM MAY BE USED AS A BIOMARKER OF CANCER RISK AND PROGRESSION. THE AUTHORS AIMED TO EVALUATE THE GLOBAL DNA METHYLATION OF GASTRIC MUCOSA IN HELICOBACTER PYLORI (HP)-RELATED CHRONIC GASTRITIS, IN GC AND IN 10 PATIENTS WITH PRENEOPLASTIC LESIONS (IE, ATROPHY AND INTESTINAL METAPLASIA) FOLLOWED UP FOR 10 YEARS. METHODS: THE AUTHORS ANALYSED 93 DYSPEPTIC PATIENTS WHO UNDERWENT UPPER ENDOSCOPY, 41 SURGICAL GC SAMPLES AND 10 PATIENTS WITH PRENEOPLASTIC GASTRIC LESIONS FOLLOWED UP FOR 10 YEARS AFTER SUCCESSFUL HP ERADICATION THERAPY. GLOBAL DNA METHYLATION STATUS AND SURROGATE MARKERS OF CELL PROLIFERATION AND APOPTOSIS WERE EVALUATED BY IMMUNOHISTOCHEMISTRY USING THE ANTI-5-METHYLCYTOSINE (5-MC), ANTI-KI-67 AND ANTI-P53 (ANTI-APOPTOTIC MARKER)-SPECIFIC ANTIBODIES, RESPECTIVELY. RESULTS: GLOBAL DNA METHYLATION OF GASTRIC MUCOSA GRADUALLY DECREASED FROM NORMAL MUCOSA TO HP-POSITIVE GASTRITIS, HP-POSITIVE CHRONIC ATROPHIC GASTRITIS, INDEPENDENT OF CAG-A STATUS AND GC; HOWEVER, THE VARIATION WAS SIGNIFICANT (P<0.05) ONLY BETWEEN HP-NEGATIVE SUBJECTS AND HP-POSITIVE CHRONIC GASTRITIS. INTERESTINGLY, THE 5-MC IMMUNOSTAINING WAS ABSENT IN AREAS OF INTESTINAL METAPLASIA. IN THE 10 PATIENTS WITH PRENEOPLASTIC LESIONS, GLOBAL DNA METHYLATION DECREASED OVER TIME DESPITE THE ERADICATION OF HP INFECTION, BUT REACHED SIGNIFICANCE ONLY AT 10 YEARS VERSUS BASELINE. THE 5-MC IMMUNOSTAINING NEGATIVELY CORRELATED WITH KI-67 AND P53 EXPRESSION IN ALL GROUPS. CONCLUSION: GLOBAL DNA HYPOMETHYLATION IS AN EARLY MOLECULAR EVENT IN HP-RELATED GASTRIC CARCINOGENESIS. FURTHER STUDIES WITH MORE CASES AND A LONGER FOLLOW-UP ARE NEEDED TO ESTABLISH THE POTENTIAL GC PREDICTIVE ROLE OF DNA HYPOMETHYLATION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
6  672  35 BRAF, KRAS AND HELICOBACTER PYLORI EPIGENETIC CHANGES-ASSOCIATED CHRONIC GASTRITIS IN EGYPTIAN PATIENTS WITH AND WITHOUT GASTRIC CANCER. WE AIMED TO STUDY MLH1 AND MGMT METHYLATION STATUS IN HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS IN EGYPTIAN PATIENTS WITH AND WITHOUT GASTRIC CANCER. 39 PATIENTS WERE INCLUDED IN OUR STUDY. THEY WERE DIVIDED INTO 2 GROUPS; PATIENTS WITHOUT (GROUP I) AND WITH GASTRIC ADENOCARCINOMA (GROUP II). PATIENTS WERE SUBJECTED TO CLINICAL EXAMINATION, ABDOMINAL ULTRASOUND AND UPPER ENDOSCOPY FOR GASTRIC BIOPSY. BIOPSIES WERE SUBJECTED TO UREASE TEST, HISTOLOGICAL EXAMINATION, AND DNA PURIFICATION. H. PYLORI, BRAF, KRAS, MLH1 AND MGMT METHYLATION WERE ASSESSED BY QUANTITATIVE PCR. DNA SEQUENCING WAS PERFORMED TO ASSESS BRAF AND KRAS GENES MUTATION. QPCR OF H. PYLORI WAS SIGNIFICANTLY HIGHER IN PATIENTS WITH ADENOCARCINOMA (GROUP II) THAN THOSE WITHOUT ADENOCARCINOMA (GROUP I); WITH A P < 0.001 AS WELL AS IN PATIENTS WITH AGE ABOVE 50 YEARS WITH A P VALUE = 0.008. BY APPLYING LOGISTIC REGRESSION ANALYSIS IT WAS REPORTED THAT THE H. PYLORI QPCR IS A SIGNIFICANT PREDICTOR TO THE ADENOCARCINOMA WITH OR = 1.025 (95 % CI: 1. 002-1.048), WITH SENSITIVITY OF 90 % AND SPECIFICITY OF 100 %. ADENOCARCINOMA PATIENTS HAD A SIGNIFICANTLY HIGHER MEAN AGE AND LEVELS OF H. PYLORI, BRAF, K-RAS, METHYLATED MGMT AND METHYLATED MLH1 THAN THOSE OF GASTRITIS PATIENTS. DNA SEQUENCE ANALYSIS OF BRAF (CODON 12) AND KRAS (CODON 600) HAD GENES MUTATION IN GASTRIC ADENOCARCINOMA VERSUS CHRONIC GASTRITIS. CONCLUSION: H. PYLORI MAY CAUSE EPIGENETIC CHANGES PREDISPOSING THE PATIENTS TO CANCER STOMACH. ESTIMATION OF H. PYLORI BY QPCR CAN BE A GOOD PREDICTOR TO ADENOCARCINOMA. BRAF AND KRAS GENES MUTATION WERE REVELED IN GASTRITIS AND ADENOCARCINOMA PATIENTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7 3413  35 HSA-MIR-29C AND HSA-MIR-135B DIFFERENTIAL EXPRESSION AS POTENTIAL BIOMARKER OF GASTRIC CARCINOGENESIS. AIM: TO INVESTIGATE THE EXPRESSION PROFILES OF HSA-MIR-29C AND HSA-MIR-135B IN GASTRIC MUCOSAL SAMPLES AND THEIR VALUES AS GASTRIC CARCINOGENESIS BIOMARKERS. METHODS: THE EXPRESSION LEVELS OF HSA-MIR-29C AND HSA-MIR-135B IN NORMAL GASTRIC MUCOSA, NON-ATROPHIC CHRONIC GASTRITIS, INTESTINAL METAPLASIA AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA WERE ANALYSED USING QUANTITATIVE REAL-TIME PCR. THE DIFFERENCE BETWEEN HSA-MIR-29C AND HSA-MIR-135B EXPRESSION PROFILES IN THE GROUPED SAMPLES WAS EVALUATED BY ANOVA AND STUDENT'S T-TEST TESTS. THE RESULTS WERE ADJUSTED FOR MULTIPLE TESTING BY USING BONFERRONI'S CORRECTION. P VALUES </= 0.05 WERE CONSIDERED STATISTICALLY SIGNIFICANT. TO EVALUATE HSA-MIR-29C AND HSA-MIR-135B EXPRESSIONS AS POTENTIAL BIOMARKERS OF GASTRIC CARCINOGENESIS, WE PERFORMED A RECEIVER OPERATING CHARACTERISTIC CURVE ANALYSIS AND THE DERIVED AREA UNDER THE CURVE, AND A CATEGORICAL PRINCIPAL COMPONENTS ANALYSIS. IN SILICO IDENTIFICATION OF THE GENETIC TARGETS OF HSA-MIR-29C AND HSA-MIR-135B WAS PERFORMED USING DIFFERENT PREDICTION TOOLS, IN ORDER TO IDENTIFY POSSIBLE GENES INVOLVED IN GASTRIC CARCINOGENESIS. RESULTS: THE EXPRESSION LEVELS OF HSA-MIR-29C WERE HIGHER IN NORMAL GASTRIC MUCOSAL SAMPLES, AND DECREASED PROGRESSIVELY IN NON-ATROPHIC CHRONIC GASTRITIS SAMPLES, INTESTINAL METAPLASIA SAMPLES AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA SAMPLES. THE EXPRESSION OF HSA-MIR-29C IN THE GASTRIC LESIONS SHOWED THAT NON-ATROPHIC GASTRITIS HAVE AN INTERMEDIATE PROFILE TO GASTRIC NORMAL MUCOSA AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA, AND THAT INTESTINAL METAPLASIA SAMPLES PRESENTED AN EXPRESSION PATTERN SIMILAR TO THAT IN INTESTINAL-TYPE GASTRIC ADENOCARCINOMA. THIS MICRORNA (MIRNA) HAS A GOOD DISCRIMINATORY ACCURACY BETWEEN NORMAL GASTRIC SAMPLES AND (1) INTESTINAL-TYPE GASTRIC ADENOCARCINOMA; AND (2) INTESTINAL METAPLASIA, AND REGULATES THE DMNT3A ONCOGENE. HSA-MIR-135B IS UP-REGULATED IN NON-ATROPHIC CHRONIC GASTRITIS AND INTESTINAL METAPLASIA SAMPLES AND DOWN-REGULATED IN NORMAL GASTRIC MUCOSA AND INTESTINAL-TYPE GASTRIC ADENOCARCINOMA SAMPLES. NON-ATROPHIC CHRONIC GASTRITIS AND INTESTINAL METAPLASIA ARE SIGNIFICANTLY DIFFERENT FROM NORMAL GASTRIC MUCOSA SAMPLES. HSA-MIR-135B EXPRESSION PRESENTED A GREATER DISCRIMINATORY ACCURACY BETWEEN NORMAL SAMPLES AND GASTRIC LESIONS. THIS MIRNA WAS ASSOCIATED WITH HELICOBACTER PYLORI PRESENCE IN NON-ATROPHIC CHRONIC GASTRITIS SAMPLES AND REGULATES THE APC AND KLF4 TUMOUR SUPPRESSOR GENES. CONCLUSION: OUR RESULTS PROVIDE EVIDENCE OF EPIGENETIC ALTERATIONS IN NON-ATROPHIC CHRONIC GASTRITIS AND INTESTINAL METAPLASIA AND SUGGEST THAT HSA-MIR-29C AND HSA-MIR-135B ARE PROMISING BIOMARKERS OF GASTRIC CARCINOGENESIS.	2016	
                                                                                                                                                                             
8 2429  32 EPIGENETIC SILENCING OF MIR-137 IS A FREQUENT EVENT IN GASTRIC CARCINOGENESIS. MICRORNAS (MIRNA) ARE INVOLVED IN POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION AND ARE DYSREGULATED DURING CARCINOGENESIS. CPG ISLAND METHYLATION OF MIR-137 IS A COMMON EVENT IN DIFFERENT CANCERS; HOWEVER, THE ROLE OF MIR-137 IN GASTRIC CANCER (GC) REMAINS LARGELY UNEXPLORED. IN THIS STUDY WE AIMED TO CHARACTERIZE THE EPIGENETIC ALTERATIONS OF MIR-137 IN GASTRIC CARCINOGENESIS. WE ANALYZED TOTAL 295 TISSUES INCLUDING PAIRED PRIMARY GASTRIC CANCER (T-GC) WITH CORRESPONDING ADJACENT GASTRIC MUCOSA (N-GC), PAIRED PRIMARY COLORECTAL CANCER (CRC) TISSUES WITH CORRESPONDING NON-TUMOROUS MUCOSA, GASTRIC TISSUES FROM CONTROLS (N), AND PATIENTS WITH CHRONIC/ATROPHIC GASTRITIS (CG) WITH AND WITHOUT HELICOBACTER PYLORI INFECTION. BISULFITE PYROSEQUENCING AND TAQMAN RT-PCR WERE USED TO ANALYZE MIR-137 METHYLATION AND EXPRESSION, RESPECTIVELY. SURVIVAL DIFFERENCES WERE EVALUATED USING KAPLAN-MEIER ANALYSES. MIR-137 CPG ISLAND METHYLATION WAS MORE FREQUENT IN TUMOROUS COMPARED TO NON-TUMOROUS CONDITIONS AND HIGHER IN CRC THAN IN GC. IN COMPARISON TO N-GC, MIR 137 METHYLATION LEVEL WAS LOWER IN N AND CG TISSUES, WHICH CORRELATES WITH CORREAS CASCADE. MIR-137 METHYLATION INVERSELY CORRELATES WITH GLOBAL LINE-1 METHYLATION AND MIR-137 EXPRESSION. MIR-137 METHYLATION WAS HIGHER IN INTESTINAL TYPE GC COMPARED TO DIFFUSE ONE, AND HIGHER IN ANTRUM COMPARED TO CARDIA AND CORPUS, HOWEVER, MIR-137 METHYLATION WAS ASSOCIATED WITH WORSE PROGNOSIS IN DIFFUSE, BUT NOT IN INTESTINAL TYPE OF GC. THE EXPRESSION IN COLON WAS SIGNIFICANTLY HIGHER COMPARED TO ANY GASTRIC TISSUES SUGGESTING FUNCTIONAL DIFFERENCE. IN SUMMARY, MIR-137 METHYLATION IS A FREQUENT EVENT IN GASTROINTESTINAL CANCERS WHICH OCCURS EARLY IN STEPWISE MANNER DURING GASTRIC CARCINOGENESIS AND INVERSELY CORRELATES WITH GLOBAL METHYLATION. (C) 2015 WILEY PERIODICALS, INC.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
9 2439  33 EPIGENETIC SILENCING OF THE MLH1 PROMOTER IN RELATION TO THE DEVELOPMENT OF GASTRIC CANCER AND ITS USE AS A BIOMARKER FOR PATIENTS WITH MICROSATELLITE INSTABILITY: A SYSTEMATIC ANALYSIS. BACKGROUND/AIMS: HUMAN MUTL HOMOLOG 1 (MLH1) PROMOTER METHYLATION WAS REPORTED IN GASTRIC CANCER (GC). THIS STUDY DETERMINED THE CLINICOPATHOLOGICAL, PROGNOSTIC, AND DIAGNOSTIC EFFECTS OF MLH1 PROMOTER METHYLATION IN GC. METHODS: THE COMBINED ODDS RATIO (OR) OR HAZARD RATIO (HR) AND THEIR CORRESPONDING 95% CONFIDENCE INTERVALS (95% CI) WERE CALCULATED. THE POOLED SENSITIVITY, SPECIFICITY, AND AREA UNDER THE CURVE (AUC) WERE ANALYZED. RESULTS: A TOTAL OF 4654 GC PATIENTS AND 3669 NON-MALIGNANT CONTROLS WERE IDENTIFIED IN THIS SYSTEMATIC ANALYSIS. MLH1 PROMOTER METHYLATION WAS SIGNIFICANTLY HIGHER IN GC SAMPLES THAN IN GASTRIC ADENOMAS, CHRONIC GASTRITIS, ADJACENT TISSUES, NORMAL GASTRIC MUCOSA, AND NORMAL HEALTHY BLOOD SAMPLES, BUT IT EXHIBITED A SIMILAR FREQUENCY IN GC VS. INTESTINAL METAPLASIA AND DYSPLASIA SAMPLES. MLH1 PROMOTER METHYLATION CORRELATED WITH AGE AND MICROSATELLITE INSTABILITY (MSI), BUT IT WAS NOT ASSOCIATED WITH GENDER, H. PYLORI INFECTION, SMOKING, DRINKING BEHAVIORS, PATHOLOGICAL HISTOLOGY, TUMOR DIFFERENTIATION, CLINICAL STAGE, LYMPH NODE STATUS, DISTANT METASTASIS, OR OVERALL SURVIVAL OF GC. MLH1 PROMOTER METHYLATION EXHIBITED A POOR SENSITIVITY VALUE (< 0.5) IN PATIENTS WITH GC COMPARED WITH ADJACENT TISSUES, GASTRIC ADENOMAS, CHRONIC GASTRITIS, NORMAL GASTRIC MUCOSA, AND NORMAL HEALTHY BLOOD SAMPLES. THE POOLED SENSITIVITY, SPECIFICITY, AND AUC OF MLH1 PROMOTER METHYLATION IN GC WITH MSI VS. GC WITH MICROSATELLITE STABILITY (MSS) SAMPLES WERE 0.64, 0.96, AND 0.90, RESPECTIVELY. CONCLUSIONS: OUR RESULTS SUGGEST THAT THE DETECTION OF MLH1 PROMOTER METHYLATION MAY BE A POTENTIAL PROGNOSTIC BIOMARKER FOR GC PATIENTS WITH MSI.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
10 3225  23 HELICOBACTER PYLORI INFECTION INTRODUCES DNA DOUBLE-STRAND BREAKS IN HOST CELLS. GASTRIC CANCER IS AN INFLAMMATION-RELATED MALIGNANCY RELATED TO LONG-STANDING ACUTE AND CHRONIC INFLAMMATION CAUSED BY INFECTION WITH THE HUMAN BACTERIAL PATHOGEN HELICOBACTER PYLORI. INFLAMMATION CAN RESULT IN GENOMIC INSTABILITY. HOWEVER, THERE ARE CONSIDERABLE DATA THAT H. PYLORI ITSELF CAN ALSO PRODUCE GENOMIC INSTABILITY BOTH DIRECTLY AND THROUGH EPIGENETIC PATHWAYS. OVERALL, THE MECHANISMS OF H. PYLORI-INDUCED HOST GENOMIC INSTABILITIES REMAIN POORLY UNDERSTOOD. WE USED MICROARRAY SCREENING OF H. PYLORI-INFECTED HUMAN GASTRIC BIOPSY SPECIMENS TO IDENTIFY CANDIDATE GENES INVOLVED IN H. PYLORI-INDUCED HOST GENOMIC INSTABILITIES. WE FOUND UPREGULATION OF ATM EXPRESSION IN VIVO IN GASTRIC MUCOSAL CELLS INFECTED WITH H. PYLORI. USING GASTRIC CANCER CELL LINES, WE CONFIRMED THAT THE H. PYLORI-RELATED ACTIVATION OF ATM WAS DUE TO THE ACCUMULATION OF DNA DOUBLE-STRAND BREAKS (DSBS). DSBS WERE OBSERVED FOLLOWING INFECTION WITH BOTH CAG PATHOGENICITY ISLAND (PAI)-POSITIVE AND -NEGATIVE STRAINS, BUT THE EFFECT WAS MORE ROBUST WITH CAG PAI-POSITIVE STRAINS. THESE RESULTS ARE CONSISTENT WITH THE FACT THAT INFECTIONS WITH BOTH CAG PAI-POSITIVE AND -NEGATIVE STRAINS ARE ASSOCIATED WITH GASTRIC CARCINOGENESIS, BUT THE RISK IS HIGHER IN INDIVIDUALS INFECTED WITH CAG PAI-POSITIVE STRAINS.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
11 6820  27 [GASTRIC CARCINOMA AND CHRONIC GASTRITIS: EPIGENETIC REGULATION OF CDH1 (E-CADHERIN), CDKN2A (P16INK4A), PTGS2 (COX-2) AND EGFR GENES THROUGH METHYLATION]. THE GENETIC AND EPIGENETIC ALTERATIONS ARE BEING STUDIED AS ONE OF THE CAUSES OF GASTRIC CANCER (GC) PROGRESSION AND DEVELOPMENT. DNA METHYLATION IS AN EPIGENETIC ALTERATION WHICH LEADS TO SUPPRESSOR GENE SILENCING AND PROTO-ONCOGENE ACTIVATION, PLAYING AN IMPORTANT ROLE IN CARCINOGENESIS. THE HISTOLOGICAL TYPES OF GASTRIC CARCINOMA HAVE DIFFERENT GENETIC PATHS AND THE KNOWLEDGE OF THE MOLECULAR BASES OF TUMORAL PROGRESSION LEADS TO DIAGNOSTIC ACCURACY AND ATTEMPTED THERAPY. CDH1 (E-CADHERIN) AND CDKN2A (P16(INK4A)) GENES ARE THOUGHT TO BE TUMORAL SUPPRESSOR GENES AND PTGS2 (COX-2) AND GENES ARE INVOLVED IN TUMOUR REGULATION AND GROWTH. IN ONE HAND, GENE SILENCING AS AN EPIGENETIC PHENOMENON, AND IN THE OTHER HAND, GENE EXPRESSION ENHANCEMENT DUE TO POSSIBLE DEMETHYLATION, SIMULTANEOUSLY, CAN FACILITATE CARCINOGENESIS AND TUMORAL PROGRESSION. OUR AIM WAS TO RELATE CDH1, P16(INK4A), COX-2 AND EGFR GENES DNA METHYLATION WITH THE SEVERAL HISTOLOGICAL TYPES OF GASTRIC CARCINOMA AND CHRONIC GASTRITIS. WE STUDIED 55 FORMALIN FIXED PARAFFIN EMBEDDED GASTRIC BIOPSIES: 35 WERE GC SPECIMENS (12 DIFFUSE TYPE, 15 INTESTINAL TYPE AND 8 INDETERMINATE TYPE, ACCORDING TO LAUREN'S CLASSIFICATION) AND 20 SAMPLES HAD CHRONIC GASTRITIS (CG). THE DNA WAS TREATED WITH SODIUM BISULFITE AFTER EXTRACTION AND THEN PERFORMED METHYLATION SPECIFIC PCR (MSP). STATISTICAL ANALYSIS WAS BASED ON CHI-SQUARE TEST AND EXACT FISHER'S TEST. CPG ISLAND METHYLATION WAS DETECTED IN 94% OF THE GC SAMPLES FOR CDH1, 91% FOR COX-2, 80% FOR P16(INK4A) AND NO METHYLATION WAS DETECTED IN EGFR GENE (0%). IN CG, CPG ISLAND METHYLATION WAS FOUND IN 100% FOR CDH1 AND COX-2 GENES, 90% FOR P16(INK4A) AND 20% FOR EGFR. THESE RESULTS REVEAL SIGNIFICANT DIFFERENCES IN EGFR GENE METHYLATION DISTINGUISHING GC FROM CG (P < 0, 01), SUGGESTING THAT GENE DEMETHYLATION LEADS TO MALIGNANT TRANSFORMATION AND FAVOURS THE USE OF TYROSINE-KINASE INHIBITORS IN ITS TREATMENT. GENES COX2 E P16INK4A LOWER METHYLATION IN INTESTINAL AND DIFFUSE TYPES OF GC, FAVOURS THEIR DIFFERENT ROLE IN RESPECTIVE HISTOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 1146  42 CONCURRENT EPIGENETIC SILENCING OF WNT/BETA-CATENIN PATHWAY INHIBITOR GENES IN B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA. BACKGROUND: THE WNT/BETA-CATENIN SIGNALLING IS ABERRANTLY ACTIVATED IN PRIMARY B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL). EPIGENETIC SILENCING OF PATHWAY INHIBITOR GENES MAY BE A MECHANISM FOR ITS ACTIVATION. IN THIS STUDY, WE INVESTIGATED SYSTEMATICALLY AND QUANTITATIVELY THE METHYLATION STATUS OF 12 WNT/BETA-CATENIN PATHWAY INHIBITOR GENES - CDH1, DACT1, DKK1, DKK2, DKK3, DKK4, SFRP1, SFRP2, SFRP3, SFRP4, SFRP5 AND WIF1 - IN THE CELL LINES EHEB AND MEC-1 AS WELL AS PATIENT SAMPLES. METHODS: QUANTIFICATION OF DNA METHYLATION WAS PERFORMED BY MEANS OF BISULPHITE PYROSEQUENCING AND CONFIRMED BY BISULPHITE SANGER SEQUENCING. GENE EXPRESSION WAS ANALYSED BY QPCR USING GAPDH AS INTERNAL CONTROL. E-CADHERIN AND BETA-CATENIN PROTEIN QUANTIFICATION WAS CARRIED OUT BY MICROSPHERE-BASED IMMUNOASSAYS. METHYLATION DIFFERENCES OBSERVED BETWEEN THE PATIENT AND CONTROL GROUPS WERE TESTED USING GENERALISED LEAST SQUARES MODELS. RESULTS: FOR 10 GENES, A HIGHER METHYLATION LEVEL WAS OBSERVED IN TUMOUR MATERIAL. ONLY DKK4 EXHIBITED SIMILARLY HIGH METHYLATION LEVELS IN BOTH TUMOUR AND NORMAL SPECIMENS, WHILE DACT1 WAS ALWAYS ESSENTIALLY UNMETHYLATED. HOWEVER, ALSO FOR THESE INHIBITORS, TREATMENT OF CELLS WITH THE DEMETHYLATING AGENT 5-AZA-2 -DEOXYCYTIDINE RESULTED IN AN INDUCTION OF THEIR EXPRESSION, AS SHOWN BY QUANTITATIVE PCR, SUGGESTING AN INDIRECT EPIGENETIC CONTROL OF ACTIVITY. WHILE THE DEGREE OF DEMETHYLATION AND ITS TRANSCRIPTIONAL CONSEQUENCES DIFFERED BETWEEN THE GENES, THERE WAS AN OVERALL HIGH CORRELATION OF DEMETHYLATION AND INCREASED ACTIVITY. PROTEIN EXPRESSION STUDIES REVEALED THAT NO CONSTITUTIVE WNT/BETA-CATENIN SIGNALLING OCCURRED IN THE CELL LINES, WHICH IS IN DISCREPANCY WITH RESULTS FROM PRIMARY CLL. HOWEVER, TREATMENT WITH 5-AZA-2 -DEOXYCYTIDINE CAUSED ACCUMULATION OF BETA-CATENIN. SIMULTANEOUSLY, E-CADHERIN EXPRESSION WAS STRONGLY INDUCED, LEADING TO THE FORMATION OF A COMPLEX WITH BETA-CATENIN AND THUS DEMONSTRATING ITS EPIGENETICALLY REGULATED INHIBITION EFFECT. CONCLUSIONS: THE RESULTS SUGGEST AN EPIGENETIC SILENCING MECHANISM OF THE WNT/BETA-CATENIN PATHWAY INHIBITOR GENES IN CLL. HYPERMETHYLATION AND SILENCING OF FUNCTIONALLY RELATED GENES MAY NOT BE COMPLETELY STOCHASTIC BUT RESULT FROM THE TUMOUR EPIGENOME REPROGRAMMING ORCHESTRATED BY POLYCOMB-GROUP REPRESSIVE COMPLEXES. THE DATA ARE OF INTEREST IN THE CONTEXT OF EPIGENETIC-BASED THERAPY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
13 4237  34 METHYLATION PATTERN OF THBS1, GATA-4, AND HIC1 IN PEDIATRIC AND ADULT PATIENTS INFECTED WITH HELICOBACTER PYLORI. BACKGROUND: HELICOBACTER PYLORI INFECTION IS USUALLY ACQUIRED IN CHILDHOOD AND PERSISTS INTO ADULTHOOD IF UNTREATED. THE BACTERIUM INDUCES A CHRONIC INFLAMMATORY RESPONSE, WHICH IS ASSOCIATED WITH EPIGENETIC ALTERATIONS IN ONCOGENES, TUMOR-SUPPRESSOR GENES, CELL-CYCLE REGULATORS, AND CELL-ADHESION MOLECULES. AIM: THE AIM OF THIS STUDY WAS TO ANALYZE THE EFFECT OF H. PYLORI INFECTION ON THE METHYLATION STATUS OF THROMBOSPONDIN-1 (THBS1), HYPERMETHYLATED IN CANCER 1 (HIC1) AND GATA BINDING PROTEIN-4 (GATA-4) IN GASTRIC BIOPSY SAMPLES FROM CHILDREN AND ADULTS INFECTED OR UNINFECTED WITH THE BACTERIUM AND IN SAMPLES OBTAINED FROM GASTRIC CANCER PATIENTS. METHODS: THE METHYLATION PATTERN WAS ANALYZED WITH METHYLATION-SPECIFIC PCR. RESULTS: OUR RESULTS SHOWED THAT H. PYLORI INFECTION WAS ASSOCIATED WITH METHYLATION OF THE PROMOTER REGIONS OF THE THBS1 AND GATA-4 GENES IN PEDIATRIC AND ADULT SAMPLES (P < 0.01). HIC1 SHOWED THE LOWEST LEVEL OF METHYLATION, WHICH WAS NOT AN EARLY EVENT DURING GASTRIC CARCINOGENESIS. CONCLUSIONS: THE RESULTS FROM THIS STUDY INDICATE THAT METHYLATION OF THBS1 AND GATA-4 OCCURS IN THE EARLY STAGES OF CHRONIC GASTRITIS AND GASTRIC CANCER IN ASSOCIATION WITH H. PYLORI INFECTION; HOWEVER, IN GASTRIC CANCER SAMPLES, OTHER MECHANISMS COOPERATE WITH THE DOWN-REGULATION OF THESE GENES. METHYLATION OF HIC1 MAY NOT BE THE PRINCIPAL MECHANISM IMPLICATED IN ITS DOWN-REGULATION IN GASTRIC CANCER SAMPLES.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
14 2379  33 EPIGENETIC REGULATION OF WNT PATHWAY ANTAGONISTS IN HUMAN GLIOBLASTOMA MULTIFORME. EPIGENETIC INACTIVATION OF TUMOR SUPPRESSOR GENES IS COMMON IN HUMAN CANCER. USING A LARGE-SCALE WHOLE-GENOME APPROACH IN AN EARLIER STUDY, THE AUTHORS IDENTIFIED EPIGENETICALLY SILENCED GENES WITH POTENTIAL TUMOR SUPPRESSOR FUNCTION IN GLIOBLASTOMA (GBM). THREE GENES IDENTIFIED IN THIS ANALYSIS-DKK1, SFRP1, AND WIF1-ARE POTENT INHIBITORS OF THE WNT SIGNAL TRANSDUCTION PATHWAY. HERE, THE AUTHORS CONFIRM DECREASED EXPRESSION OF THESE GENES IN GBM TUMOR TISSUE SAMPLES RELATIVE TO NONTUMOR BRAIN TISSUE SAMPLES USING REAL-TIME PCR. THEY THEN SHOW THAT EXPRESSION OF ALL 3 GENES IS RESTORED IN T98 GBM CELLS BY TREATMENT WITH THE HISTONE DEACETYLASE INHIBITOR TRICHOSTATIN A (TSA), BUT ONLY DKK1 EXPRESSION IS RESTORED BY TREATMENT WITH THE DEMETHYLATING AGENT 5-AZACYTIDINE. BISULFITE SEQUENCING DID NOT REVEAL SIGNIFICANT METHYLATION IN THE PROMOTER REGION OF DKK1, WHEREAS HISTONE ACETYLATION AND CHROMATIN ACCESSIBILITY INCREASED SIGNIFICANTLY FOR ALL 3 GENES AFTER TSA TREATMENT. ECTOPIC EXPRESSION OF DKK1 SIGNIFICANTLY REDUCES COLONY FORMATION AND INCREASES CHEMOTHERAPY-INDUCED APOPTOSIS IN T98 CELLS. ECTOPIC EXPRESSION OF THE CANONICAL WNT PATHWAY INHIBITORS WIF1 AND SFRP1 SHOWS A RELATIVE LACK OF RESPONSE. CHRONIC WNT3A STIMULATION ONLY PARTIALLY REVERSES GROWTH SUPPRESSION AFTER DKK1 REEXPRESSION, WHEREAS A SPECIFIC INHIBITOR OF THE JNK PATHWAY SIGNIFICANTLY REVERSES THE EFFECT OF DKK1 REEXPRESSION ON COLONY FORMATION AND APOPTOSIS IN T98 CELLS. THESE RESULTS SUPPORT A POTENTIAL GROWTH-SUPPRESSIVE FUNCTION FOR EPIGENETICALLY SILENCED DKK1 IN GBM AND SUGGEST THAT DKK1 RESTORATION COULD MODULATE WNT SIGNALING THROUGH BOTH CANONICAL AND NONCANONICAL PATHWAYS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 3298  28 HIGH-DEFINITION CPG METHYLATION OF NOVEL GENES IN GASTRIC CARCINOGENESIS IDENTIFIED BY NEXT-GENERATION SEQUENCING. GASTRIC CANCERS ARE THE MOST FREQUENT GASTRIC MALIGNANCY AND USUALLY ARISE IN THE SEQUENCE OF HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS. CPG METHYLATION IS A CENTRAL MECHANISM OF EPIGENETIC GENE REGULATION AFFECTING CANCER-RELATED GENES, AND OCCURS EARLY IN GASTRIC CARCINOGENESIS. DNA SAMPLES FROM NON-METAPLASTIC GASTRIC MUCOSA WITH VARIABLE LEVELS OF GASTRITIS (NON-METAPLASTIC MUCOSA), INTESTINAL METAPLASIA, OR GASTRIC CANCER WERE SCREENED WITH METHYLATION ARRAYS FOR CPG METHYLATION OF CANCER-RELATED GENES AND 30 GENE TARGETS WERE FURTHER CHARACTERIZED BY HIGH-DEFINITION BISULFITE NEXT-GENERATION SEQUENCING. IN ADDITION, DATA FROM THE CANCER GENOME ATLAS WERE ANALYZED FOR CORRELATION OF METHYLATION WITH GENE EXPRESSION. OVERALL, 13 GENES HAD SIGNIFICANTLY INCREASED CPG METHYLATION IN GASTRIC CANCER VS NON-METAPLASTIC MUCOSA (BRINP1, CDH11, CHFR, EPHA5, EPHA7, FGF2, FLI1, GALR1, HS3ST2, PDGFRA, SEZ6L, SGCE, AND SNRPN). FURTHER, MOST OF THESE GENES HAD CORRESPONDING REDUCED EXPRESSION LEVELS IN GASTRIC CANCER COMPARED WITH INTESTINAL METAPLASIA, INCLUDING NOVEL HYPERMETHYLATED GENES IN GASTRIC CANCER (FLI1, GALR1, SGCE, AND SNRPN), SUGGESTING THAT THEY MAY REGULATE NEOPLASTIC TRANSFORMATION FROM NON-MALIGNANT INTESTINAL METAPLASIA TO CANCER. OUR DATA SUGGEST A TUMOR-SUPPRESSOR ROLE FOR FLI1 IN GASTRIC CANCER, CONSISTENT WITH RECENTLY REPORTED DATA IN BREAST CANCER. FOR THE GENES WITH STRONGEST METHYLATION/EXPRESSION CORRELATION, NAMELY FLI1, THE EXPRESSION WAS LOWEST IN MICROSATELLITE-UNSTABLE TUMORS COMPARED WITH OTHER GASTRIC CANCER MOLECULAR SUBTYPES. IMPORTANTLY, REDUCED EXPRESSION OF HYPERMETHYLATED BRINP1 AND SGCE WAS SIGNIFICANTLY ASSOCIATED WITH FAVORABLE SURVIVAL IN GASTRIC CANCER. IN SUMMARY, WE REPORT NOVEL METHYLATION GENE TARGETS THAT MAY HAVE FUNCTIONAL ROLES IN DISCRETE STAGES OF GASTRIC CARCINOGENESIS AND MAY SERVE AS BIOMARKERS FOR DIAGNOSIS AND PROGNOSIS OF GASTRIC CANCER.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
16 2090  32 EPIGENETIC DYSREGULATION OF THE WNT SIGNALLING PATHWAY IN CHRONIC LYMPHOCYTIC LEUKAEMIA. BACKGROUND: WNT SIGNALLING HAS RECENTLY BEEN IMPLICATED IN THE PATHOGENESIS OF CANCER. METHODS: THIS STUDY INVESTIGATED THE ACTIVITY OF WNT SIGNALLING IN PERIPHERAL BLOOD CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) LYMPHOCYTES, AND THE METHYLATION STATUS OF SEVEN SOLUBLE WNT ANTAGONIST GENES, INCLUDING WIF1, DKK3, APC, SFRP1, SFRP2, SFRP4 AND SFRP5, BY USING METHYLATION-SPECIFIC PCR IN THE PERIPHERAL BLOOD CLL LYMPHOCYTES AND BONE MARROW SAMPLES OF PATIENTS WITH CLL AT DIAGNOSIS. RESULTS: IN THE PERIPHERAL BLOOD CLL LYMPHOCYTES, CONSTITUTIVE ACTIVATION OF WNT SIGNALLING WAS DETECTED, ASSOCIATED WITH HYPERMETHYLATION OF THE SOLUBLE WNT INHIBITOR GENES. IN THE DIAGNOSTIC CLL MARROW SAMPLES, METHYLATION OF THE SEVEN GENES WAS DETECTED IN UP TO 36.4% OF SAMPLES. MOREOVER, 23 (52.3%) PATIENTS HAD METHYLATION OF AT LEAST ONE OF THE SEVEN GENES, OF WHOM 14 (60.8%) HAD METHYLATION OF TWO OR MORE WNT INHIBITOR GENES. APART FROM AN ASSOCIATION OF ADVANCED AGE WITH DKK3 METHYLATION, THERE WAS NO ASSOCIATION OF GENE HYPERMETHYLATION WITH EITHER CLINICAL CHARACTERISTICS (INCLUDING AGE, GENDER, LYMPHOCYTE COUNT AT DIAGNOSIS, RAI STAGE AND POOR-RISK KARYOTYPE) OR SURVIVAL. CONCLUSION: WNT SIGNALLING IS CONSTITUTIVELY ACTIVATED IN CLL B LYMPHOCYTES IN ASSOCIATION WITH METHYLATION OF MULTIPLE SOLUBLE WNT ANTAGONIST GENES. METHYLATION OF THESE SOLUBLE WNT ANTAGONIST GENES, OCCASIONALLY MULTIPLE GENES, IN PRIMARY CLL MARROW SAMPLES SUGGESTS AN IMPORTANT ROLE IN CLL PATHOGENESIS. MOREOVER, THIS STUDY UNDERSCORED THE IMPORTANCE OF STUDYING METHYLATION OF A PANEL OF, BUT NOT INDIVIDUAL, GENES REGULATING A CELLULAR PATHWAY.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
17 1830  30 EFFECTS OF LONG-TERM ASPIRIN USE ON MOLECULAR ALTERATIONS IN PRECANCEROUS GASTRIC MUCOSA IN PATIENTS WITH AND WITHOUT GASTRIC CANCER. THE RISK OF GASTRIC CANCER (GC) REMAINS EVEN AFTER H. PYLORI ERADICATION; THUS, OTHER COMBINATION TREATMENTS, SUCH AS CHEMOPREVENTIVE DRUGS, ARE NEEDED. WE EVALUATED THE EFFECTS OF ASPIRIN ON GENETIC/EPIGENETIC ALTERATIONS IN PRECANCEROUS CONDITIONS, I.E., ATROPHIC MUCOSA (AM) AND INTESTINAL METAPLASIA (IM), IN PATIENTS WITH CHRONIC GASTRITIS WHO HAD TAKEN ASPIRIN FOR MORE THAN 3 YEARS. A TOTAL OF 221 BIOPSY SPECIMENS FROM 74 PATIENTS, INCLUDING ATROPHIC GASTRITIS (AG) CASES WITHOUT ASPIRIN USE (CONTROL), AG CASES WITH ASPIRIN USE (AG GROUP), AND GC CASES WITH ASPIRIN USE (GC GROUP), WERE ANALYZED. ASPIRIN USE WAS ASSOCIATED WITH A SIGNIFICANT REDUCTION OF CDH1 METHYLATION IN AM (OR: 0.15, 95% CI: 0.06-0.41, P = 0.0002), BUT WAS LESS EFFECTIVE IN REVERSING THE METHYLATION THAT OCCURRED IN IM. FREQUENT HYPERMETHYLATION INCLUDING THAT OF CDH1 IN AM INCREASED IN THE GC GROUP COMPARED TO THE AG GROUP, AND CDH1 METHYLATION WAS AN INDEPENDENT PREDICTIVE MARKER OF GC (OR: 8.50, 95% CI: 2.64-25.33, P = 0.0003). IN PATIENTS WITH LONG-TERM ASPIRIN USE, THE CHANGES OF MOLECULAR EVENTS IN AM BUT NOT IM MAY BE AN IMPORTANT FACTOR IN THE REDUCTION OF CANCER INCIDENCE. IN ADDITION, METHYLATION OF THE CDH1 GENE IN AM MAY BE A SURROGATE OF GC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
18 4114  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
19 2071  32 EPIGENETIC CONTROL OF THE E-CADHERIN GENE (CDH1) BY CPG METHYLATION IN COLECTOMY SAMPLES OF PATIENTS WITH ULCERATIVE COLITIS. E-CADHERIN BELONGS TO THE CADHERIN FAMILY OF CALCIUM-DEPENDENT CELL-ADHESION MOLECULES. THE CADHERINS PLAY AN ESSENTIAL ROLE IN BIOLOGICAL PROCESSES SUCH AS ORDERING OF CELL SORTING, MIGRATION, AND DIFFERENTIATION, AND THEIR MALFUNCTIONING IS CONNECTED WITH NEOPLASIA. NEOPLASTIC PROGRESSION IN PATIENTS WITH CHRONIC ULCERATIVE COLITIS IS CHARACTERIZED BY THE DEVELOPMENT OF EPITHELIAL DYSPLASIA. TRANSCRIPTIONAL SILENCING OF TUMOR-SUPPRESSOR GENES BY PROMOTER METHYLATION HAS BEEN OBSERVED IN DIFFERENT TYPES OF HUMAN CANCERS AND DYSPLASIA. TO EXPLORE THE MODE OF E-CADHERIN REGULATION, 156 BIOPSY SAMPLES FROM 26 PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS WERE SCREENED. TO DETECT THE METHYLATION STATUS OF OUR SAMPLES, A METHYLATION-SPECIFIC PCR WAS APPLIED. METHYLATION OF THE E-CADHERIN (CDH1) PROMOTER WAS DETECTED IN 93% OF THE PATIENTS WITH DYSPLASTIC BIOPSY SAMPLES, IN CONTRAST TO ONLY 6% OF THE PATIENTS WITHOUT DYSPLASIA (P < 0.001). WE ALSO EXAMINED THE LEVEL OF SYNTHESIS OF E-CADHERIN PROTEIN BY IMMUNOHISTOCHEMICAL STAINING IN DIFFERENT PARAFFIN-EMBEDDED SAMPLES OF DYSPLASTIC AND NON-DYSPLASTIC ORIGIN IN A SUBSET OF OUR PATIENTS. SAMPLES WITH DYSPLASIA DISPLAYED REDUCED LEVELS, WHEREAS SAMPLES WITHOUT DYSPLASIA REVEALED NORMAL E-CADHERIN PROTEIN SYNTHESIS. THESE RESULTS SHOW THAT THE E-CADHERIN PROMOTER IS SUBJECTED TO EPIGENETIC CONTROL IN COLORECTAL ULCERATION. OBVIOUSLY, THIS EVENT MAY PLAY AN IMPORTANT ROLE IN THE PROGRESSION FROM CHRONIC INFLAMMATION TO COLORECTAL CANCER. FOR THIS REASON, METHYLATION OF THE CDH1 PROMOTER IS AN ATTRACTIVE NEW BIOMARKER FOR DETECTING ULCERATIVE COLITIS PATIENTS WITH A HIGH RISK FOR DEVELOPING COLORECTAL CANCERS.	2002	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
20 3444  23 HYPERMETHYLATION OF E-CADHERIN IN LEUKEMIA. E-CADHERIN GENE IS OFTEN TERMED A "METASTASIS SUPPRESSOR" GENE BECAUSE THE E-CADHERIN PROTEIN CAN SUPPRESS TUMOR CELL INVASION AND METASTASIS. INACTIVATION OF THE E-CADHERIN GENE OCCURS IN UNDIFFERENTIATED SOLID TUMORS BY BOTH GENETIC AND EPIGENETIC MECHANISMS; HOWEVER, THE ROLE OF E-CADHERIN IN HEMATOLOGIC MALIGNANCIES IS ONLY NOW BEING RECOGNIZED. E-CADHERIN EXPRESSION IS ESSENTIAL FOR ERYTHROBLAST AND NORMOBLAST MATURATION, YET EXPRESSION IS REDUCED OR ABSENT IN LEUKEMIC BLAST CELLS. THIS STUDY EXAMINED THE MESSENGER RNA (MRNA) AND PROTEIN EXPRESSION OF THE E-CADHERIN GENE IN BONE MARROW AND BLOOD SAMPLES FROM NORMAL DONORS AND PATIENTS WITH LEUKEMIA. WE FOUND THAT ALL NORMAL DONOR SAMPLES EXPRESSED E-CADHERIN MRNA, WHEREAS BOTH SAMPLES OF ACUTE MYELOGENOUS LEUKEMIA AND CHRONIC LYMPHOCYTIC LEUKEMIA HAD A SIGNIFICANT REDUCTION OR ABSENCE OF EXPRESSION. HOWEVER, NORMAL BLAST COUNTERPARTS EXPRESSED ONLY A LOW LEVEL OF E-CADHERIN SURFACE PROTEIN. SODIUM BISULPHITE GENOMIC SEQUENCING WAS USED TO FULLY CHARACTERIZE THE METHYLATION PATTERNS OF THE CPG ISLAND ASSOCIATED WITH THE E-CADHERIN GENE PROMOTER IN THOSE SAMPLES WITH MATCHED DNA. ALL OF THE NORMAL CONTROL SAMPLES WERE ESSENTIALLY UNMETHYLATED; HOWEVER, 14 OF 18 (78%) OF THE LEUKEMIA SAMPLES HAD ABNORMAL HYPERMETHYLATION OF THE E-CADHERIN CPG ISLAND. IN FACT BOTH ALLELES OF THE E-CADHERIN GENE WERE OFTEN HYPERMETHYLATED. WE CONCLUDE THE E-CADHERIN GENE IS A COMMON TARGET FOR HYPERMETHYLATION IN HEMATOLOGIC MALIGNANCIES.	2000