1  185 137 ACCUMULATION OF ABERRANT CPG HYPERMETHYLATION BY HELICOBACTER PYLORI INFECTION PROMOTES DEVELOPMENT AND PROGRESSION OF GASTRIC MALT LYMPHOMA. ABERRANT DNA HYPERMETHYLATION IS AN IMPORTANT MECHANISM FOR THE INACTIVATION OF TUMOR-RELATED GENES IN HUMAN TUMORS. GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMAS ARISE FROM HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS; MOST PATIENTS ARE H. PYLORI-POSITIVE AND ERADICATION THERAPY IS HIGHLY EFFECTIVE. IN THE PRESENT STUDY, WE USED METHYLATION-SPECIFIC PCR TO ANALYZE THE DNA METHYLATION STATUS OF 11 TUMOR-RELATED GENES (KIP2, P16, HMLH-1, P15, P73, MGMT, DAPK, MINT1, MINT2, MINT31 AND HCAD) IN 21 SPECIMENS OF MALT LYMPHOMA, 5 SPECIMENS OF MALT LYMPHOMA WITH LARGE CELL COMPONENT (HIGH-GRADE MALT LYMPHOMA), 15 SPECIMENS OF DIFFUSE LARGE B-CELL LYMPHOMA (DLBCL), 8 SPECIMENS OF COMPLETE REMISSION OF MALT LYMPHOMA AFTER ERADICATION THERAPY, 5 SPECIMENS WITH NO EVIDENCE OF MALIGNANCY AND PBMCS FROM 10 HEALTHY DONORS. THE AVERAGE NUMBER OF METHYLATED GENES WAS SIGNIFICANTLY GREATER IN GASTRIC LYMPHOMAS AS COMPARED TO NORMAL CONTROLS (P<0.001). THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WAS OBSERVED IN 93.3% (14/15) OF DLBCLS, 100% (5/5) OF HIGH-GRADE MALT LYMPHOMAS AND 61.9% (13/21) OF MALT LYMPHOMAS; IN CONTRAST, CIMP WAS NOT FOUND IN THE CONTROL GROUP (0%). THE AVERAGE NUMBER OF METHYLATED GENES AND THE CIMP INCIDENCE SIGNIFICANTLY INCREASED WITH H. PYLORI INFECTION. FURTHERMORE, ABERRANT CPG METHYLATION OF SPECIFIC GENES, SUCH AS P16, MGMT AND MINT31, WAS CONSISTENTLY ASSOCIATED WITH H. PYLORI INFECTION. THESE FINDINGS STRONGLY SUGGEST THAT H. PYLORI INFECTION CAUSES THE ABERRANT DNA HYPERMETHYLATION OF SPECIFIC GENES AND INDUCES CIMP, WHICH IS AN IMPORTANT EPIGENETIC MECHANISM FOR THE DEVELOPMENT AND PROGRESSION OF GASTRIC MALT LYMPHOMA; ADDITIONALLY, OUR FINDINGS PROVIDE NEW EPIGENETIC MARKERS.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 1056  37 CLINICAL MANIFESTATIONS AND EPIGENETIC MECHANISMS OF GASTRIC MUCOSA ASSOCIATED LYMPHOID TISSUE LYMPHOMA AND LONG-TERM FOLLOW-UP FOLLOWING HELICOBACTER PYLORI ERADICATION. THE CURRENT STUDY AIMED TO SUMMARIZE THE CLINICAL MANIFESTATIONS AND IDENTIFY THE EPIGENETIC MECHANISMS OF GASTRIC MUCOSA ASSOCIATED LYMPHOID TISSUE (MALT) LYMPHOMA, AS WELL AS EVALUATE THE LONG-TERM EFFECTS OF HELICOBACTER PYLORI (H. PYLORI) ERADICATION. A TOTAL OF 122 PATIENTS WITH MARGINAL ZONE B-CELL LYMPHOMA OF PRIMARY GASTRIC MALT LYMPHOMA WERE ENROLLED IN THE PRESENT STUDY. THE CLINICAL MANIFESTATIONS OF GASTRIC MALT LYMPHOMA, INCLUDING SYMPTOMS, H. PYLORI STATE AND ENDOSCOPIC TYPE, WERE SUMMARIZED. THE RESPONSE TO THERAPY WAS EVALUATED IN PATIENTS THAT UNDERWENT H. PYLORI ERADICATION. SURVIVAL ANALYSIS WAS ESTIMATED USING THE KAPLAN-MEIER METHOD. THE EXPRESSION OF MICRORNA-383 (MIR-383) IN TUMOR TISSUES AND CELL LINES WAS DETERMINED USING REVERSE TRANSCRIPTION QUANTITATIVE POLYMERASE CHAIN REACTION. FURTHERMORE, BIOINFORMATIC ANALYSES, LUCIFERASE REPORTER ASSAYS. AND WESTERN BLOT ANALYSIS IDENTIFIED ZINC FINGER E-BOX BINDING HOMEOBOX 2 (ZEB2) AS A DIRECT TARGET GENE OF MIR-383. AN MTT ASSAY WAS USED TO EXAMINE THE FUNCTION OF MIR-383 AND ZEB2 IN MALT LYMPHOMA. THE CLINICAL SYMPTOMS OF PATIENTS WITH GASTRIC MALT LYMPHOMA WERE NON-SPECIFIC AND INCLUDED EPIGASTRIC PAIN, ABDOMINAL DISCOMFORT AND BLEEDING. THE MAJORITY OF ENDOSCOPIC TYPES WERE CLASSIFIED AS ULCER, EROSION AND MUCOSA EDEMA. THE H. PYLORI INFECTION RATE WAS 79.5% (97/122) AND A TOTAL OF 47 PATIENTS UNDERWENT ERADICATION THERAPY. LYMPHOMA REMISSION WAS ACHIEVED IN 93.6% (44/47) OF PATIENTS AND COMPLETE REMISSION (CR) WAS ACHIEVED IN 74.4% (35/47). THE MEDIAN FOLLOW-UP TIME WAS 38 MONTHS (RANGE, 10-132 MONTHS) AND THE MEDIAN TIME TAKEN TO ACHIEVE CR WAS 4 MONTHS (RANGE, 3-7 MONTHS). THE ESTIMATED 3-YEAR SURVIVAL RATE WAS 90.3% AND THE 5-YEAR SURVIVAL RATE WAS 76.2%. THEREFORE, IT WAS DETERMINED THAT PATIENTS WITH STAGE I OR II GASTRIC MALT LYMPHOMA ARE ABLE TO UNDERGO H. PYLORI ERADICATION AS A FIRST-LINE TREATMENT AND THAT THE SURVIVAL RATE OF PATIENTS UNDERGOING THIS TREATMENT IS HIGH. FURTHERMORE, IT WAS DETERMINED THAT THE MECHANISM BY WHICH MIR-383 AND ZEB2 CONTRIBUTE TO MALT LYMPHOMA PROGRESSION IS BY THE TARGETING OF ZEB2 BY MIR-383, WHICH INHIBITS THE PROLIFERATION OF CANCER CELLS.	2018	
                                                                              
3 4725  38 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 3298  41 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	
                                                                                                                                                                                                                                                                                                                                                                                                              
5 4232  37 METHYLATION OF RUNX3 IN VARIOUS TYPES OF HUMAN CANCERS AND PREMALIGNANT STAGES OF GASTRIC CARCINOMA. ACCUMULATING EVIDENCE HAS IDENTIFIED A MECHANISM POTENTIALLY RESPONSIBLE FOR THE INACTIVATION OF TUMOR SUPPRESSOR GENES, NAMELY TRANSCRIPTIONAL SILENCING BY ABERRANT METHYLATION OF CPG ISLANDS. A PREVIOUS STUDY HAS SHOWN THE LOSS OF RUNX3 EXPRESSION, DUE TO ABERRANT METHYLATION OF ITS CPG ISLAND, IN GASTRIC CANCER CELL LINES, SUGGESTING THAT RUNX3 IS A TARGET FOR EPIGENETIC GENE SILENCING IN GASTRIC CARCINOGENESIS. HOWEVER, THERE ARE LIMITED DATA ON THE METHYLATION STATUS OF RUNX3 IN THE NEOPLASTIC AND NON-NEOPLASTIC TISSUES IN VARIOUS TYPES OF HUMAN CANCERS, INCLUDING GASTRIC CANCER. HERE, WE REPORT THAT 60% OF GASTRIC CANCER CELL LINES AND 64% OF PRIMARY GASTRIC CARCINOMAS (N=75) WERE METHYLATED AT THE RUNX3 CPG ISLAND. RUNX3 METHYLATION WAS ALSO DETECTED IN HEPATOCELLULAR CARCINOMAS (73%, N=48), LARYNX CANCERS (62%, N=37), LUNG CANCERS (46%, N=24), BREAST CANCERS (25%, N=25), PROSTATE CANCERS (23%, N=44), ENDOMETRIAL CANCERS (12.5%, N=24), COLON CANCERS (4.9%, N=61) AND UTERINE CERVICAL CANCERS (2.5%, N=40), SHOWING THAT RUNX3 METHYLATION IS NOT RESTRICTED TO GASTRIC CANCER. INTERESTINGLY, THE RUNX3 METHYLATION WAS ESPECIALLY FREQUENT IN TUMORS FROM TISSUES OF A FOREGUT DERIVATIVE, THAT IS, THE STOMACH, LIVER, LARYNX AND LUNG. NEXT, THE METHYLATION STATUS OF RUNX3 IN VARIOUS NON-NEOPLASTIC TISSUES WAS EXAMINED, INCLUDING THE PREMALIGNANT LESIONS OF GASTRIC CARCINOMAS. THE RUNX3 METHYLATION WAS FOUND IN 8.1% OF CHRONIC GASTRITIS (N=99), 28.1% OF INTESTINAL METAPLASIA (N=32), 27.3% OF GASTRIC ADENOMAS (N=77) AND 64% OF GASTRIC CARCINOMAS (N=75), BUT NOT IN CHRONIC HEPATITIS B, NORMAL PROSTATE AND COLON MUCOSA, EVEN THOUGH IN CASES OF CHRONIC HEPATITIS, THE METHYLATION FREQUENCY OF ITS NEOPLASTIC TISSUES WAS VERY HIGH. IN CONCLUSION, RUNX3 METHYLATION IS FREQUENTLY FOUND IN HUMAN CANCERS, INCLUDING GASTRIC CANCER, AND IS MOSTLY CANCER SPECIFIC, WITH THE EXCEPTION OF THE STOMACH, AND THUS, MIGHT BE USEFUL AS A POTENTIAL DIAGNOSTIC BIOMARKER OF CANCER.	2004	
                                                                                                                                                                                                                                                                                                                                                                     
6 1342  37 DETECTING ABNORMAL METHYLATION OF TUMOR SUPPRESSOR GENES GSTP1, P16, RIZ1, AND RASSF1A IN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL SIGNIFICANCE. HEPATOCELLULAR CARCINOMA (HCC) HAS A HIGH RATE OF MORTALITY. FURTHER STUDIES INTO EPIGENETIC CHANGES IN HCC, PARTICULARLY THE ABNORMAL METHYLATION OF TUMOR SUPPRESSOR GENES (TSGS), ARE REQUIRED, SINCE THESE CHANGES MAY PROVIDE NOVEL BIOMARKERS FOR EARLY SCREENING AND DIAGNOSIS OF HCC. BY USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP), THE PRESENT STUDY DETECTED THE METHYLATION STATUS IN THE PROMOTER REGION OF 4 CANDIDATE TSGS, GSTP1, P16, RIZ1, AND RASSF1A, RESPECTIVELY, IN 35 PAIRED HCC AND TUMOR-ADJACENT LIVER TISSUES IN ADDITION TO 20 NORMAL LIVER TISSUES. THEIR EFFECT ON THE INITIATION AND PROGRESSION OF HCC WAS ALSO INVESTIGATED BY ANALYZING THE CLINICOPATHOLOGICAL DATA. THE RESULTS OF THE PRESENT STUDY REVEALED THAT THE METHYLATION LEVEL OF RIZ1 AND GSTP1 GENES IN HCC WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN THE ADJACENT TISSUES (P<0.01) AND THE NORMAL LIVER TISSUES (P<0.01). THE METHYLATION FREQUENCY OF P16 AND RASSF1A GENES WAS NOT SIGNIFICANTLY INCREASED COMPARED WITH THAT OBSERVED IN THE ADJACENT TISSUES (P>0.05) BUT WAS SIGNIFICANTLY INCREASED COMPARED WITH THE NORMAL TISSUES (P<0.01). IN HCC TISSUES, THE METHYLATION FREQUENCY OF THE GSTP1 GENE IN TUMORS WITH CAPSULAR INVASION WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN TUMORS WITHOUT CAPSULAR INVASION (P<0.05). THE METHYLATION FREQUENCY OF P16 GENE IN HEPATITIS B SURFACE ANTIGEN (HBSAG)-POSITIVE HCC PATIENTS WAS SIGNIFICANTLY INCREASED COMPARED WITH THAT IN HBSAG-NEGATIVE PATIENTS (P<0.05). THE METHYLATION STATUS OF RIZ1 AND RASSF1A GENES WAS NOT SIGNIFICANTLY CORRELATED WITH THE CLINICOPATHOLOGICAL DATA (P>0.05). PREVIOUS STUDIES HAVE DEMONSTRATED THAT THE METHYLATION STATUS OF RIZ1 AND GSTP1 GENES IS HCC-SPECIFIC, AND THUS MAY BE USED AS A BIOMARKER TO ASSIST THE CLINICAL DIAGNOSIS OF HCC. WHILE THE METHYLATION OF GSTP1 GENE PROMOTER MAY ASSOCIATE WITH THE INVASIVENESS OF HCC, CHRONIC HEPATITIS B VIRUS INFECTION MAY BE THE CAUSE OF METHYLATION-INDUCED P16 INACTIVATION.	2015	
                                                                                                                                                                                                                                                                                                               
7 2262  38 EPIGENETIC PROFILING IN CHRONIC LYMPHOCYTIC LEUKEMIA REVEALS NOVEL METHYLATION TARGETS. CPG ISLAND METHYLATION IS AN EPIGENETIC ALTERATION THAT CONTRIBUTES TO TUMORIGENESIS BY TRANSCRIPTIONAL INACTIVATION OF GENES. LITTLE IS KNOWN ABOUT THE OVERALL LEVELS OF CPG ISLAND METHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). TO PROVIDE A BASELINE ESTIMATE OF GLOBAL ABERRANT METHYLATION AND IDENTIFY TARGET SEQUENCES FOR ADDITIONAL INVESTIGATION, WE PERFORMED RESTRICTION LANDMARK GENOMIC SCANNING ON 10 CLL SAMPLES. TWO METHYLATION-SENSITIVE LANDMARK ENZYMES WERE USED (NOTI AND ASCI), ALLOWING ASSESSMENT OF OVER 3000 CPG ISLANDS IN EACH SAMPLE. TUMOR-DERIVED RESTRICTION LANDMARK GENOMIC SCANNING PROFILES WERE COMPARED WITH PROFILES FROM CD19-SELECTED B CELLS FROM NORMAL VOLUNTEERS AND MATCHED NORMAL NEUTROPHILS FROM 4 CLL PATIENTS. WE FOUND 2.5-8.1% (MEAN 4.8%) OF THE CPG ISLANDS IN CLL SAMPLES WERE ABERRANTLY METHYLATED COMPARED WITH CONTROLS, AND THE METHYLATION EVENTS HAD A NONRANDOM DISTRIBUTION (P < 0.0001). FURTHERMORE, WE IDENTIFIED 193 ABERRANTLY METHYLATED SEQUENCES, OF WHICH 93% HAVE CPG ISLAND CHARACTERISTICS AND 90% HAVE HOMOLOGY TO GENES OR EXPRESSED SEQUENCES. ONE SUCH GENE, THE G PROTEIN-COUPLED METABOTROPIC GLUTAMATE RECEPTOR 7 (GRM7), POSSIBLY INHIBITS CYCLIC AMP SIGNALING IN THE INDUCTION OF APOPTOSIS. BISULFITE SEQUENCING OF GRM7 CONFIRMED EXTENSIVE CPG ISLAND METHYLATION, AND TREATMENT WITH 5-AZA-2'-DEOXYCYTIDINE (DECITABINE) RESULTED IN UP-REGULATED EXPRESSION OF SEVERAL GENES IN VITRO WITH CONCURRENT CELLULAR DEPLETION OF DNMT1 PROTEIN. OUR DUAL-ENZYME GLOBAL METHYLATION STUDY SHOWS THAT CLL IS CHARACTERIZED BY WIDESPREAD NONRANDOM CPG ISLAND METHYLATION SIMILAR TO OTHER TUMORS AND PROVIDES A PANEL OF NOVEL METHYLATION TARGETS THAT CAN BE USED IN LARGER STUDIES DESIGNED TO ASSESS IMPACT ON DISEASE PROGRESSION AND SURVIVAL.	2004	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
8 1424  32 DIFFERENTIAL DNA METHYLATION OF GENE PROMOTERS IN SMALL B-CELL LYMPHOMAS. IMPROVED CARE OF PATIENTS WITH SMALL B-CELL LYMPHOMAS (SBCLS) IS LIKELY TO RESULT FROM THE ONGOING DISCOVERY OF MOLECULAR MARKERS THAT BETTER DEFINE THESE MALIGNANT NEOPLASMS. WE IDENTIFIED MULTIPLE GENE LOCI WHOSE DNA METHYLATION PATTERNS DIFFERED BETWEEN 3 TYPES OF SBCL: B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA/SMALL LYMPHOCYTIC LYMPHOMA, MANTLE CELL LYMPHOMA, AND GRADES I AND II FOLLICULAR LYMPHOMA. THIS ANALYSIS WAS PERFORMED USING AN OLIGONUCLEOTIDE MICROARRAY THAT ALLOWED DETERMINATION OF THE DNA METHYLATION STATUS OF 156 LOCI IN 38 GENES. COMBINED BISULFITE RESTRICTION ANALYSIS AND METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WERE USED TO VALIDATE THE DIFFERENTIAL METHYLATION OF 6 OF THESE GENES. BY USING NON-HODGKIN LYMPHOMA CELL LINES AS MODELS, THESE GENES WERE EXAMINED FURTHER FOR METHYLATION AND GENE EXPRESSION RELATIONSHIPS. THIS STUDY ILLUSTRATES NONRANDOM EPIGENETIC ALTERATIONS IN SBCLS THAT SEEM TO PREFERENTIALLY INVOLVE LYMPHOMAS OF GERMINAL CENTER DERIVATION.	2005	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
9  672  33 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
10 5270  36 PROMOTER DNA METHYLATION FREQUENCY AND CLINICOPATHOLOGICAL ROLE OF MIR-129-2 GENE IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA. OBJECTIVES: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY THE ACCUMULATION OF APPARENTLY MATURE B-TYPE LYMPHOCYTES IN THE LYMPHOHEMATOPOIETIC ORGANS. METHYLATION IN PROMOTERS OF TUMOR SUPPRESSOR GENES IS ONE OF THE MECHANISMS THAT CAUSES BLOOD MALIGNANCY. IN THIS STUDY, WE EVALUATED THE PROMOTER DNA METHYLATION STATUS OF MIR-129-2 TUMOR SUPPRESSOR GENE AND ITS ASSOCIATION WITH CLINICAL AND LABORATORY PARAMETERS OF PATIENTS WITH CLL. METHODS: WE STUDIED THE PROMOTER DNA METHYLATION FREQUENCY OF THE MIR-129-2 GENE IN 50 PATIENTS WITH CLL AND 50 HEALTHY CONTROLS USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION METHODS. STATISTICAL ANALYSIS WAS PERFORMED USING SPSS-18 SOFTWARE, AND A P-VALUE < 0.050 WAS CONSIDERED STATISTICALLY SIGNIFICANT. RESULTS: THE FREQUENCY OF PROMOTER DNA METHYLATION OF THE MIR-129-2 GENE WAS SIGNIFICANTLY HIGHER IN THE CLL GROUP COMPARED WITH CONTROL GROUP (38.0% VS. 0.0%, P < 0.001; CHI(2) = 23.457). THE PROMOTER DNA METHYLATION FREQUENCY OF MIR-129-2 GENE WAS NOT SIGNIFICANTLY DIFFERENT BETWEEN THE TWO SEXES (P = 0.236). A SIGNIFICANT BUT WEAK CORRELATION WAS SEEN BETWEEN THE METHYLATED STATE OF THE MIR-129-2 GENE AND ORGANOMEGALY (P = 0.019, R = 0.330) AS WELL AS HEMOGLOBIN LEVELS (P = 0.020, R = -0.233). HOWEVER, BINARY LOGISTIC REGRESSION ANALYSIS INDICATED ORGANOMEGALY AS THE ONLY CLINICAL BIOMARKER WITH A STATISTICALLY SIGNIFICANT ASSOCIATION WITH THE HYPERMETHYLATED MIR-129-2 GENE STATE (P = 0.046). CONCLUSIONS: THE HIGH FREQUENCY OF PROMOTER DNA METHYLATION OF THE MIR-129-2 GENE IN THE CLL GROUP COMPARED TO THE CONTROL GROUP, AS WELL AS ITS SIGNIFICANT ASSOCIATION WITH ORGANOMEGALY, SUGGESTS THE IMPORTANCE OF THIS EPIGENETIC BIOMARKER IN THE PATHOGENESIS AND PROGNOSIS OF CLL DISEASE.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 3231  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12 6820  45 [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	
                                                                                                                                                                                                                  
13 3134  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                
14 5435  34 RELATIVE ROLE OF METHYLATOR AND TUMOR SUPPRESSOR PATHWAYS IN ULCERATIVE COLITIS-ASSOCIATED COLON CANCER. BACKGROUND: CHRONIC ULCERATIVE COLITIS (UC) IS ASSOCIATED WITH AN INCREASED COLORECTAL CANCER RISK WHICH MAY BE SECONDARY TO REPETITIVE MUCOSAL INJURY. BOTH EPIGENETIC METHYLATION AND THE CLASSIC ADENOMA-TO-CARCINOMA SEQUENCE HAVE BEEN IMPLICATED IN THIS MALIGNANT TRANSFORMATION, BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN POORLY DEFINED. THIS STUDY COMPARES THE MOLECULAR CHARACTERISTICS OF COLITIS-ASSOCIATED AND COMMON COLORECTAL CANCERS. METHODS: NINETEEN PATIENTS WITH COLORECTAL ADENOCARCINOMAS ARISING WITHIN UC WERE MATCHED FOR AGE AND CANCER SITE WITH 54 PATIENTS WITH SPORADIC ADENOCARCINOMAS. TUMOR TISSUE WAS EXAMINED FOR BRAF MUTATIONS, CPG ISLAND METHYLATOR PHENOTYPE (CIMP), AND MLH1 PROMOTER METHYLATION. MUTATIONS OF KRAS AND P53 WERE ASSESSED BY SEQUENCING. RESULTS: PATIENT DEMOGRAPHICS WERE SIMILAR FOR THE TWO GROUPS. CIMP WAS OBSERVED IN 22% OF SPORADIC COLORECTAL CANCERS AND IN 5% OF UC CANCERS (P = 0.162). RATES OF BRAF MUTATION (4% VS 5%, P = 1.0), MLH1 METHYLATION (9% VERSUS 5%, P = 0.682), AND KRAS MUTATIONS (24% VERSUS 32%, P = 0.552) WERE SIMILAR BETWEEN THE GROUPS. HOWEVER, COLITIS-ASSOCIATED COLORECTAL CANCERS WERE MORE LIKELY TO HAVE A P53 MUTATION COMPARED TO SPORADIC ADENOCARCINOMAS (95% VERSUS 53%, P = 0.001). THE DOMINANT MUTATION FOR COLITIS-ASSOCIATED CANCERS WAS A MUTATION IN CODON 4, REPRESENTING HALF OF THE MUTATIONS. FURTHERMORE, COLITIS-ASSOCIATED CANCERS HAD A HIGHER RATE OF MUTATION IN CODON 8 (48% VERSUS 6%, P < 0.001) THAN SPORADIC COUNTERPARTS. CONCLUSIONS: UNLIKE OTHER INFLAMMATORY GASTROINTESTINAL CANCERS, COLITIS-ASSOCIATED COLORECTAL CANCERS DO NOT PREFERENTIALLY ARISE VIA A METHYLATOR PATHWAY WHEN COMPARED TO SPORADIC COLORECTAL CANCERS. CHROMOSOMAL INSTABILITY REMAINS AN IMPORTANT ETIOLOGY, BUT WITH A UNIQUE P53 FREQUENCY AND MUTATION PATTERN.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
15 2847  28 FREQUENT P15 PROMOTER METHYLATION IN TUMOR AND PERIPHERAL BLOOD FROM HEPATOCELLULAR CARCINOMA PATIENTS. WE PROSPECTIVELY ANALYZED P15 METHYLATION PATTERNS IN 25 SURGICALLY RESECTED TUMORS AND 130 PLASMA, SERUM, AND BUFFY COAT SAMPLES FROM HEPATOCELLULAR CARCINOMA (HCC) PATIENTS, CONTROLS WITH CHRONIC HEPATITIS/CIRRHOSIS, AND HEALTHY SUBJECTS. USING METHYLATION-SPECIFIC PCR, WE DEMONSTRATED FOR THE FIRST TIME P15 PROMOTER METHYLATION IN 64% OF TUMORS AND 25% (4 OF 16) OF PATIENTS' PLASMA AND SERUM SAMPLES. CONCURRENT P15 AND P16 METHYLATION WAS SHOWN IN 48% OF TUMORS, AND P15/P16 METHYLATION WAS DETECTED IN THE PLASMA/SERUM OF 92% (11 OF 12) OF PATIENTS. OF NOTE, 75% OF 12 PATIENTS WITH CONCURRENT TUMOR METHYLATION DEVELOPED CLINICAL METASTASIS/RECURRENCE (P = 0.027). IN BUFFY COAT SAMPLES, P15 METHYLATION WAS DETECTED IN ALL EIGHT PATIENTS WITH TUMOR P15 METHYLATION, SUGGESTING THE PRESENCE OF CIRCULATING TUMOR CELLS. NONE OF THE CONTROL SAMPLES WERE METHYLATION POSITIVE. OUR DATA UNDERSCORE THE IMPORTANT ROLE(S) OF P15 AND P16 METHYLATION IN HEPATOCARCINOGENESIS AND TUMOR PROGRESSION. AMONG 92% (23 OF 25) OF PATIENTS WITH TUMOR P15/P16 METHYLATION, CIRCULATING TUMOR DNA AND HCC CELLS WERE DETECTED IN THE PERIPHERAL BLOOD OF 87% (20 OF 23) OF PATIENTS. THE COMBINATION OF THESE EPIGENETIC MARKERS MAY PROVE VALUABLE FOR NONINVASIVE HCC DIAGNOSIS AND DISEASE MONITORING.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16 3225  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 5277  42 PROMOTER METHYLATION PROFILE IN PRENEOPLASTIC AND NEOPLASTIC GALLBLADDER LESIONS. GALLBLADDER CARCINOMA (GBC) IS A HIGHLY MALIGNANT NEOPLASM AND REPRESENTS THE LEADING CAUSE OF CANCER DEATH IN CHILEAN WOMEN. IN ORDER TO DETERMINE THE POTENTIAL ROLE OF PROMOTER METHYLATION IN GALLBLADDER CARCINOGENESIS, WE INVESTIGATED THE FREQUENCY OF THIS EPIGENETIC MECHANISM BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) IN 35 CHRONIC CHOLECYSTITIS (CC, SEPARATED ACCORDING TO THE PRESENCE OR ABSENCE OF METAPLASIA), 19 EARLY CANCERS (MUCOSA OR MUSCULARIS PROPIA INVASION) AND 48 ADVANCED CARCINOMAS WITH INVASION OF THE GALLBLADDER SUBSEROSA (25 CASES) AND SEROSA (23 CASES). WE EXAMINED 14 GENES AND OBSERVED AN INCREASE OF MULTIGENIC METHYLATION DURING TUMORAL PROGRESSION WHICH WAS NOT SIGNIFICANTLY ASSOCIATED WITH THE PATIENT'S AGE. FOUR GENES (DAPK1, DLC1, TIMP3, AND RARBETA2) DISPLAYED A PROGRESSIVE INCREASE IN THEIR METHYLATION STATUS FROM CC WITHOUT METAPLASIA TO ADVANCED CARCINOMA INVADING THE SEROSA LAYER (P <OR= 0.05). THE SURVIVAL ANALYSIS INDICATED THAT A METHYLATED CONDITION OF DLC1 GENE IS SIGNIFICANTLY ASSOCIATED WITH POOR PROGNOSIS (P = 0.04), WHEREAS A METHYLATED STATE OF MGMT GENE CORRELATED WITH BETTER PATIENT SURVIVAL (P = 0.006). OUR FINDINGS INDICATE THAT ABERRANT HYPERMETHYLATION OF PROMOTER REGIONS IS AN EARLY, PROGRESSIVE AND CUMULATIVE EVENT IN GALLBLADDER CARCINOGENESIS. FURTHERMORE, THE METHYLATION LEVELS SEEMS TO ACCUMULATE IN THE PROGRESSION OF CC WITHOUT METAPLASIA TO CC WITH METAPLASIA, A FACT THAT COULD PROVIDE NEW EVIDENCE TO CONSIDER THIS MORPHOLOGICAL ADAPTATION OF GB MUCOSA AS A PREMALIGNANT LESION. FINALLY, THE METHYLATION STATUS OF SOME INDIVIDUAL GENES COULD BE USEFUL BIOMARKERS WITH POTENTIAL CLINICAL APPLICATION IN DIAGNOSIS OR PROGNOSIS OF GBC IF THEY ARE VALIDATED IN A GREATER NUMBER OF CLINICAL SAMPLES.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
18 2843  42 FREQUENT CPG ISLAND METHYLATION IN PRECURSOR LESIONS AND EARLY GASTRIC ADENOCARCINOMAS. GASTRIC CARCINOGENESIS INVOLVES MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS. EPIGENETIC SILENCING OF TUMOR-RELATED GENES DUE TO CPG ISLAND METHYLATION (CIM) HAS BEEN RECENTLY REPORTED IN GASTRIC CANCER, BUT THE ROLE IN PRECURSOR LESIONS IS NOT WELL UNDERSTOOD. WE ANALYSED THE METHYLATION STATUS OF THE TUMOR SUPPRESSOR GENE P16, THE DNA MISMATCH REPAIR GENE HMLH1, AND FOUR CPG ISLANDS (MINT1, MINT2, MINT25, AND MINT31) USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION IN 35 POLYPOID ADENOMAS AND 46 FLAT DYSPLASIAS UNASSOCIATED WITH CARCINOMA, 34 EARLY ADENOCARCINOMAS (T1N0M0) AND ASSOCIATED ADENOMAS/DYSPLASIAS, AND CORRESPONDING ADJACENT NON-NEOPLASTIC MUCOSA. THE EXTENT OF CIM WAS DEFINED BY THE FRACTION OF METHYLATED LOCI (METHYLATION INDEX), AND COMPARED WITH PREVIOUSLY CHARACTERIZED GENETIC ALTERATIONS (MICROSATELLITE INSTABILITY (MSI) AND APC GENE MUTATION). WE FOUND THAT METHYLATION OF P16 WAS MORE FREQUENT IN ADENOCARCINOMA-ASSOCIATED DYSPLASIAS/ADENOMAS (29%) AND ADENOCARCINOMAS (44%) AS COMPARED TO FLAT DYSPLASIAS (4%) AND ADENOMAS (18%) UNASSOCIATED WITH ADENOCARCINOMA (P=0.001). THE MEAN METHYLATION INDEX INCREASED FROM NORMAL/CHRONIC GASTRITIS (CG) MUCOSA (0.09) TO INTESTINAL METAPLASIA (IM) (0.16), FLAT DYSPLASIAS (0.40) OR POLYPOID ADENOMAS (0.41) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH CARCINOMA (0.44), AND ADENOCARCINOMAS (0.44). THERE WAS NO DIFFERENCE IN FREQUENCIES OF HIGH-LEVEL CPG ISLAND METHYLATION (CIM-H, METHYLATION INDEX > OR =0.5) AMONG FLAT DYSPLASIAS (50%) AND POLYPOID ADENOMAS (51%) UNASSOCIATED WITH CARCINOMA, DYSPLASIAS/ADENOMAS ASSOCIATED WITH ADENOCARCINOMA (47%), AND ADENOCARCINOMA (47%). CIM-H WAS PRESENT IN 15% OF IM, BUT NOT IN NORMAL/CG MUCOSA. THERE WAS A SIGNIFICANT CORRELATION BETWEEN METHYLATION OF HMLH1 AND HIGH-LEVEL OF MICROSATELLITE INSTABILITY (MSI-H): METHYLATION OF HMLH1 WAS PRESENT IN 71% OF MSI-H TUMORS, BUT ONLY 8% OF MSI-LOW TUMORS AND 13% OF MICROSATELLITE-STABLE TUMORS (P=0.0001). THERE WAS NO STATISTICAL DIFFERENCE BETWEEN METHYLATION INDEX AND APC MUTATION. OUR RESULTS INDICATE THAT CONCURRENT PROMOTER METHYLATION IS AN EARLY AND FREQUENT EVENT IN GASTRIC TUMORIGENESIS, INCLUDING BOTH MSI-H AND MICROSATELLITE-STABLE NEOPLASMS. METHYLATION OF THE P16 GENE MAY CONTRIBUTE TO THE MALIGNANT TRANSFORMATION OF GASTRIC PRECURSOR LESIONS.	2004	

19 2439  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
20  494  30 ASSESSMENT OF PROMOTER METHYLATION IDENTIFIES PTCH AS A PUTATIVE TUMOR-SUPPRESSOR GENE IN HUMAN CLL. BACKGROUND: CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS CHARACTERIZED BY A CLONAL ACCUMULATION OF NEOPLASTIC LYMPHOCYTES, INDICATING DISRUPTION OF APOPTOSIS. PATIENTS AND METHODS: DIFFERENTIAL METHYLATION HYBRIDIZATION ANALYSIS WAS PERFORMED TO IDENTIFY NOVEL TARGET GENES SILENCED BY CPG ISLAND METHYLATION IN PATIENTS WITH CLL. RESULTS: PATCHED (PTCH), A TUMOR-SUPPRESSOR GENE, WAS FOUND TO BE FREQUENTLY METHYLATED IN CLL SAMPLES COMPARED TO SAMPLES DERIVED FROM HEALTHY INDIVIDUALS. DE NOVO METHYLATION OF A CPG ISLAND REGION LOCATED UPSTREAM OF PTCH EXON 1 WAS CONFIRMED BY PYROSEQUENCING IN 17/37 (46%) OF PERIPHERAL BLOOD MONONUCLEAR CELLS OF PATIENTS WITH CLL, BUT IN NONE ISOLATED FROM SEVEN HEALTHY INDIVIDUALS. NO ASSOCIATION WAS FOUND BETWEEN PTCH HYPERMETHYLATION AND CURRENTLY USED PROGNOSTIC CLL FACTORS. CONCLUSION: OUR INVESTIGATION SUGGESTS THAT EPIGENETIC SILENCING OF PTCH IS A MECHANISM CONTRIBUTING TO CLL TUMORIGENESIS.	2016