1  511 172 ASSOCIATION OF RASSF1A HYPERMETHYLATION WITH RISK OF HBV/HCV-INDUCED HEPATOCELLULAR CARCINOMA: A META-ANALYSIS. BACKGROUND: RESEARCHERS HAVE DISCOVERED A LARGE NUMBER OF DNA METHYLATION PATTERNS IN HUMAN CANCER. THESE CANCER-SPECIFIC METHYLATION PATTERNS CAN PROVIDE INFORMATION FOR THE DIAGNOSIS, TREATMENT, AND PROGNOSIS OF CANCER. METHYLATION STUDIES CAN FIND NEW BIOMARKERS BASED ON EPIGENETIC ANALYSIS AND APPLY THESE BIOMARKERS TO CLINICAL ONCOLOGY. MANY STUDIES ON THE ASSOCIATION BETWEEN RAASF1A METHYLATION STATUS AND SUSCEPTIBILITY TO HEPATITIS B VIRUS (HBV)/HEPATITIS C VIRUS (HCV)-INDUCED HEPATOCELLULAR CARCINOMA (HCC) HAVE REACHED CONTROVERSIAL CONCLUSIONS. HENCE, THE CURRENT REVIEW COMPREHENSIVELY ASSESSED THE CORRELATION BETWEEN RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) METHYLATION AND THE RISK OF THE HCV/HBV-INDUCED HCC. METHODS: THE APPROPRIATED PUBLICATIONS WERE EXTRACTED IN EMBASE, PUBMED, WEB OF SCIENCE, COCHRANE LIBRARY, AND CHINA NATIONAL KNOWLEDGE INFRASTRUCTURE DATABASES USING STATA 5.0 SOFTWARE. THE ODDS RATIOS (ORS) WITH 95 % CONFIDENCE INTERVAL (95 % CI) OF RASSF1A METHYLATION WERE COMPUTED. RESULTS: A TOTAL OF 1015 HBV/HCV-RELATED HCC SAMPLES, 124 NON-HBV/HCV-RELATED HCC (NBNC-HCC) SAMPLES, AND 1225 NONTUMOROUS CONTROLS WERE EXTRACTED AND EXAMINED IN THIS RESEARCH. THE FREQUENCY OF THE METHYLATED RASSF1A IN THE HBV/HCV-RELATED TUMOR CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE OVERALL NONTUMOR SAMPLES (OR = 19.372, 95 % CI = 11.060-33.931, P = 0.000). THE FREQUENCY OF THE METHYLATED RASSF1A IN HBV/HCV-RELATED NEOPLASM CASES DISPLAYED A SIGNIFICANTLY INCREASED OR COMPARED WITH THE NON-HBV/HCV-RELATED NEOPLASM (NBNC-NEOPLASM) SAMPLES (OR = 2.150, 95 % CI = 1.398-3.308, P = 0.000). COMPARED WITH NORMAL, CHRONIC HEPATITIS B OR C, CIRRHOSIS, AND PARACANCEROUS SAMPLES, THE POOLED OR OF THE RASSF1A PROMOTER METHYLATION IN THE HBV/HCV-INDUCED HCC SAMPLES WAS 62.785(95 % CI = 35.224-111.909), 25.07 (95 % CI = 13.85-45.36), 6.89 (95 % CI = 3.33-14.264) AND 9.02 (95 % CI = 0.91-89.80), RESPECTIVELY. THE RATE OF RASSF1A HYPERMETHYLATION WAS ROBUSTLY CORRELATED WITH TUMOR SIZE AND VASCULAR INVASION, AND THE POOLED OR WAS 0.346 (95 % CI = 0.210 - 0.569) AND 0.081 (95 % CI = 0.022 - 0.303), RESPECTIVELY. CONCLUSION: RESULTS SHOWED ROBUST ASSOCIATIONS BETWEEN RASSF1A GENE METHYLATION IN PROMOTER REGION AND ENHANCED HBV/HCV-RELATED HCC SUSCEPTIBILITY, THEREBY REVEALING THAT RASSF1A METHYLATION STATUS MAY SERVE AS AN IMPORTANT INDICATOR FOR HCC ONCOGENESIS.	2020	
                                                     
2 1457  48 DISEASE PROGRESSION FROM CHRONIC HEPATITIS C TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IS ASSOCIATED WITH INCREASING DNA PROMOTER METHYLATION. BACKGROUND: CHANGES IN DNA METHYLATION PATTERNS ARE BELIEVED TO BE EARLY EVENTS IN HEPATOCARCINOGENESIS. A BETTER UNDERSTANDING OF METHYLATION STATES AND HOW THEY CORRELATE WITH DISEASE PROGRESSION WILL AID IN FINDING POTENTIAL STRATEGIES FOR EARLY DETECTION OF HCC. THE AIM OF OUR STUDY WAS TO ANALYZE THE METHYLATION FREQUENCY OF TUMOR SUPPRESSOR GENES, P14, P15, AND P73, AND A MISMATCH REPAIR GENE (O6MGMT) IN HCV RELATED CHRONIC LIVER DISEASE AND HCC TO IDENTIFY CANDIDATE EPIGENETIC BIOMARKERS FOR HCC PREDICTION. MATERIALS AND METHODS: 516 EGYPTIAN PATIENTS WITH HCV-RELATED LIVER DISEASE WERE RECRUITED FROM KASR ALAINI MULTIDISCIPLINARY HCC CLINIC FROM APRIL 2010 TO JANUARY 2012. SUBJECTS WERE DIVIDED INTO 4 DIFFERENT CLINICALLY DEFINED GROUPS - HCC GROUP (N=208), LIVER CIRRHOSIS GROUP (N=108), CHRONIC HEPATITIS C GROUP (N=100), AND CONTROL GROUP (N=100) - TO ANALYZE THE METHYLATION STATUS OF THE TARGET GENES IN PATIENT PLASMA USING EPITECT METHYL QPCR ARRAY TECHNOLOGY. METHYLATION WAS CONSIDERED TO BE HYPERMETHYLATED IF >10% AND/OR INTERMEDIATELY METHYLATED IF >60%. RESULTS: IN OUR SERIES, A SIGNIFICANT DIFFERENCE IN THE HYPERMETHYLATION STATUS OF ALL STUDIED GENES WAS NOTED WITHIN THE DIFFERENT STAGES OF CHRONIC LIVER DISEASE AND ULTIMATELY HCC. HYPERMETHYLATION OF THE P14 GENE WAS DETECTED IN 100/208 (48.1%), 52/108 (48.1%), 16/100 (16%) AND 8/100 (8%) AMONG HCC, LIVER CIRRHOSIS, CHRONIC HEPATITIS AND CONTROL GROUPS, RESPECTIVELY, WITH A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN THE STUDIED GROUPS (P-VALUE 0.008). WE ALSO DETECTED P15 HYPERMETHYLATION IN 92/208 (44.2%), 36/108 (33.3%), 20/100 (20%) AND 4/100 (4%) , RESPECTIVELY (P-VALUE 0.006). IN ADDITION, HYPERMETHYLATION OF P73 WAS DETECTED IN 136/208 (65.4%), 72/108 (66.7%), 32/100 (32%) AND 4/100 (4%) (P-VALUE <0.001). ALSO, WE DETECTED O6MGMT HYPERMETHYLATION IN 84/208 (40.4%), 60/108 (55.3%), 20/100 (20%) AND 4/100 (4%), RESPECTIVELY (P VALUE <0.001. CONCLUSIONS: THE EPIGENETIC CHANGES OBSERVED IN THIS STUDY INDICATE THAT HCC TUMORS EXHIBIT SPECIFIC DNA METHYLATION SIGNATURES WITH POTENTIAL CLINICAL APPLICATIONS IN DIAGNOSIS AND PROGNOSIS. IN ADDITION, METHYLATION FREQUENCY COULD BE USED TO MONITOR WHETHER A PATIENT WITH CHRONIC HEPATITIS C IS LIKELY TO PROGRESS TO LIVER CIRRHOSIS OR EVEN HCC. WE CAN CONCLUDE THAT METHYLATION PROCESSES ARE NOT JUST EARLY EVENTS IN HEPATOCARCINOGENESIS BUT ACCUMULATE WITH PROGRESSION TO CANCER.	2014	

3 2125  30 EPIGENETIC INACTIVATION OF DLX4 IS ASSOCIATED WITH DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION OF VARIOUS GENES HAS BEEN IDENTIFIED TO BE ASSOCIATED WITH DISEASE PROGRESSION IN CHRONIC MYELOID LEUKEMIA (CML). OUR STUDY WAS INTENDED TO INVESTIGATE DLX4 METHYLATION PATTERN IN DIFFERENT CLINICAL STAGES OF CML AND FURTHER DETERMINE ITS ROLE IN REGULATING DLX4 EXPRESSION. REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC PCR AND BISULFITE SEQUENCING PCR WERE APPLIED TO DETECT DLX4 METHYLATION. 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) WAS USED FOR DEMETHYLATION STUDIES. DLX4 WAS SIGNIFICANTLY HYPERMETHYLATED IN CML PATIENTS (P = 0.002) ESPECIALLY IN BLASTIC PHASE (BC) STAGE (P < 0.001) AS COMPARED WITH CONTROLS. MOREOVER, DLX4 METHYLATION LEVEL IN BC STAGE WAS SIGNIFICANTLY HIGHER THAN IN CHRONIC PHASE (CP) STAGE (P < 0.001). DLX4 METHYLATION DENSITY WAS SIGNIFICANTLY INCREASED DURING THE PROGRESSION OF CML AMONG THE TESTED TWO PATIENTS (P < 0.001). DLX4 HYPERMETHYLATION OCCURRED WITH THE HIGHEST INCIDENCE IN BC STAGE (83%), LOWER INCIDENCE IN ACUTE PHASE (AP) STAGE (43%), AND THE LOWEST INCIDENCE IN CP STAGE (26%) (P = 0.001). MOREOVER, T(9; 22) WITH ADDITIONAL ALTERATION CASES HAD SIGNIFICANTLY HIGHER FREQUENCY OF DLX4 HYPERMETHYLATION COMPARED WITH THE OTHER CYTOGENETICS (P = 0.010). SIGNIFICANTLY NEGATIVE CORRELATION WAS OBSERVED BETWEEN DLX4 METHYLATION AND DLX4-TV2 (THE SHORTER DLX4 ISOFORM) EXPRESSION (R = -0.382, P = 0.001, N = 78) BUT NOT BETWEEN DLX4 METHYLATION AND BP1 (THE LONGER DLX4 ISOFORM) EXPRESSION (R = 0.134, P = 0.244, N = 78) IN CML PATIENTS. BOTH DLX4-TV2 AND BP1 MRNA WERE SIGNIFICANTLY INCREASED AFTER 5-AZA-DC TREATMENT IN K562 CELL LINE (P < 0.001). OUR STUDY INDICATED THAT HYPERMETHYLATION OF DLX4 CORRELATED WITH DISEASE PROGRESSION OF CML. MOREOVER, DLX4 EXPRESSION WAS REGULATED BY ITS METHYLATION IN CML.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4 3879  36 KERATIN 19-EXPRESSING HEPATOCELLULAR CARCINOMA AND SMALL-DUCT TYPE INTRAHEPATIC CHOLANGIOCARCINOMA SHOW A SIMILAR POSTOPERATIVE CLINICAL COURSE BUT HAVE DISTINCT GENETIC FEATURES. AIMS: THE PRESENT STUDY AIMED TO SYSTEMATICALLY COMPARE CLINICOPATHOLOGICAL AND GENETIC FEATURES BETWEEN KERATIN 19 (K19)-EXPRESSING HEPATOCELLULAR CARCINOMA (HCC) AND INTRAHEPATIC CHOLANGIOCARCINOMA (ICCA). METHODS AND RESULTS: CONSECUTIVE CASES OF HCC (N = 430) WERE CLASSIFIED INTO K19(+) AND K19(-) USING IMMUNOHISTOCHEMISTRY. ICCA CASES WERE ALSO SEPARATED INTO SMALL-(S-ICCA; N = 36) AND LARGE-DUCT TYPES (N = 22) BASED ON RECENTLY PROPOSED CRITERIA, WITH THE FORMER BEING USED IN THE PRESENT STUDY. MUTATIONAL HOT-SPOTS IN TERT, CTNNB1, KRAS AND IDH1 WERE SEQUENCED. TWENTY-SIX CASES (6%) OF HCC EXPRESSED K19. K19(+) HCC WAS MORE STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B THAN K19(-) HCC AND S-ICCA (46% VERSUS 17% AND 6%; BOTH P < 0.001). LYMPH NODE METASTASIS WAS OBSERVED IN K19(+) HCC (8%) AND S-ICCA (22%), BUT WAS EXCEPTIONAL IN K19(-) HCC (1%). K19(+) HCC HAD TERT PROMOTER MUTATIONS LESS FREQUENTLY THAN K19(-) HCC (31% VERSUS 59%; P = 0.022), AND LACKED ALTERATIONS IN KRAS AND IDH1. CTNNB1 MUTATIONS WERE SIMILARLY OBSERVED IN K19(+) AND K19(-) HCC (23% AND 19%, RESPECTIVELY), BUT RARE IN S-ICCA (3%). THE POSTOPERATIVE SURVIVAL CURVE OF K19(+) HCC WAS ALMOST IDENTICAL TO THAT OF S-ICCA IN THE FIRST 5 YEARS (APPROXIMATELY 50% AT 5 YEARS), AND SIGNIFICANTLY WORSE THAN THAT OF K19(-) HCC (P = 0.040). EXTRAHEPATIC RECURRENCE WAS MORE COMMON IN K19(+) HCC (50%) AND S-ICCA (35%) THAN IN K19(-) HCC (15%) (P = 0.001). CONCLUSIONS: ALTHOUGH K19(+) HCC AND S-ICCA SHOWED SIMILAR BIOLOGICAL BEHAVIOURS, THEY DID NOT SHARE ANY DRIVER GENE MUTATIONS, SUGGESTING THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS IN THE ICCA-LIKE FEATURES OF K19(+) HCC.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
5 3907  38 LEUCOCYTIC DNA METHYLATION OF INTERLEUKIN-6 PROMOTER REDUCTION IN PRE-HYPERTENSIVE YOUNG ADULTS. BACKGROUND: PRE-HYPERTENSION IS ASSOCIATED WITH INCREASED RISK OF CARDIOVASCULAR DISEASE. CHRONIC INFLAMMATION PLAYS AN IMPORTANT ROLE IN THE PATHOPHYSIOLOGY OF ESSENTIAL HYPERTENSION, WITH EPIGENETIC DYSREGULATION INVOLVEMENT. NEVERTHELESS, THE ROLE OF DNA METHYLATION IN PREHYPERTENSIVE STATE IS UNKNOWN. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE ASSOCIATION BETWEEN DNA METHYLATION LEVEL OF INTERLEUKIN-6 (IL-6) PROMOTER IN PRE-HYPERTENSIVE (PREHT) AND NORMOTENSIVE (NT) YOUNG ADULTS. METHODS: A TOTAL OF 80 NT AND 80 PREHT HEALTHY SUBJECTS AGED BETWEEN 18-45 YEARS WERE RECRUITED IN KUANTAN, PAHANG, MALAYSIA USING AN OBSERVATIONAL CROSS-SECTIONAL STUDY APPROACH. DNA METHYLATION LEVEL OF IL-6 PROMOTER IN PERIPHERAL LEUKOCYTES WERE MEASURED USING BISULPHITE CONVERSION AND METHYLIGHT ASSAY. RESULTS: THERE WAS NO SIGNIFICANT DIFFERENCE IN AGE BETWEEN NT AND PREHT (P = 0.655). THE MEAN BLOOD PRESSURE WAS 110(8)/73(5) MMHG IN NT AND 125(7)/82(5) MMHG IN PREHT SUBJECTS. THE IL-6 PROMOTER METHYLATION LEVEL WAS SIGNIFICANTLY LOWER IN PREHT COMPARED TO NT SUBJECTS (P < 0.001). CONCLUSION: THE CURRENT STUDY DEMONSTRATES THAT HYPOMETHYLATION OF IL-6 PROMOTER WAS ASSOCIATED WITH PRE-HYPERTENSION IN YOUNG ADULTS. THUS, IL-6 METHYLATION COULD BE USED AS AN EARLY INDICATOR FOR PREDICTING HYPERTENSION AND RELATED RISK OF CARDIOVASCULAR DISEASES IN PREHYPERTENSIVE SUBJECTS. GENE EXPRESSION AND LONGITUDINAL STUDIES ARE WARRANTED TO EXAMINE THE METHYLATION EFFECT ON IL-6 EXPRESSION OVER TIME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 2974  28 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7 1067  36 CLINICAL UTILITY OF PDSS2 EXPRESSION TO STRATIFY PATIENTS AT RISK FOR RECURRENCE OF HEPATOCELLULAR CARCINOMA. IDENTIFICATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS IS REQUIRED FOR OPTIMAL STRATIFICATION OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC) AT RISK FOR RECURRENCE AND ADVERSE PROGNOSIS. COENZYME Q10 (COQ10), WHICH MEDIATES APOPTOSIS, IS SYNTHESIZED BY PRENYL DIPHOSPHATE SYNTHASE SUBUNIT 2 (PDSS2). IN THE PRESENT STUDY WE EVALUATED THE CLINICAL SIGNIFICANCE AND REGULATORY MECHANISMS OF PDSS2 EXPRESSION IN HCC. PDSS2 EXPRESSION LEVELS AND THOSE OF GENES ENCODING POTENTIALLY INTERACTING PROTEINS AS WELL AS THE METHYLATION STATUS OF THE PDSS2 PROMOTER REGION WERE ANALYZED IN HCC CELL LINES. PDSS2 MRNA LEVELS IN 151 PAIRS OF RESECTED SPECIMENS WERE DETERMINED TO EVALUATE THE ASSOCIATION OF PDSS2 EXPRESSION AND CLINICOPATHOLOGICAL FACTORS. THE EXPRESSION AND DISTRIBUTION OF PDSS2 WERE DETERMINED USING IMMUNOHISTOCHEMISTRY. PDSS2 MRNA EXPRESSION WAS DECREASED IN SIX OF NINE HCC CELL LINES AND SIGNIFICANTLY CORRELATED WITH THOSE OF HEPATOCYTE NUCLEAR FACTOR 4ALPHA. PDSS2 TRANSCRIPTION IN HCC CELLS WITH DECREASED PDSS2 EXPRESSION ACCOMPANYING HYPERMETHYLATION WAS REACTIVATED AFTER TREATING THESE CELLS WITH A METHYLATION INHIBITOR. MEAN EXPRESSION LEVELS OF PDSS2 MRNA RELATIVE TO THAT OF UNINVOLVED LIVER DIMINISHED GRADUALLY IN THE ORDER OF CHRONIC HEPATITIS TO CIRRHOSIS, AND EACH WAS SIGNIFICANTLY HIGHER THAN THOSE OF HCCS. PDSS2 AND PDSS2 MRNA LEVELS WERE CONSISTENT. DECREASED PDSS2 MRNA LEVELS WERE DETECTED IN HCC TISSUES OF 56 PATIENTS, CORRELATED WITH SHORTER DISEASE-SPECIFIC SURVIVAL, AND WAS IDENTIFIED AS AN INDEPENDENT PROGNOSTIC FACTOR. PDSS2 IS A PUTATIVE TUMOR SUPPRESSOR, AND PROMOTER HYPERMETHYLATION IS A KEY REGULATORY MECHANISM IN HCC. DECREASED LEVELS OF PDSS2 MRNA EXPRESSION MAY REPRESENT A NOVEL BIOMARKER OF HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8 2688  30 EVIDENCE THAT METHYLATION OF HEPATITIS B VIRUS COVALENTLY CLOSED CIRCULAR DNA IN LIVER TISSUES OF PATIENTS WITH CHRONIC HEPATITIS B MODULATES HBV REPLICATION. EPIGENETIC FACTORS MAY MODULATE CHRONIC HEPATITIS B VIRAL INFECTION BY AFFECTING VIRION GENE TRANSCRIPTION. THE AIM OF THIS STUDY WAS TO COMPARE THE METHYLATION STATUS OF THE INTRAHEPATIC COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) CPG ISLAND 2 AND HBV REPLICATION CAPABILITY. HBV CCCDNA WAS EXTRACTED FROM LIVER BIOPSIES OF 55 HBSAG-POSITIVE PATIENTS WITH CHRONIC HEPATITIS B (32 HBEAG-POSITIVE AND 23 HBEAG-NEGATIVE), AND WAS ANALYZED FOR METHYLATION STATUS AND QUANTITY. THE TWO HPA II RECOGNITION SEQUENCES CCPGG IN THE CPG ISLAND 2 WERE METHYLATED IN INFECTED LIVER TISSUES FROM 24 (43.6%) OF 55 PATIENTS. POSITIVE RATIOS OF CCCDNA METHYLATION WERE SIGNIFICANTLY HIGHER IN HBEAG-NEGATIVE PATIENTS (15/23, 65.2%) THAN HBEAG-POSITIVE PATIENTS (9/32, 28.1%) (P < 0.05). THE PERCENTAGE OF METHYLATED-CCCDNA/TOTAL-CCCDNA OF HBEAG-NEGATIVE SAMPLES (A MEDIAN OF 48%, RANGING FROM 5% TO 83%) WAS SIGNIFICANTLY HIGHER (P < 0.001) THAN HBEAG-POSITIVE SAMPLES (A MEDIAN OF 14%, RANGING FROM 0.26% TO 35%). RATIOS OF RELAXED CIRCULAR DNA (RCDNA) TO CCCDNA MOLECULES REVEALED THAT CCCDNA METHYLATION CORRELATED WITH IMPAIRED VIRION PRODUCTIVITY IN HBEAG-POSITIVE INDIVIDUALS (P < 0.05). THE BISULFITE DNA SEQUENCING SHOWED THAT METHYLATION DENSITY WAS SIGNIFICANTLY HIGHER IN HBEAG-NEGATIVE THAN IN HBEAG-POSITIVE PATIENTS (P < 0.05). THE METHYLATION LEVEL OF THE CPG ISLAND 2 OF THE CCCDNA IN HBEAG-NEGATIVE PATIENTS WAS HIGHER THAN THAT IN HBEAG-POSITIVE PATIENTS, SUGGESTING THAT HBV CCCDNA METHYLATION MAY BE RELEVANT TO REPLICATION CAPABILITY OF HBV.	2009	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 6632  28 UNDERSTANDING THE ROLE OF THE CHROMOSOME 15Q25.1 IN COPD THROUGH EPIGENETICS AND TRANSCRIPTOMICS. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A MAJOR HEALTH BURDEN IN ADULTS AND CIGARETTE SMOKING IS CONSIDERED THE MOST IMPORTANT ENVIRONMENTAL RISK FACTOR OF COPD. CHROMOSOME 15Q25.1 LOCUS IS ASSOCIATED WITH BOTH COPD AND SMOKING. OUR STUDY AIMS AT UNDERSTANDING THE MECHANISM UNDERLYING THE ASSOCIATION OF CHROMOSOME 15Q25.1 WITH COPD THROUGH EPIGENETIC AND TRANSCRIPTIONAL VARIATION IN A POPULATION-BASED SETTING. TO ASSESS IF COPD-ASSOCIATED VARIANTS IN 15Q25.1 ARE METHYLATION QUANTITATIVE TRAIT LOCI, EPIGENOME-WIDE ASSOCIATION ANALYSIS OF FOUR GENETIC VARIANTS, PREVIOUSLY ASSOCIATED WITH COPD (P < 5 X 10(-8)) IN THE 15Q25.1 LOCUS (RS12914385:C>T-CHRNA3, RS8034191:T>C-HYKK, RS13180:C>T-IREB2 AND RS8042238:C>T-IREB2), WAS PERFORMED IN THE ROTTERDAM STUDY (N = 1489). ALL FOUR VARIANTS WERE SIGNIFICANTLY ASSOCIATED (P < 1.4 X 10(-6)) WITH BLOOD DNA METHYLATION OF IREB2, CHRNA3 AND PSMA4, OF WHICH TWO, INCLUDING IREB2 AND PSMA4, WERE ALSO DIFFERENTIALLY METHYLATED IN COPD CASES AND CONTROLS (P < 0.04). FURTHER ADDITIVE AND MULTIPLICATIVE EFFECTS OF SMOKING WERE EVALUATED AND NO SIGNIFICANT EFFECT WAS OBSERVED. TO EVALUATE IF THESE FOUR GENETIC VARIANTS ARE EXPRESSION QUANTITATIVE TRAIT LOCI, TRANSCRIPTOME-WIDE ASSOCIATION ANALYSIS WAS PERFORMED IN 1087 LUNG SAMPLES. ALL FOUR VARIANTS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH DIFFERENTIAL EXPRESSION OF THE IREB2 3'UTR IN LUNG TISSUES (P < 5.4 X 10(-95)). WE CONCLUDE THAT REGULATORY MECHANISMS AFFECTING THE EXPRESSION OF IREB2 GENE, SUCH AS DNA METHYLATION, MAY EXPLAIN THE ASSOCIATION BETWEEN GENETIC VARIANTS IN CHROMOSOME 15Q25.1 AND COPD, LARGELY INDEPENDENT OF SMOKING.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
10 1496  22 DNA IS HYPOMETHYLATED IN CIRCADIAN MANIFESTATIONS OF BRUXISM. OBJECTIVE: THE AIM OF THIS STUDY WAS TO COMPARE THE GLOBAL DNA METHYLATION LEVELS IN PATIENTS UNDER BRUXISM TREATMENT AND A CONTROL GROUP. METHODS: SUBJECTS UNDERGOING BRUXISM TREATMENT WERE CLASSIFIED IN AWAKE BRUXISM (42 PATIENTS), SLEEP BRUXISM (32 PATIENTS) AND BOTH CONDITIONS (42 PATIENTS). THE CONTROL GROUP INCLUDED 42 INDIVIDUALS. A COLORIMETRIC ASSAY (METHYLFLASH METHYLATED DNA 5-MC QUANTIFICATION KIT, EPIGENETIC GROUP INC., NY, USA) WAS USED TO DETERMINE THE GLOBAL DNA METHYLATION LEVELS. RESULTS: STATISTICALLY SIGNIFICANT DIFFERENCES WERE FOUND IN AMOUNTS OF METHYLATED DNA IN ALL CIRCADIAN MANIFESTATIONS OF BRUXISM COMPARED WITH A CONTROL GROUP (SLEEP BRUXISM = 0.95% +/- 2.02%; AWAKE BRUXISM = 0.87% +/- 2.1%; SLEEP AND AWAKE BRUXISM = 0.17% +/- 0.25%; CONTROL = 1.69% +/- 1.6%; KRUSKAL-WALLIS TEST [P = .0001] FOLLOWED BY DUNN'S TEST [P < .05]). CONCLUSION: PATIENTS UNDERGOING BRUXISM TREATMENT EXHIBITED HYPOMETHYLATED DNA LEVELS WHEN COMPARED TO CONTROL GROUP. OUR RESULTS SUGGEST THAT DNA HYPOMETHYLATION MIGHT BE A NOVEL AETIOLOGIC FACTOR IN BRUXISM AETIOLOGY. FURTHER RESEARCHES MUST BE PERFORMED EXPLORING THE ROLE OF EPIGENETICS MODIFICATIONS IN CIRCADIAN MANIFESTATIONS OF BRUXISM.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
11  145  37 ABERRANT DNA METHYLATION STATUS AND MRNA EXPRESSION LEVEL OF SMG1 GENE IN CHRONIC MYELOID LEUKEMIA: A CASE-CONTROL STUDY. OOBJECTIVE: CHRONIC MYELOID LEUKEMIA (CML) IS A MYELOPROLIFERATIVE MALIGNANCY WITH DIFFERENT STAGES. ABERRANT EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLATION, HAVE BEEN INTRODUCED AS A SIGNATURE FOR DIVERSE CANCERS WHICH ALSO PLAYS A CRUCIAL ROLE IN CML PATHOGENESIS AND DEVELOPMENT. SUPPRESSOR WITH MORPHOGENETIC EFFECT ON GENITALIA (SMG1) GENE RECENTLY HAS BEEN BROUGHT TO THE SPOTLIGHT AS A POTENT TUMOR SUPPRESSOR GENE THAT CAN BE SUPPRESSED BY TUMORS FOR FURTHER PROGRESS. THE PRESENT STUDY AIMS TO INVESTIGATE SMG1 STATUS IN CML PATIENTS. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, PERIPHERAL BLOOD FROM 30 PATIENTS WITH DIFFERENT PHASES OF CML [NEW CASE (N)=10, COMPLETE MOLECULAR REMISSION (CMR)=10, BLASTIC PHASE (BP)=10] AND 10 HEALTHY SUBJECTS WERE COLLECTED. METHYLATION STATUS AND EXPRESSION LEVEL OF SMG1 GENE PROMOTER WAS ASSESSED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) AND QUANTITATIVE REVERSE-TRANSCRIPTION PCR, RESPECTIVELY. RESULTS: MSP RESULTS OF SMG1 GENE PROMOTOR IN THE NEW CASE GROUP WERE METHYLATED (60% METHYLATED, 30% HEMIMETHYLATED AND 10% UNMETHYLATED). ALL CMR AND CONTROL GROUP PATIENTS WERE UNMETHYLATED IN THE SMG1 GENE PROMOTER. IN THE BP GROUP, METHYLATED SMG1 PROMOTER WAS SEEN (50% OF PATIENTS HAD A METHYLATED STATUS AND 50% HAD HEMIMETHYLATED STATUS). IN COMPARISON WITH THE HEALTHY SUBJECTS, EXPRESSION LEVEL OF SMG1 IN THE NEW CASE GROUP WAS DECREASED (P<0.01); IN THE CMR GROUP AND BP-CML GROUPS, IT WAS INCREASED (P<0.05). NO SIGNIFICANT CORRELATION BETWEEN PATIENTS' HEMATOLOGICAL FEATURES AND SMG1 METHYLATION WAS SEEN. CONCLUSION: OUR RESULTS DEMONSTRATED THAT ABERRANT METHYLATION OF SMG1 OCCURRED IN CML PATIENTS AND IT HAD A SIGNIFICANT ASSOCIATION WITH SMG1 EXPRESSION. SMG1 GENE PROMOTER SHOWED DIVERSE METHYLATED STATUS AND SUBSEQUENT EXPRESSION LEVELS IN DIFFERENT PHASES OF CML. THESE FINDINGS SUGGESTED POSSIBLE PARTICIPATION OF SMG1 SUPPRESSION IN THE CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12  515  31 ASSOCIATION OF SOCS1 (- 820) (RS33977706) GENE POLYMORPHISM WITH CHRONIC PERIODONTITIS: A CASE-CONTROL STUDY IN BRAZILIANS. IT IS EVIDENT THAT THE ACCUMULATION OF PERIODONTAL PATHOGENS OVER THE TEETH SURFACE TRIGGERS PERIODONTITIS; HOWEVER, ITS AGGRAVATION AND SEVERITY DEPEND ON OTHER ELEMENTS SUCH AS ENVIRONMENTAL FACTORS, SYSTEMIC HEALTH AND THE HOST GENETIC AND/OR EPIGENETIC BACKGROUND. TO ADDRESS THIS ISSUE, WE INVESTIGATED THE ASSOCIATION OF TWO GENETIC POLYMORPHISMS PLACED ON PROMOTER REGION OF SOCS1 GENE WITH CHRONIC PERIODONTAL DISEASE. SOCS1 REGULATES JAK/KINASE SIGNALING PATHWAY AND CHANGES IN ITS MRNA EXPRESSION HAVE BEEN RELATED TO DIFFERENT TYPES OF CANCER AND CHRONIC INFLAMMATION, INCLUDING CHRONIC PERIODONTITIS. THE FREQUENCY OF ALLELES AND GENOTYPES OF TWO POLYMORPHISMS IN SOCS1 GENE PROMOTER (POSITION - 820 (RS33977706) AND POSITION - 1478 (RS33989964)) WERE ANALYZED BY PERFORMING RFLP AND TAQMAN SYSTEM IN A TOTAL OF 257 NON-SMOKING SUBJECTS. WE FOUND A LOW FREQUENCY OF A ALLELE AND A/A GENOTYPE OF SOCS1(- 820) POLYMORPHISM IN THE CHRONIC PERIODONTITIS GROUP, ESPECIALLY WHEN SEVERE PERIODONTITIS SAMPLES WERE SEPARATELY ANALYZED (OR = 0.3933; P = 0.0084 (IC95% 0.2112 < MU < 0.7324)), SUGGESTING THAT A ALLELE PLAYS PROTECTIVE EFFECT AGAINST CHRONIC PERIODONTITIS. WE DID NOT FIND ASSOCIATION BETWEEN SOCS1-1478 POLYMORPHISM AND PERIODONTITIS. IN ADDITION, ANALYSIS OF SOCS1 (- 820/- 1478) HAPLOTYPE REVEALED THAT THE FREQUENCY OF A(- 820)/CA(- 1478) HAPLOTYPE DECREASES IN CHRP (P = 0.0089). IN CONCLUSION, OUR STUDY FOUND THAT SOCS1(- 820) POLYMORPHISM IS ASSOCIATED WITH CHRONIC PERIODONTITIS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
13 4225  31 METHYLATION DEGREE OF METALLOPROTEINASE INHIBITOR RECK GENE: LINKS TO RECK PROTEIN LEVEL AND HEPATOCELLULAR CARCINOMA IN CHRONIC HCV INFECTION PATIENTS. THE RECK GENE, A TUMOR SUPPRESSOR GENE, INHIBITS ANGIOGENESIS, INVASION, AND TUMOR METASTASIS. EPIGENETIC REGULATION OF THE RECK GENE CONSTITUTES A POTENT APPROACH TO THE MOLECULAR BASIS OF LIVER MALIGNANCY. THIS STUDY AIMS TO EVALUATE THE PROMOTER METHYLATION STATUS OF THE RECK GENE AND ITS SERUM LEVEL IN PATIENTS WITH HEPATITIS C VIRUS (HCV)-RELATED HEPATOCELLULAR CARCINOMA (HCC) AND THE POTENTIAL ASSOCIATION OF RECK GENE METHYLATION WITH CLINICAL CRITERIA OF HCC. ONE HUNDRED AND FIFTY-FIVE SUBJECTS WERE INCLUDED (HEALTHY CONTROL [55], CHRONIC HCV PATIENTS [55], HCV-RELATED HCC PATIENTS [45]). THE METHYLATION STATUS OF THE RECK GENE PROMOTER AND SERUM RECK LEVEL WERE INVESTIGATED BY METHYLATION-SPECIFIC PCR AND ENZYME-LINKED IMMUNOSORBENT ASSAY TECHNIQUES, RESPECTIVELY. RECK GENE PROMOTER HYPERMETHYLATION WAS RECORDED IN 46.7% OF HCC PATIENTS, AND 10.9% OF HCV PATIENTS, BUT NOT IN CONTROL SUBJECTS (0%). IT WAS RELATED TO RECK PROTEIN LEVEL, VARICES, EDEMA, ASCITES, LYMPH NODE METASTASIS, VASCULAR INVASION, AND THE LARGEST DIAMETER OF FOCAL LESIONS. MEANWHILE, IT WAS NOT ASSOCIATED WITH FOCAL LESION NUMBER NOR DISTANT METASTASIS OF HCC. IN CONCLUSION, RECK GENE PROMOTER HYPERMETHYLATION IS LINKED TO HCV GENOTYPE-4-RELATED HCC. MOREOVER, DIFFERENT DEGREES OF RECK GENE PROMOTER METHYLATION ARE ASSOCIATED WITH SERUM RECK LEVEL, LYMPH NODE METASTASIS, AND VASCULAR INVASION, WHICH COULD PROVE ITS PATHOGENIC ROLE IN HEPATOCARCINOGENESIS IN CHRONIC HCV-INFECTED PATIENTS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
14 2626  33 EPIGENOME-WIDE ASSOCIATION STUDY IDENTIFIES DNA METHYLATION MARKERS FOR ASTHMA REMISSION IN WHOLE BLOOD AND NASAL EPITHELIUM. BACKGROUND: ASTHMA IS A CHRONIC RESPIRATORY DISEASE WHICH IS NOT CURABLE, YET SOME PATIENTS EXPERIENCE SPONTANEOUS REMISSION. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS MAY BE INVOLVED IN ASTHMA REMISSION. METHODS: CLINICAL REMISSION (CLINR) WAS DEFINED AS THE ABSENCE OF ASTHMA SYMPTOMS AND MEDICATION FOR AT LEAST 12 MONTHS, AND COMPLETE REMISSION (COMR) WAS DEFINED AS CLINR WITH NORMAL LUNG FUNCTION AND ABSENCE OF AIRWAY HYPERRESPONSIVENESS. WE ANALYZED DIFFERENTIAL DNA METHYLATION OF CLINR AND COMR COMPARING TO PERSISTENT ASTHMA (PERSA) IN WHOLE BLOOD SAMPLES (N = 72) AND NASAL BRUSHING SAMPLES (N = 97) IN A LONGITUDINAL COHORT OF WELL CHARACTERIZED ASTHMA PATIENTS. SIGNIFICANT FINDINGS OF WHOLE BLOOD DNA METHYLATION WERE TESTED FOR REPLICATION IN TWO INDEPENDENT COHORTS, LIFELINES AND EPIDEMIOLOGICAL STUDY ON THE GENETICS AND ENVIRONMENT OF ASTHMA (EGEA). RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES ASSOCIATED WITH CLINR (7 CPG SITES) AND COMR (129 CPG SITES) IN WHOLE BLOOD. ONE CPG (CG13378519, CHR1) ASSOCIATED WITH CLINR WAS REPLICATED AND ANNOTATED TO PEX11 (PEROXISOMAL BIOGENESIS FACTOR 11 BETA). THE WHOLE BLOOD DNA METHYLATION LEVELS OF THIS CPG WERE ALSO DIFFERENT BETWEEN CLINR AND HEALTHY SUBJECTS. ONE COMR-ASSOCIATED CPG (CG24788483, CHR10) THAT ANNOTATED TO TCF7L2 (TRANSCRIPTION FACTOR 7 LIKE 2) WAS REPLICATED AND ASSOCIATED WITH EXPRESSION OF TCF7L2 GENE. ONE OUT OF SEVEN CLINR-ASSOCIATED CPG SITES AND 8 OUT OF 129 COMR-ASSOCIATED CPG SITES IDENTIFIED FROM WHOLE BLOOD SAMPLES SHOWED NOMINAL SIGNIFICANCE (P < 0.05) AND THE SAME DIRECTION OF EFFECT IN NASAL BRUSHES. CONCLUSION: WE IDENTIFIED DNA METHYLATION MARKERS POSSIBLY ASSOCIATED WITH CLINICAL AND COMPLETE ASTHMA REMISSION IN NASAL BRUSHES AND WHOLE BLOOD, AND TWO CPG SITES IDENTIFIED FROM WHOLE BLOOD CAN BE REPLICATED IN INDEPENDENT COHORTS AND MAY PLAY A ROLE IN PEROXISOME PROLIFERATION AND WNT SIGNALING PATHWAY.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
15 1622  33 DNA METHYLTRANSFERASES IN MALAR MELASMA AND THEIR MODIFICATION BY SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. BACKGROUND: MALAR MELASMA HAS A CHRONIC AND RECURRENT CHARACTER THAT MAY BE RELATED TO EPIGENETIC CHANGES. OBJECTIVE: TO RECOGNIZE THE EXPRESSION AND DNA METHYLATION OF DNA METHYLTRANSFERASES (DNMTS) IN MALAR MELASMA AND PERILESIONAL SKIN, AS WELL AS THE CHANGES IN DNMTS AFTER THEIR TREATMENT WITH SUNSCREEN IN COMBINATION WITH 4% NIACINAMIDE, 0.05% RETINOIC ACID, OR PLACEBO. METHODS: THIRTY FEMALE PATIENTS WERE CLINICALLY EVALUATED FOR THE EXPRESSION OF DNMT1 AND DNMT3B USING REAL-TIME PCR AND IMMUNOFLUORESCENCE. THESE INITIAL RESULTS WERE COMPARED TO RESULTS AFTER EIGHT WEEKS OF TREATMENT WITH SUNSCREEN IN COMBINATION WITH NIACINAMIDE, RETINOIC ACID, OR PLACEBO. RESULTS: THE RELATIVE EXPRESSION OF DNMT1 WAS SIGNIFICANTLY ELEVATED IN MELASMA COMPARED WITH UNAFFECTED SKIN IN ALL SUBJECTS, INDICATING DNA HYPERMETHYLATION. AFTER TREATMENT, IT WAS DECREASED IN ALL GROUPS: NIACINAMIDE (7 VERSUS 1; P<0.01), RETINOIC ACID (7 VERSUS 2; P<0.05), AND PLACEBO (7 VERSUS 3; P<0.05), WHICH CORRELATES WITH CLINICAL IMPROVEMENT. DNMT3B WAS NOT OVEREXPRESSED IN LESIONAL SKIN BUT REDUCED IN ALL GROUPS. CONCLUSIONS: WE FOUND DNA HYPERMETHYLATION IN MELASMA LESIONS. ENVIRONMENTAL FACTORS SUCH AS SOLAR RADIATION MAY INDUCE CELLULAR CHANGES THAT TRIGGER HYPERPIGMENTATION THROUGH THE ACTIVATION OF PATHWAYS REGULATED BY EPIGENETIC MODIFICATIONS. HOWEVER, LIMITING OR DECREASING DNA METHYLATION THROUGH SUNSCREEN, NIACINAMIDE, AND RETINOIC ACID TREATMENTS THAT PROVIDE PHOTOPROTECTION AND GENETIC TRANSCRIPTION CAN COUNTERACT THIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
16 3453  42 HYPOMETHYLATED UBIQUITIN-CONJUGATING ENZYME2 Q1 (UBE2Q1) GENE PROMOTER IN THE SERUM IS A PROMISING BIOMARKER FOR HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. ABERRANT DNA METHYLATION, WHICH CAN BE DETECTED IN CIRCULATING CELL-FREE DNA (CFDNA), IS ONE OF THE MAJOR EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA (HCC). UBE2Q1, A PUTATIVE MEMBER OF THE UBIQUITIN-CONJUGATING ENZYME FAMILY, MIGHT PLAY SUBSTANTIAL ROLES IN TUMORIGENESIS. HOWEVER, THE METHYLATION STATUS OF THE UBE2Q1 GENE IN HCC REMAINS UNKNOWN. WE AIMED TO DETERMINE THE METHYLATION STATUS OF THE UBE2Q1 GENE PROMOTER AND TO EVALUATE ITS POTENTIAL CLINICAL SIGNIFICANCE FOR HCC DETECTION. THE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) ASSAY WAS USED TO DETECT THE UBE2Q1 GENE METHYLATION STATUS IN SERUM SAMPLES FROM 80 PATIENTS WITH HEPATITIS B VIRUS (HBV)-RELATED HCC, 40 PATIENTS WITH LIVER CIRRHOSIS (LC), 40 PATIENTS WITH CHRONIC HEPATITIS B (CHB), AND 20 HEALTHY CONTROLS (HCS). SIGNIFICANTLY LOWER METHYLATION FREQUENCIES WERE DETECTED IN HCC PATIENTS (33.75%) COMPARED WITH LC PATIENTS (55.00%, P = 0.026) AND CHB PATIENTS (60.00%, P = 0.006) AND HCS (65.00%, P = 0.011). HYPOMETHYLATION OF THE UBE2Q1 GENE WAS NEGATIVELY ASSOCIATED WITH THE TUMOR NODE METASTASIS STAGE (R(S) = -0.30, P = 0.008). THE UBE2Q1 GENE METHYLATION STATUS COMBINED WITH ALPHA FETOPROTEIN USING CUT-OFF POINTS OF 20, 200 AND 400 NG/ML SHOWED SENSITIVITY AND SPECIFICITY VALUES OF 58.8% AND 75.0%, 53.8% AND 87.5%, AND 37.5% AND 88.7%, RESPECTIVELY, AND YIELDED A SIGNIFICANTLY INCREASED AREA UNDER THE ROC CURVE (0.720, 0.760 AND 0.694, RESPECTIVELY) FOR DISCRIMINATING HCC FROM LC AND CHB. OUR STUDY RESULTS SUGGEST THAT HYPOMETHYLATION OF THE UBE2Q1 GENE PROMOTER IS A POTENTIAL BIOMARKER FOR DETECTING HBV-ASSOCIATED HCC.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17 6036  34 THE CHARACTERISTICS OF EXTRACHROMOSOMAL CIRCULAR DNA IN PATIENTS WITH END-STAGE RENAL DISEASE. BACKGROUND: END-STAGE RENAL DISEASE (ESRD) IS THE FINAL STAGE OF CHRONIC KIDNEY DISEASE (CKD). IN ADDITION TO THE STRUCTURALLY INTACT CHROMOSOME GENOMIC DNA, THERE IS A DOUBLE-STRANDED CIRCULAR DNA CALLED EXTRACHROMOSOMAL CIRCULAR DNA (ECCDNA), WHICH IS THOUGHT TO BE INVOLVED IN THE EPIGENETIC REGULATION OF HUMAN DISEASE. HOWEVER, THE FEATURES OF ECCDNA IN ESRD PATIENTS ARE BARELY KNOWN. IN THIS STUDY, WE IDENTIFIED ECCDNA FROM ESRD PATIENTS AND HEALTHY PEOPLE, AS WELL AS REVEALED THE CHARACTERISTICS OF ECCDNA IN PATIENTS WITH ESRD. METHODS: USING THE HIGH-THROUGHPUT CIRCLE-SEQUENCING TECHNIQUE, WE EXAMINED THE ECCDNA IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM HEALTHY PEOPLE (NC) (N = 12) AND ESRD PATIENTS (N = 16). WE ANALYZED THE LENGTH DISTRIBUTION, GENOME ELEMENTS, AND MOTIFS FEATURE OF ECCDNA IN ESRD PATIENTS. THEN, AFTER IDENTIFYING THE SPECIFIC ECCDNA IN ESRD PATIENTS, WE EXPLORED THE POTENTIAL FUNCTIONS OF THE TARGET GENES OF THE SPECIFIC ECCDNA. FINALLY, WE INVESTIGATED THE PROBABLE HUB ECCDNA USING ALGORITHMS. RESULTS: IN TOTAL, 14,431 AND 11,324 ECCDNAS WERE FOUND IN THE ESRD AND NC GROUPS, RESPECTIVELY, WITH SIZES RANGING FROM 0.01 KB TO 60 KB AT MOST. ADDITIONALLY, THE ESRD GROUP HAD A GREATER DISTRIBUTION OF ECCDNA ON CHROMOSOMES 4, 11, 13, AND 20. IN TWO GROUPS, WE ALSO DISCOVERED SEVERAL MOTIFS OF SPECIFIC ECCDNAS. FURTHERMORE, WE IDENTIFIED 13,715 SPECIFIC ECCDNAS IN THE ESRD GROUP AND 10,585 SPECIFIC ECCDNAS IN THE NC GROUP, BOTH OF WHICH WERE LARGELY ANNOTATED AS MRNA CATALOG. PATHWAY STUDIES USING GENE ONTOLOGY (GO) AND THE KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) SHOWED THAT THE SPECIFIC ECCDNA IN ESRD WAS MARKEDLY ENRICHED IN CELL JUNCTION AND COMMUNICATION PATHWAYS. FURTHERMORE, WE IDENTIFIED POTENTIALLY 20 HUB ECCDNA-TARGETING GENES FROM ALL ESRD-SPECIFIC ECCDNA-TARGETING GENES. ALSO, WE FOUND THAT 39 ECCDNA-TARGETING GENES WERE ASSOCIATED WITH ESRD, AND SOME OF THESE ECCDNAS MAY BE RELATED TO THE PATHOGENESIS OF ESRD. CONCLUSIONS: OUR FINDINGS REVEALED THE CHARACTERISTICS OF ECCDNA IN ESRD PATIENTS AND DISCOVERED POTENTIALLY HUB AND ESRD-RELEVANT ECCDNA-TARGETING GENES, SUGGESTING A NOVEL PROBABLE MECHANISM OF ESRD.	2023	
                                                                                                                                                                                                                                                                                                
18 3574  37 IMPACT OF METHIONINE SYNTHASE REDUCTASE POLYMORPHISMS IN CHRONIC MYELOID LEUKEMIA PATIENTS. INTRODUCTION: METABOLISM METHIONINE AND OF FOLATE PLAY A VITAL FUNCTION IN CELLULAR METHYLATION REACTIONS, DNA SYNTHESIS AND EPIGENETIC PROCESS.HOWEVER, POLYMORPHISMS OF METHIONINE HAVE RECEIVED MUCH ATTENTION IN RECENT MEDICAL GENETICS RESEARCH. OBJECTIVES: TO ASCERTAIN WHETHER THE COMMON POLYMORPHISMS OF THE MTRR (METHIONINE SYNTHASE REDUCTASE) A66G GENE COULD PLAY A ROLE IN AFFECTING SUSCEPTIBILITY TO CHRONIC MYELOID LEUKEMIA (CML) IN SUDANESE INDIVIDUALS. METHODS: IN A CASE-CONTROLLED STUDY, WE EXTRACTED AND ANALYZED DNA FROM 200 CML PATIENTS AND 100 HEALTHY CONTROL SUBJECTS BY THE PCR-RFLP METHOD. RESULTS: WE FOUND NO SIGNIFICANT DIFFERENCE IN AGE ORGENDER BETWEEN THE PATIENT GROUP AND CONTROLS. THE MTRR A66G GENOTYPES WERE DISTRIBUTED BASED ON THE HARDY-WEINBERG EQUILIBRIUM (P > 0.05). THE VARIATION OF MTRR A66G WAS LESS SIGNIFICANTLY FREQUENT IN CASES WITH CML (68.35%) THAN IN CONTROLS (87%) (OR = 0.146, 95% CI = 0.162-0.662, P < 0.002). ADDITIONALLY, AG AND GG GENOTYPES AND G ALLELE WERE REDUCING THE CML RISK (ODDS RATIO [OR] = 0.365; 95% CI [0.179-0.746]; P = 0.006; OR = 0.292; 95% CI [0.145-0.590]; P = 0.001 AND OR = 0.146; 95% CI [0.162-0.662]; P = 0.002 AND OR = 2.0; 95% CI [1.3853-2.817]; RESPECTIVELY, (P = 0.000)). CONCLUSIONS: OUR DATA DEMONSTRATED THAT HETEROZYGOUS AND HOMOZYGOUS MUTANT GENOTYPES OF MTRR POLYMORPHISMS WERE ASSOCIATED WITH DECREASED RISK OF DEVELOPING CML IN THE SUDANESE POPULATION.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 1422  26 DIFFERENTIAL CPG DNA METHYLATION OF PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES IN IGG4-RELATED DISEASE. OBJECTIVES: IMMUNOGLOBULIN-G4-RELATED DISEASE (IGG4-RD) IS A DISTINCT SYSTEMIC AUTOIMMUNE-MEDIATED DISEASE MANIFESTING AS CHRONIC INFLAMMATION AND TISSUE FIBROSIS. SINCE THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF IGG4-RD IS STILL UNCLEAR, WE CONDUCT THIS STUDY TO INVESTIGATE EPIGENETIC MODIFICATIONS IN IGG4-RD. METHODS: A GENOME-WIDE DNA METHYLATION STUDY WAS CONDUCTED WITH B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS AND MATCHED CONTROLS BY USING THE ILLUMINA HUMANMETHYLATION 850K BEADCHIP. WE FURTHER PERFORMED PYROSEQUENCING AND IMMUNOHISTOCHEMISTRY ASSAYS TO VALIDATE THE METHYLATION STATUS OF SOME TARGETS OF INTEREST. RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES INCLUDING 44 HYPOMETHYLATED AND 166 HYPERMETHYLATED DIFFERENTIALLY METHYLATED PROBES (DMPS) IN B CELLS AND 260 HYPOMETHYLATED AND 112 HYPERMETHYLATED DMPS IN CD4(+) T CELLS FROM 10 IGG4-RD PATIENTS COMPARED WITH 10 HEALTHY CONTROLS. WE ALSO IDENTIFIED 36945 HYPOMETHYLATED AND 78380 HYPERMETHYLATED DMPS IN SALIVARY GLAND TISSUES OF 4 IGG4-RD PATIENTS COMPARED WITH 4 CONTROLS. DPM2 (CG21181453), IQCK (CG10266221), AND ABCC13 (CG05699681, CG04985582) WERE HYPERMETHYLATED AND MBP (CG18455083) WAS HYPOMETHYLATED IN B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS. WE ALSO OBSERVED THE HYPOMETHYLATED HLA-DQB2 IN CD4(+) T CELLS FROM IGG4-RD PATIENTS. KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSIS OF DMPS IN SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS REVEALED ENRICHMENT OF PATHWAYS INVOLVED IN THE REGULATION OF IMMUNE CELL RESPONSES AND FIBROSIS. CONCLUSION: THIS IS THE FIRST DNA METHYLATION STUDY IN PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS. OUR FINDINGS HIGHLIGHTED THE ROLE OF EPIGENETIC MODIFICATION OF DNA METHYLATION AND IDENTIFIED SEVERAL GENES AND PATHWAYS POSSIBLY INVOLVED IN IGG4-RD PATHOGENESIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20 6248  26 THE METHYLATION STATUS OF THE DDX43 PROMOTER IN CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA. ABERRANT DNA METHYLATION IS A COMMON EPIGENETIC ALTERATION AND AN IMPORTANT FEATURE IN HUMAN CANCERS. THE DEAD BOX POLYPEPTIDE 43 (DDX43) HAS BEEN FOUND TO BE OVEREXPRESSED IN VARIOUS SOLID TUMORS AND SOME HEMATOLOGIC MALIGNANCIES. IN THE PRESENT STUDY, WE INVESTIGATED THE METHYLATION STATUS OF THE DDX43 PROMOTER IN 87 CHINESE PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) USING REAL-TIME QUANTITATIVE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION AND EXAMINED THE DDX43 TRANSCRIPT IN 35 PATIENTS USING REAL-TIME QUANTITATIVE POLYMERASE CHAIN REACTION. DDX43 PROMOTER HYPOMETHYLATION WAS OBSERVED IN 22 (25.3%) CML PATIENTS. NO SIGNIFICANT CORRELATION WAS FOUND BETWEEN THE HYPOMETHYLATION OF THE DDX43 PROMOTER WITH THE AGE, SEX, WHITE BLOOD CELL COUNTS, HEMOGLOBIN CONCENTRATION, PLATELET COUNTS, AND CHROMOSOMAL ABNORMALITIES OF CML PATIENTS (P>0.05). THE FREQUENCY OF DDX43 HYPOMETHYLATION IN PATIENTS IN THE CHRONIC PHASE, IN THE ACCELERATED PHASE, AND IN BLAST CRISIS WAS 23.4% (15/64), 25.0% (2/8), AND 33.3% (5/15), RESPECTIVELY (P>0.05). THERE WAS A SIGNIFICANT CORRELATION BETWEEN DDX43 HYPOMETHYLATION AND DDX43 TRANSCRIPT (R=0.469, P=0.004). OUR DATA SUGGEST THAT HYPOMETHYLATION OF THE DDX43 PROMOTER MAY BE AN EARLY AND FREQUENT MOLECULAR EVENT IN THE DEVELOPMENT OF CML IN CHINESE PATIENTS.	2013