1 3574 131 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
2 2125  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
3 3956  39 LONG NON-CODING RNA GENES POLYMORPHISMS H19 (RS2251375) AND MALAT1 (RS3200401) ASSOCIATION WITH RHEUMATOID ARTHRITIS AND THEIR CORRELATION WITH DISEASE ACTIVITY IN A COHORT OF EGYPTIAN PATIENTS: A PILOT STUDY. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, PROGRESSIVE, INFLAMMATORY, AUTOIMMUNE DISEASE THAT COULD BE DISABLING THROUGHOUT ITS COURSE. IT AFFECTS PEOPLE IN THEIR MOST REPRODUCTIVE YEARS WITH RELATIVELY HIGH MORBIDITY AND MORTALITY. LONG NON-CODING RNAS BECAME ONE OF THE EPIGENETIC MECHANISMS TO PROVE A LINK TO RA PATHOGENESIS AND DEVELOPMENT, INCLUDING H19 AND MALAT1 GENES. THESE TWO GENES' EXPRESSIONS HAD PROVED TO INCREASE IN MULTIPLE DISEASES, ATTRACTING ATTENTION TO THEIR POLYMORPHISMS AND THEIR POSSIBLE RISK ROLE. ASSESS THE ASSOCIATION BETWEEN H19 SNP (RS2251375) AND MALAT1 SNP (RS3200401) AND THE SUSCEPTIBILITY OF RA AND ITS DISEASE ACTIVITY. IN THIS PILOT STUDY, 200 HUNDRED SUBJECTS (100 RA PATIENTS AND 100 HEALTHY CONTROLS) WERE INVESTIGATED FOR A POSSIBLE LINK BETWEEN THE POLYMORPHISMS H19 SNP (RS2251375) AND MALAT1 SNP (3200401) AND RA SUSCEPTIBILITY AND DISEASE ACTIVITY. RA-RELATED INVESTIGATIONS AND CLINICAL ASSESSMENT WERE DONE. REAL-TIME PCR GENOTYPING OF BOTH SNPS WAS DONE USING TAQMAN(R) MGB PROBES. THERE WAS NO ASSOCIATION BETWEEN THE SNPS AND RISK OF DEVELOPING RA. HOWEVER, BOTH SNPS HAD A SIGNIFICANT ASSOCIATION WITH HIGH DISEASE ACTIVITY. H19 SNP (RS2251375) HETEROZYGOUS GENOTYPE CA HAD AN ASSOCIATION WITH ELEVATED LEVELS OF ESR (P = 0.04) AND HIGHER DAS28-ESR SCORE (P = 0.03). MALAT1 (RS3200401) C ALLELE HAD AN ASSOCIATION WITH ELEVATED ESR (P = 0.001), DAS28-ESR (P = 0.03), AND DAS28-CRP (P = 0.007), WHILE CC GENOTYPE HAD AN ASSOCIATION WITH DAS28-CRP (P = 0.015). LINKAGE DISEQUILIBRIUM AND HAPLOTYPING OF THE ALLELES OF BOTH SNPS WERE ANALYZED AS BOTH GENES ARE PRESENT ON CHROMOSOME 11, BUT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN ANY OF THE COMBINATIONS OF THE ALLELES (P > 0.05), DENOTING THAT (RS2251375) AND (RS3200401) ARE NOT IN LINKAGE DISEQUILIBRIUM. THERE IS NO ASSOCIATION BETWEEN H19 SNP (RS2251375) AND MALAT1 SNP (RS3200401) AND THE SUSCEPTIBILITY OF RA. HOWEVER, THERE IS AN ASSOCIATION BETWEEN H19 SNP (RS2251375) GENOTYPE CA AND MALAT1 SNP (RS3200401) GENOTYPE CC WITH RA HIGH DISEASE ACTIVITY.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 3310  40 HIGHER ORDER GENES INTERACTION IN DNA REPAIR AND CYTOKINE GENES POLYMORPHISM AND RISK TO LUNG CANCER IN NORTH INDIANS. CONTEXT: LUNG CANCER PATHOLOGICAL PROCESS INVOLVES CUMULATIVE EFFECTS EXERTED BY GENE POLYMORPHISM(S), EPIGENETIC MODIFICATIONS, AND ALTERATIONS IN DNA REPAIR MACHINERY. FURTHER, DNA DAMAGE DUE TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, AND THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS IS ALSO AN ETIOLOGIC MILIEU OF THIS MALIGNANT DISEASE. AIMS: THE PRESENT STUDY AIMS TO ASSESS THE PROGNOSTIC VALUE OF DNA REPAIR, CYTOKINES, AND GST GENE POLYMORPHISM IN LUNG CANCER PATIENTS WHO HAD NOT RECEIVED ANY NEOADJUVANT THERAPY. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, 127 CASES AND 120 CONTROLS WERE ENROLLED. DNA FROM THE BLOOD SAMPLES OF BOTH PATIENTS AND CONTROLS WAS USED TO GENOTYPE XRCC1ARG399GLN, XPDLYS751GLN, AND INTERLEUKIN-1 (IL-1BETA) GENES BY POLYMERASE CHAIN REACTION (PCR)-RESTRICTION FRAGMENT LENGTH POLYMORPHISM METHOD, WHEREAS MULTIPLEX PCR WAS PERFORMED TO GENOTYPE GSTT1 AND GSTM1. RESULTS: BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT XRCC1ARG399GLN-MUTANT GENOTYPE (GLN/GLN, ODDS RATIO [OR] = 4.6, 95% CONFIDENCE INTERVAL [CI]: 2.2-9.6) AND GSTT1 NULL (OR = 2.7, 95% CI: 1.6-4.5) WERE LINKED TO CANCER SUSCEPTIBILITY. GENERALIZED MULTIDIMENSIONAL REDUCTION ANALYSIS OF HIGHER ORDER GENE-GENE INTERACTION USING CROSS-VALIDATION TESTING (CVT) ACCURACY SHOWED THAT GSTT1 (CVT 0.62, P = 0.001), XPD751 AND IL-1BETA (CVT 0.6, P = 0.001), AND XRCC1399, XPD751, AND INTERLEUKIN-1 RECEPTOR ANTAGONISTS (IL-1RN) (CVT 0.98, P = 0.001) WERE SINGLE-, TWO-, AND THREE-FACTOR BEST MODEL PREDICTED, RESPECTIVELY, FOR LUNG CANCER RISK. CLASSIFICATION AND REGRESSION TREE ANALYSIS RESULTS SHOWED THAT TERMINAL NODES WHICH CONTAIN XRCC1399-MUTANT GENOTYPE (AA) HAD INCREASED THE RISK TO LUNG CANCER. CONCLUSION: THE PRESENT STUDY DEMONSTRATED THAT XRCC1399 (GLN/GLN), GSTT1, AND IL-1RN ALLELE I, I/II SERVED AS THE RISK GENOTYPES. THESE GENES COULD SERVE AS THE BIOMARKERS TO PREDICT LUNG CANCER RISK.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
5  145  43 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6 4986  32 PATIENT-REPORTED SYMPTOM OUTCOMES AND MICROSATELLITE INSTABILITY IN PATIENTS WITH METASTATIC COLORECTAL CANCER. BACKGROUND: THE SURVIVAL OF PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IS INFLUENCED BY THE GENETIC AND EPIGENETIC CHANGES THAT MIGHT INFLUENCE THE PATIENT EXPERIENCE OF SYMPTOM BURDEN. UNDERSTANDING THE ASSOCIATION OF MOLECULAR CHANGES WITH THE SYMPTOM BURDEN COULD HELP CLINICIANS GAIN INSIGHT INTO THE MOLECULAR BASIS OF SYMPTOM BURDEN AND IMPROVE TREATMENT TOLERANCE. TO DATE, NO STUDIES HAVE COMPARED THE PATIENT-REPORTED SYMPTOM BURDEN WITH THESE MOLECULAR SUBSETS AMONG PATIENTS WITH MCRC. PATIENTS AND METHODS: WE RECRUITED PATIENTS WITH MCRC THAT WAS REFRACTORY TO >/= 1 LINE OF THERAPY WHO HAD BEEN ENROLLED IN THE ASSESSMENT OF TARGETED THERAPIES AGAINST COLORECTAL CANCER TRIAL AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. ALL PATIENTS COMPLETED A BASELINE GASTROINTESTINAL SYMPTOM INVENTORY (MD ANDERSON SYMPTOM INVENTORY, GASTROINTESTINAL). THE SYMPTOM BURDEN ACROSS KEY DEMOGRAPHIC VARIABLES AND MOLECULAR CHANGES, INCLUDING CRC-ASSOCIATED MUTATIONS, MICROSATELLITE INSTABILITY (MSI) STATUS, AND THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WERE COMPARED USING CHI(2) TESTS. ASSOCIATION OF THE SYMPTOM BURDEN WITH OVERALL SURVIVAL WAS EXAMINED USING COX REGRESSION MODELS. RESULTS: PATIENTS WITH AN MSI-HIGH (MSI-H) PHENOTYPE REPORTED GREATER PAIN (ODDS RATIO [OR], 3.06; 95% CONFIDENCE INTERVAL [CI], 1.61-5.84), FATIGUE (OR, 2.78; 95% CI, 1.41-5.49), SLEEP (OR, 2.52; 95% CI, 1.32-4.08); AND DROWSINESS (OR, 2.51; 95% CI, 1.32-4.78) COMPARED WITH MICROSATELLITE STABLE PATIENTS. PATIENTS WITH AN MSI-H PHENOTYPE ALSO HAD GREATER ODDS OF OVERALL SYMPTOM BURDEN (OR, 2.48; 95% CI, 1.29-4.74) COMPARED WITH MICROSATELLITE STABLE PATIENTS. THE CIMP-HIGH PATIENTS EXPERIENCED GREATER ODDS OF PAIN COMPARED WITH THE CIMP-NEGATIVE PATIENTS (OR, 1.72; 95% CI, 1.06-2.80). A GREATER OVERALL SYMPTOM BURDEN WAS ASSOCIATED WITH POOR OVERALL SURVIVAL (HAZARD RATIO, 1.42; 95% CI, 0.98-2.06]), ALTHOUGH THE DIFFERENCE WAS NOT SIGNIFICANT (P = .06). CONCLUSION: CORRELATION OF MSI-H-ASSOCIATED TUMOR FEATURES WITH THE SYMPTOM BURDEN COULD HELP PROVIDE A BETTER UNDERSTANDING OF UNDERLYING MECHANISMS ASSOCIATED WITH OUR FINDINGS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7  511  37 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	
                                                                                                                                                                                                   
8 6248  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
9 3907  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
10 6832  30 [HYPOMETHYLATION OF TNF-ALPHA GENE PROMOTER IN THE PATIENTS WITH ACUTE-ON-CHRONIC HEPATITIS B LIVER FAILURE]. OBJECTIVE: THE PRESENT STUDY WAS DESIGNED TO INVESTIGATE THE POSSIBLE EPIGENETIC ALTERATION IN THE PROMOTER OF TNF-ALPHA IN THE PATIENTS WITH ACUTE-ON-CHRONIC HEPATITIS B LIVER FAILURE (ACHBLF). METHODS: THE METHYLATION OF TNF-ALPHA PROMOTER IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WAS MEASURED BY METHYLATION SPECIFIC PCR (MSP). THE LEVEL OF SERUM TNF-ALPHA WAS DETERMINED BY ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA). MODEL FOR END-STAGE LIVER DISEASE (MELD) WAS PERFORMED FOR THE EVALUATION OF LIVER FAILURE. RESULTS: THE SERUM LEVEL OF TNF-ALPHA IN PATIENTS WITH ACHBLF(44.9260 +/- 26.48523) WAS HIGHER THAN THAT IN CHB (18.92505 +/- 9.04461) AND HEALTHY CONTROLS (11.9172 +/- 5.04612) (P < 0.05). MOREOVER, THE SERUM TNF-ALPHA LEVEL WAS SIGNIFICANTLY DECREASED IN METHYLATION GROUP AS COMPARED TO UNMETHYLAITON GROUP IN PATIENTS WITH ACHBLF (P < 0.05). MELD WAS NOT SIGNIFICANTLY DIFFERENT BETWEEN METHYLATED AND UNMETHYLATED GROUP OF ACHBLF PATIENTS (P > 0.05). IN ADDITION, THE SERUM LEVEL OF TNF-ALPHA WAS FOUND TO BE POSITIVELY CORRELATED WITH SERUM TOTAL BILIRUBIN (R = 0.891, P < 0.01) AND MELD SCORE (R = 0.792, P < 0.01), BUT TO BE NEGATIVELY CORRELATED WITH PROTHROMBIN ACTIVITY (R = - 0.511, P < 0.05) IN PATIENTS WITH ACHBLF. CONCLUSION: THE TNF-ALPHA METHYLATION PATTEN IS STABLE FOR THE LIVER FAILURE, SUGGESTING THE EFFECT OF ENVIRONMENT ON METHYLATION.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11 2626  35 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
12 5621  27 SCREENING METHYLATION OF DNA REPAIR GENES IN THE ORAL MUCOSA OF CHRONIC SMOKERS. OBJECTIVE: THE AIM OF THIS STUDY WAS TO EVALUATE THE EPIGENETIC CHANGES IN THE PROCESS OF ORAL CARCINOGENESIS BY SCREENING THE METHYLATION OF REPAIR GENES IN CHRONIC SMOKERS. DESIGN: TWO GROUPS WERE FORMED: GROUP 1: 16 SMOKERS WITH CONSUMPTION OF 20 CIGARETTES/DAY FOR AT LEAST 10 YEARS; AND GROUP 2: 10 NON-SMOKING. EXFOLIATIVE CYTOLOGY OF THE TONGUE WAS PERFORMED, AND THE EXTRACTED DNA WAS TREATED BY ENZYMES. THE PCR ARRAY SYSTEM PERFORMED METHYLATION SCREENING TO EVALUATE 22 DNA REPAIR GENES, AND THE RESULTS WERE VALIDATED BY RT-QPCR FOR EACH GENE WITH METHYLATION LEVELS >/=10%. RESULTS: HIGHEST PERCENTAGES OF METHYLATION WERE OBSERVED FOR MLH3 AND XRCC1 GENES (11-20% METHYLATION) AND IN ONE CASE FOR MRE11A AND PMS2 (>50% METHYLATION). STATISTICAL ANALYSIS SHOWED SIGNIFICANT DIFFERENCES IN THE EXPRESSION OF THE GENES MRE11A (P = 0.0002), PMS2(P = 0.0068), XRCC1 (P = 0.0080) AND MLH3 (0.0057) BETWEEN THE TWO GROUPS. CONCLUSION: THE EFFECTS OF CHRONIC SMOKING ON ORAL MUCOSA LED TO THE METHYLATION OF GENES MRE11A PMS2, XRCC1 AND MLH3, BUT RESULTED IN A REDUCTION OF GENE EXPRESSION OF MRE11A AND PMS2, WHICH SHOWED >/=50% METHYLATION. THESE RESULTS PROVIDE EVIDENCE THAT SMOKING CAUSE METHYLATION AND REDUCED EXPRESSION OF REPAIR GENES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
13 2304  28 EPIGENETIC REGULATION OF CATHEPSIN L EXPRESSION IN CHRONIC MYELOID LEUKAEMIA. THE EXPRESSION AND SIGNIFICANCE OF CATHEPSIN L (CTSL) HAS BEEN EXTENSIVELY STUDIED IN SOLID TUMOURS. HOWEVER NO SUCH INFORMATION IN CHRONIC MYELOID LEUKAEMIA (CML) WAS AVAILABLE. WE INVESTIGATED THE ACTIVITY AND EXPRESSION OF THIS PROTEASE IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) OF 47 ADULT CML PATIENTS. THIRTY ADULTS SUFFERING FROM SYSTEMIC DISEASES AND 50 HEALTHY VOLUNTEERS SERVED AS CONTROLS. THE MRNA LEVELS OF CTSL, ITS SPECIFIC ENDOGENOUS INHIBITOR CYSTATIN C AND TRANSCRIPTIONAL UP-REGULATOR VASCULAR ENDOTHELIAL GROWTH FACTOR (VEGF) WERE QUANTITATED BY REAL-TIME QPCR. CTSL PROTEASE ACTIVITY AND ITS MRNA EXPRESSION WERE SIGNIFICANTLY HIGHER IN CML CHRONIC PHASE (CP) PATIENTS COMPARED TO CML ACCELERATED PHASE/BLAST CRISIS (AP/BC) PATIENTS AND CONTROLS (P</= 0.001). VEGF WHOSE EXPRESSION WAS MOST PRONOUNCED IN CP AND DECLINED (P</= 0.001) IN THE ADVANCED PHASES OF THE MALIGNANCY EXHIBITED A STRONG POSITIVE CORRELATION WITH CTSL EXPRESSION (R= 0.97; P</= 0.001). CYSTATIN C EXPRESSION WAS SIGNIFICANTLY LOWER (P</= 0.001) IN CML AND DISPLAYED INVERSE CORRELATION WITH CTSL (R=-0.713; P</= 0.001) ACTIVITY. CTSL PROMOTER WAS SIGNIFICANTLY HYPOMETHYLATED IN CML CP COMPARED TO CML AP/BC PATIENTS AS WELL AS CONTROLS. K562, A BC CML CELL LINE DISPLAYED CTSL ACTIVITY, EXPRESSION AND METHYLATION STATUS OF CTSL PROMOTER THAT WAS COMPARABLE TO CML AP/BC PATIENTS. TREATMENT OF THESE CELLS OR PBMCS ISOLATED FROM CML AP/BC PATIENTS WITH 5'-AZA-CYTIDINE RESULTED IN A DRAMATIC INCREASE IN CSTL ACTIVITY AND/OR EXPRESSION THEREBY DEMONSTRATING THE ROLE OF PROMOTER METHYLATION IN THE STAGE SPECIFIC EXPRESSION OF CTSL IN CML. DIFFERENTIAL EXPRESSION OF CTSL IN CML AT VARIOUS STAGES OF MALIGNANCY MAY PROVE USEFUL IN IDENTIFICATION OF THE HIGH-RISK PATIENTS THEREBY FACILITATING BETTER MANAGEMENT OF DISEASE.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 3168  39 GTPASE REGULATOR ASSOCIATED WITH THE FOCAL ADHESION KINASE (GRAF) TRANSCRIPT WAS DOWN-REGULATED IN PATIENTS WITH MYELOID MALIGNANCIES. BACKGROUND: GTPASE REGULATOR ASSOCIATED WITH THE FOCAL ADHESION KINASE (GRAF), A PUTATIVE TUMOR SUPPRESSOR GENE, IS FOUND INACTIVATED IN HEMATOPOIETIC MALIGNANCIES BY EITHER GENETIC OR EPIGENETIC ABNORMALITIES. HOWEVER, THE EXPRESSION LEVEL OF GRAF GENE HAS NOT YET BEEN STUDIED IN LEUKEMIA. THE AIM OF THIS STUDY WAS TO INVESTIGATE THE EXPRESSION LEVEL OF GRAF GENE IN THOSE PATIENTS WITH MYELOID MALIGNANCIES INCLUDING ACUTE MYELOID LEUKEMIA (AML), MYELODYSPLASTIC SYNDROME (MDS) AND CHRONIC MYELOID LEUKEMIA (CML). METHODS: THE EXPRESSION LEVELS OF GRAF TRANSCRIPT WERE DETERMINED IN 94 PATIENTS USING REAL-TIME QUANTITATIVE PCR (RQ-PCR). CLINICAL AND LABORATORY DATA OF THESE PATIENTS WERE COLLECTED AND ANALYZED. RESULTS: THE SIGNIFICANTLY DECREASED LEVEL OF GRAF TRANSCRIPT WAS OBSERVED IN THREE MYELOID MALIGNANCIES COMPARED TO CONTROLS. WITHIN AML, THERE WAS NO DIFFERENCE IN THE LEVEL OF GRAF TRANSCRIPT AMONG DIFFERENT FAB SUBTYPES (P > 0.05). DIFFERENCE WAS NOT OBSERVED IN THE AMOUNT OF GRAF MRNA BETWEEN CML AT CHRONIC PHASE AND CONTROLS. AS CML PROGRESSED, GRAF TRANSCRIPT SIGNIFICANTLY DECREASED. IN MDS, THREE CASES WITH 5Q DELETION HAD LOWER GRAF TRANSCRIPT THAN FOUR WITHOUT 5Q DELETION (MEDIAN 0.76 VS 2.99) (P > 0.05). CONCLUSION: OUR RESULTS DEMONSTRATE THAT THE GRAF TRANSCRIPT IS DECREASED IN MYELOID MALIGNANCIES.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
15 1991  34 EPIGENETIC ANALYSIS OF THE IFNLAMBDA3 GENE IDENTIFIES A NOVEL MARKER FOR RESPONSE TO THERAPY IN HCV-INFECTED SUBJECTS. CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IS CHARACTERIZED BY HIGH INTERINDIVIDUAL VARIABILITY IN RESPONSE TO PEGYLATED INTERFERON AND RIBAVIRIN. A GENETIC POLYMORPHISM ON CHROMOSOME 19 (RS12979860) UPSTREAM OF INTERFERON-LAMBDA3 (IFNLAMBDA3) IS ASSOCIATED WITH A TWOFOLD CHANGE IN SUSTAINED VIROLOGIC RESPONSE RATE AFTER 48 WEEKS OF TREATMENT WITH PEGYLATED INTERFERON/RIBAVIRIN IN HCV GENOTYPE 1 (GT1) TREATMENT-NAIVE PATIENTS. WE CONDUCTED EPIGENETIC ANALYSIS ON THE IFNLAMBDA3 PROMOTER TO INVESTIGATE WHETHER DNA METHYLATION IS ASSOCIATED WITH RESPONSE TO HCV THERAPY. DNA SAMPLES FROM HCV GT1-INFECTED SUBJECTS RECEIVING AN INTERFERON-FREE PARITAPREVIR-CONTAINING COMBINATION REGIMEN (N=540) AND FROM HCV-UNINFECTED, HEALTHY CONTROLS (N=124) WERE ANALYSED FOR IFNLAMBDA3 METHYLATION LEVELS. METHYLATION WAS STRONGLY ASSOCIATED WITH RS12979860 ALLELE STATUS WHETHER ADJUSTING FOR HCV STATUS (R=65.0%, 95% CI: [60.2%, 69.5%]), OR NOT (R=64.4%), BOTH WITH P<2.2X10(-16) . IN HCV GT1-INFECTED SUBJECTS, C/C GENOTYPES HAD SIGNIFICANTLY LOWER METHYLATION LEVELS RELATIVE TO C/T OR T/T GENOTYPES (P<1X10(-14) ), WITH EACH T ALLELE RESULTING IN A NINE-UNIT INCREASE IN MEAN METHYLATION LEVEL. METHYLATION LEVELS DID NOT CORRELATE WITH RESPONSE IN SUBJECTS TREATED FOR 12 OR 24 WEEKS. HOWEVER, NON-C/C SUBJECTS WITH HIGHER METHYLATION LEVELS WERE MORE LIKELY TO RELAPSE WHEN TREATMENT DURATION WAS 8 WEEKS. THIS ANALYSIS SUGGESTS THAT METHYLATION STATUS OF THE IFNLAMBDA3 PROMOTER REGION MAY BE A USEFUL PARAMETER THAT IDENTIFIES PATIENTS MORE LIKELY TO RELAPSE FOLLOWING HCV THERAPY; HOWEVER, CONTINUING THERAPY FOR A SUFFICIENT DURATION CAN OVERCOME THIS DIFFERENCE. THESE FINDINGS MAY PROVIDE MECHANISTIC INSIGHT INTO THE ROLE OF IFNLAMBDA3 GENETIC VARIANTS IN HCV TREATMENT RESPONSE.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
16 3484  34 IDENTIFICATION OF CHROMATIN REMODELING GENES ARID4A AND ARID4B AS LEUKEMIA SUPPRESSOR GENES. BACKGROUND: LEUKEMIA EVOLVES THROUGH A MULTISTEP PROCESS FROM PREMALIGNANCY TO MALIGNANCY. EPIGENETIC ALTERATIONS, INCLUDING HISTONE MODIFICATIONS, HAVE BEEN PROPOSED TO PLAY AN IMPORTANT ROLE IN TUMORIGENESIS. THE INVOLVEMENT OF TWO CHROMATIN REMODELING GENES, RETINOBLASTOMA-BINDING PROTEIN 1 (RBBP1/ARID4A) AND RBBP1-LIKE 1 (RBBP1L1/ARID4B), IN LEUKEMOGENESIS WAS NOT CHARACTERIZED. METHODS: THE LEUKEMIC PHENOTYPE OF MICE DEFICIENT FOR ARID4A WITH OR WITHOUT HAPLOINSUFFICIENCY FOR ARID4B WAS INVESTIGATED BY SERIALLY MONITORING COMPLETE BLOOD COUNTS TOGETHER WITH MICROSCOPIC HISTOLOGIC ANALYSIS AND FLOW CYTOMETRIC ANALYSIS OF BONE MARROW AND SPLEEN FROM THE ARID4A(-/-) MICE OR ARID4A(-/-)ARID4B(+/-) MICE. REGULATION IN BONE MARROW CELLS OF DOWNSTREAM GENES IMPORTANT FOR NORMAL HEMATOPOIESIS WAS ANALYZED BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION. GENOTYPIC EFFECTS ON HISTONE MODIFICATIONS WERE EXAMINED BY WESTERN BLOTTING AND IMMUNOFLUORESCENCE ANALYSIS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: YOUNG (2-5 MONTHS OLD) ARID4A-DEFICIENT MICE HAD INEFFECTIVE BLOOD CELL PRODUCTION IN ALL HEMATOPOIETIC LINEAGES. BEYOND 5 MONTHS OF AGE, THE ARID4A(-/-) MICE MANIFESTED MONOCYTOSIS, ACCOMPANIED BY SEVERE ANEMIA AND THROMBOCYTOPENIA. THESE SICK ARID4A(-/-) MICE SHOWED BONE MARROW FAILURE WITH MYELOFIBROSIS ASSOCIATED WITH SPLENOMEGALY AND HEPATOMEGALY. FIVE OF 42 ARID4A(-/-) MICE AND 10 OF 12 ARID4A(-/-)ARID4B(+/-) MICE PROGRESSED TO ACUTE MYELOID LEUKEMIA (AML) AND HAD RAPID FURTHER INCREASES OF LEUKOCYTE COUNTS. EXPRESSION OF HOX GENES (HOXB3, HOXB5, HOXB6, AND HOXB8) WAS DECREASED IN ARID4A-DEFICIENT BONE MARROW CELLS WITH OR WITHOUT ARID4B HAPLOINSUFFICIENCY, AND FOXP3 EXPRESSION WAS REDUCED IN ARID4A(-/-)ARID4B(+/-) BONE MARROW. INCREASES OF HISTONE TRIMETHYLATION OF H3K4, H3K9, AND H4K20 (FOLD INCREASES IN TRIMETHYLATION = 32, 95% CONFIDENCE INTERVAL [CI] = 27 TO 32; 45, 95% CI = 41 TO 49; AND 2.2, 95% CI = 1.7 TO 2.7, RESPECTIVELY) WERE OBSERVED IN THE BONE MARROW OF ARID4A-DEFICIENT MICE. CONCLUSIONS: ARID4A-DEFICIENT MICE INITIALLY DISPLAY INEFFECTIVE HEMATOPOIESIS, FOLLOWED BY TRANSITION TO CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML)-LIKE MYELODYSPLASTIC/MYELOPROLIFERATIVE DISORDER, AND THEN TRANSFORMATION TO AML. THE DISEASE PROCESSES IN THE ARID4A-DEFICIENT MICE ARE VERY SIMILAR TO THE COURSE OF EVENTS IN HUMANS WITH CMML AND AML. THIS MOUSE MODEL HAS THE POTENTIAL TO FURNISH ADDITIONAL INSIGHTS INTO THE ROLE OF EPIGENETIC ALTERATIONS IN LEUKEMOGENESIS, AND IT MAY BE USEFUL IN DEVELOPING NOVEL PHARMACOLOGICAL APPROACHES TO TREATMENT OF PRELEUKEMIC AND LEUKEMIC STATES.	2008	

17 1622  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18 1457  40 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	
                                                                                                                                             
19 6632  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
20 2390  30 EPIGENETIC REPRESSION OF CCDC37 AND MAP1B LINKS CHRONIC OBSTRUCTIVE PULMONARY DISEASE TO LUNG CANCER. INTRODUCTION: LUNG CANCER AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) SHARE ENVIRONMENTAL RISK FACTORS. COPD ALSO INCREASES THE RISK OF LUNG CANCER; HOWEVER, THE MOLECULAR MECHANISMS ARE UNCLEAR. METHODS: AN EPIGENOME-WIDE ASSOCIATION STUDY OF LUNG TUMORS AND CANCER-FREE LUNG TISSUE (CFLT) PAIRS FROM NON-SMALL-CELL LUNG CANCER CASES WITH (N = 18) OR WITHOUT (N = 17) COPD WAS CONDUCTED USING THE HUMANMETHYLATION450 BEADCHIP (HM450K). COPD-ASSOCIATED METHYLATION OF TOP-RANKED GENES WAS CONFIRMED IN A LARGER SAMPLE SET, INDEPENDENTLY VALIDATED, AND THEIR POTENTIAL AS SPUTUM-BASED BIOMARKERS WAS INVESTIGATED. RESULTS: METHYLATION OF CCDC37 AND MAP1B WAS MORE PREVALENT IN LUNG TUMORS FROM COPD THAN NON-COPD CASES [54 OF 71 (76%) VERSUS 20 OF 46 (43%), P = 0.0013] AND [48 OF 71 (68%) VERSUS 17 OF 46 (37%), P = 0.0035], RESPECTIVELY, AFTER ADJUSTMENT FOR AGE, SEX, SMOKING STATUS, AND TUMOR HISTOLOGY. HM450K PROBES ACROSS CCDC37 AND MAP1B PROMOTERS SHOWED HIGHER METHYLATION IN TUMORS THAN CFLT WITH THE HIGHEST METHYLATION SEEN IN TUMORS FROM COPD CASES (P < 0.05). THESE RESULTS WERE INDEPENDENTLY VALIDATED USING THE CANCER GENOME ATLAS DATA. CCDC37 METHYLATION WAS MORE PREVALENT IN SPUTUM FROM COPD THAN NON-COPD SMOKERS (P < 0.005) FROM TWO COHORTS. CCDC37 AND MAP1B EXPRESSION WAS DRAMATICALLY REPRESSED IN TUMORS AND CFLT FROM COPD THAN NON-COPD CASES, P LESS THAN 0.02. CONCLUSIONS: THE REDUCED EXPRESSION OF CCDC37 AND MAP1B ASSOCIATED WITH COPD LIKELY PREDISPOSES THESE GENES TO METHYLATION THAT IN TURN, MAY CONTRIBUTE TO LUNG CANCER.	2015