1 5289 166 PROSTANOID RECEPTOR GENES CONFER POOR PROGNOSIS IN HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA EPIGENETIC INACTIVATION. BACKGROUND: CHRONIC INFLAMMATION IS A RISK FACTOR FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AND OTHER DISEASES. PROSTANOID RECEPTORS ARE CLEARLY INVOLVED IN THE DEVELOPMENT OF MANY TYPES OF CANCER. HOWEVER, THEIR ROLE IS NOT SIMPLE AND IS POORLY UNDERSTOOD IN HNSCC. METHODS: METHYLATION PROFILES OF PROSTANOID RECEPTOR FAMILY GENES WERE GENERATED FOR TUMOUR SAMPLES OBTAINED FROM 274 PATIENTS WITH HNSCC, INCLUDING 69 HYPOPHARYNX, 51 LARYNX, 79 ORAL CAVITY, AND 75 OROPHARYNX TUMOUR SAMPLES, BY QUANTITATIVE METHYLATION-SPECIFIC PCR. PROMOTER METHYLATION WAS THEN EVALUATED WITH RESPECT TO VARIOUS CLINICAL CHARACTERISTICS AND PATIENT SURVIVAL. RESULTS: THE MEAN NUMBER OF METHYLATED GENES PER SAMPLE WAS 2.05 +/- 2.59 (RANGE 0 TO 9). PROMOTERS OF PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, AND TBXA2R WERE METHYLATED IN 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, AND 11.3% OF THE SAMPLES, RESPECTIVELY. METHYLATION INDICES FOR PROSTANOID RECEPTOR FAMILY GENES TENDED TO BE HIGHER AS THE NUMBER OF TET METHYLATION EVENTS INCREASED. PATIENTS WITH 5-9 METHYLATED GENES HAD A SIGNIFICANTLY LOWER SURVIVAL RATE THAN THAT OF PATIENTS WITH 0-4 METHYLATED GENES (LOG-RANK TEST, P= 0.007). IN MULTIVARIATE ANALYSES, PTGDR1 METHYLATION WAS MOST HIGHLY CORRELATED WITH RECURRENCE IN PATIENTS WITH HYPOPHARYNGEAL CANCER (P = 0.014). A SIMILAR CORRELATION WAS OBSERVED FOR PTGER4 IN PATIENTS WITH LARYNGEAL CANCER (P = 0.046). METHYLATION OF THE PTGIR AND TBXA2R PROMOTERS WAS POSITIVELY CORRELATED WITH RECURRENCE IN OROPHARYNGEAL CANCER (P = 0.028 AND P = 0.006, RESPECTIVELY). MOREOVER, PATIENTS WITH 5-9 METHYLATED GENES WERE EXTREMELY LOWER OF 5HMC LEVELS (P = 0.035) AND WAS CORRELATED WITH INCREASING EXPRESSION OF DNMT3A AND DNMT3B (P < 0.05 AND P < 0.05, RESPECTIVELY). CONCLUSION: WE CHARACTERISED THE RELATIONSHIP BETWEEN THE METHYLATION STATUS OF PROSTANOID RECEPTOR GENES AND RECURRENCE IN HNSCC. THESE RESULTS PROVIDE NEW PERSPECTIVES FOR THE DEVELOPMENT OF MOLECULAR TARGETED TREATMENT APPROACHES.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                  
2  145  40 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
3 5621  30 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 2390  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
5 2626  37 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
6 1624  36 DNA-METHYLOME-BASED TUMOR HYPOXIA CLASSIFIER IDENTIFIES HPV-NEGATIVE HEAD AND NECK CANCER PATIENTS AT RISK FOR LOCOREGIONAL RECURRENCE AFTER PRIMARY RADIOCHEMOTHERAPY. PURPOSE: TUMOR HYPOXIA IS A PARADIGMATIC NEGATIVE PROGNOSTICATOR OF TREATMENT RESISTANCE IN HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC). THE LACK OF ROBUST AND RELIABLE HYPOXIA CLASSIFIERS LIMITS THE ADAPTATION OF STRATIFIED THERAPIES. WE HYPOTHESIZED THAT THE TUMOR DNA METHYLATION LANDSCAPE MIGHT INDICATE EPIGENETIC REPROGRAMMING INDUCED BY CHRONIC INTRATUMORAL HYPOXIA. EXPERIMENTAL DESIGN: A DNA-METHYLOME-BASED TUMOR HYPOXIA CLASSIFIER (HYPOXIA-M) WAS TRAINED IN THE TCGA (THE CANCER GENOME ATLAS)-HNSCC COHORT BASED ON MATCHED ASSIGNMENTS USING GENE EXPRESSION-BASED SIGNATURES OF HYPOXIA (HYPOXIA-GES). HYPOXIA-M WAS VALIDATED IN A MULTICENTER DKTK-ROG TRIAL CONSISTING OF HUMAN PAPILLOMAVIRUS (HPV)-NEGATIVE PATIENTS WITH HNSCC TREATED WITH PRIMARY RADIOCHEMOTHERAPY (RCHT). RESULTS: ALTHOUGH HYPOXIA-GES FAILED TO STRATIFY PATIENTS IN THE DKTK-ROG, HYPOXIA-M WAS INDEPENDENTLY PROGNOSTIC FOR LOCAL RECURRENCE (HR, 4.3; P = 0.001) AND OVERALL SURVIVAL (HR, 2.34; P = 0.03) BUT NOT DISTANT METASTASIS AFTER RCHT IN BOTH COHORTS. HYPOXIA-M STATUS WAS INVERSELY ASSOCIATED WITH CD8 T-CELL INFILTRATION IN BOTH COHORTS. HYPOXIA-M WAS FURTHER PROGNOSTIC IN THE TCGA-PANCANCER COHORT (HR, 1.83; P = 0.04), UNDERSCORING THE BREADTH OF THIS CLASSIFIER FOR PREDICTING TUMOR HYPOXIA STATUS. CONCLUSIONS: OUR FINDINGS HIGHLIGHT AN UNEXPLORED AVENUE FOR DNA METHYLATION-BASED CLASSIFIERS AS BIOMARKERS OF TUMORAL HYPOXIA FOR IDENTIFYING HIGH-RISK FEATURES IN PATIENTS WITH HNSCC TUMORS. SEE RELATED COMMENTARY BY HEFT NEAL AND BRENNER, P. 2954.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
7 6248  28 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
8  388  37 AN INTEGRATED ANALYSIS OF SOCS1 DOWN-REGULATION IN HBV INFECTION-RELATED HEPATOCELLULAR CARCINOMA. PERSISTENT INFLAMMATION TOGETHER WITH GENETIC/EPIGENETIC ABERRATIONS IS STRONGLY ASSOCIATED WITH CHRONIC HEPATITIS B VIRUS (HBV) INFECTION-RELATED HEPATOCARCINOGENESIS. HERE, WE INVESTIGATED THE ALTERATIONS OF THE SUPPRESSOR OF CYTOKINE SIGNALLING (SOCS) FAMILY GENES IN HBV-RELATED HEPATOCELLULAR CARCINOMA (HCC). A TOTAL OF 116 PATIENTS WITH HCC WERE ENROLLED IN THIS STUDY. THE METHYLATION STATUSES OF SOCS1-7 AND CISH GENES WERE QUANTITATIVELY MEASURED AND CLINICOPATHOLOGICAL SIGNIFICANCE OF SOCS1 METHYLATION WAS STATISTICALLY ANALYSED. THE GENE COPY NUMBER VARIATION WAS ASSAYED BY ACGH. LUCIFERASE REPORTER ASSAY AND WESTERN BLOT WERE USED TO DETECT THE INVOLVEMENT OF SOCS1 IN P53 SIGNALLING. WE FOUND HIGH FREQUENCIES OF SOCS1 GENE HYPERMETHYLATION IN BOTH TUMOUR (56.03%) AND ADJACENT NONTUMOUR TISSUES (54.31%), BUT TUMOUR TISSUES EXHIBITED INCREASED METHYLATION INTENSITY (24.01% VS 13.11%, P < 0.0001), PARTICULARLY IN PATIENTS WITH LARGER TUMOUR SIZE OR CIRRHOSIS BACKGROUND (P < 0.0001). IN ADDITION, THE FREQUENCY AND INTENSITY OF SOCS1 HYPERMETHYLATION IN TUMOUR TISSUES WERE BOTH SIGNIFICANTLY HIGHER THAN THOSE IN NONTUMOUR TISSUES IN MALE GENDER PATIENTS AND IN PATIENTS >/=45 YEARS OLD (P = 0.0214 AND P < 0.0001, P = 0.0232 AND P < 0.0001, RESPECTIVELY). SOCS1 GENE DELETION WAS FOUND IN 8 OF 25 ACGH ASSAYED TUMOUR SPECIMENS, WHICH WAS ASSOCIATED WITH LOWER SOCS1 MRNA EXPRESSION (P = 0.0448). FURTHERMORE, ECTOPIC SOCS1 OVEREXPRESSION COULD ACTIVATE THE P53 SIGNALLING PATHWAY IN HCC CELL LINES. HYPERMETHYLATION OF SOCS2-7 AND CISH GENES WAS SELDOM FOUND IN HCC. OUR RESULTS SUGGESTED THAT THE GENE LOSS AND EPIGENETIC SILENCING OF SOCS1 WERE STRONGLY ASSOCIATED WITH HBV-RELATED HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9 1457  43 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	

10   11  38 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11 6832  32 [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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12 3168  38 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13 2304  37 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 1990  31 EPIGENETIC ANALYSIS OF PAGET'S DISEASE OF BONE IDENTIFIES DIFFERENTIALLY METHYLATED LOCI THAT PREDICT DISEASE STATUS. PAGET'S DISEASE OF BONE (PDB) IS CHARACTERIZED BY FOCAL INCREASES IN DISORGANIZED BONE REMODELING. THIS STUDY AIMS TO CHARACTERIZE PDB-ASSOCIATED CHANGES IN DNA METHYLATION PROFILES IN PATIENTS' BLOOD. META-ANALYSIS OF DATA FROM THE DISCOVERY AND CROSS-VALIDATION SET, EACH COMPRISING 116 PDB CASES AND 130 CONTROLS, REVEALED SIGNIFICANT DIFFERENCES IN DNA METHYLATION AT 14 CPG SITES, 4 CPG ISLANDS, AND 6 GENE-BODY REGIONS. THESE LOCI, INCLUDING TWO CHARACTERIZED AS FUNCTIONAL THROUGH EXPRESSION QUANTITATIVE TRAIT-METHYLATION ANALYSIS, WERE ASSOCIATED WITH FUNCTIONS RELATED TO OSTEOCLAST DIFFERENTIATION, MECHANICAL LOADING, IMMUNE FUNCTION, AND VIRAL INFECTION. A MULTIVARIATE CLASSIFIER BASED ON DISCOVERY SAMPLES WAS FOUND TO DISCRIMINATE PDB CASES AND CONTROLS FROM THE CROSS-VALIDATION WITH A SENSITIVITY OF 0.84, SPECIFICITY OF 0.81, AND AN AREA UNDER CURVE OF 92.8%. IN CONCLUSION, THIS STUDY HAS SHOWN FOR THE FIRST TIME THAT EPIGENETIC FACTORS CONTRIBUTE TO THE PATHOGENESIS OF PDB AND MAY OFFER DIAGNOSTIC MARKERS FOR PREDICTION OF THE DISEASE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15 3956  42 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	
                                                                                                                                                                                                                                                                                                              
16 4220  35 METHYLATED CYSTEINE DIOXYGENASE-1 GENE PROMOTER IN THE SERUM IS A POTENTIAL BIOMARKER FOR HEPATITIS B VIRUS-RELATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. EPIGENETIC ANALYSIS HAS ATTRACTED INCREASING ATTENTION IN THE MOLECULAR DIAGNOSIS OF HCC. CYSTEINE DIOXYGENASE 1 (CDO1) IS A KEY ENZYME IN THE TAURINE BIOSYNTHETIC PATHWAY AND CONVERTS CYSTEINE TO CYSTEINE SULFINATE. THE CDO1 GENE IS A TUMOR SUPPRESSOR GENE AND IS USUALLY SILENCED BY THE METHYLATION OF ITS PROMOTER IN CARCINOGENESIS. IN THIS STUDY, WE EVALUATED WHETHER THE METHYLATION STATUS OF CDO1 GENE PROMOTER IS OF DIAGNOSTIC VALUE FOR HEPATITIS B VIRUS (HBV)-RELATED HCC. THE CDO1 PROMOTER METHYLATION STATUS WAS DETERMINED IN SERUM SAMPLES USING METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) IN A COHORT OF 123 PATIENTS WITH HBV-RELATED HCC, 28 WITH LIVER CIRRHOSIS (LC), 29 WITH CHRONIC HEPATITIS B (CHB) AND 20 HEALTHY CONTROLS. THE FREQUENCY OF THE CDO1 PROMOTER METHYLATION IN HBV-RELATED HCC (42.3%) WAS SIGNIFICANTLY HIGHER THAN THAT IN LC (14.3%), CHB (6.9%) AND HEALTHY CONTROLS (0%) (P = 0.006; P < 0.0001; P < 0.0001; RESPECTIVELY). FURTHERMORE, IN HCC PATIENTS, THE FREQUENCY OF CDO1 PROMOTER METHYLATION WAS HIGHER IN ADVANCED STAGES (III-IV) (53%) THAN THE EARLY STAGES (I-II) (20%) (P = 0.001). EVALUATION OF THE CDO1 PROMOTER METHYLATION STATUS IN SERUM, IN COMBINATION WITH AFP (> 20 NG/ML), SIGNIFICANTLY IMPROVED THE DIAGNOSTIC VALUE, WITH SENSITIVITY AND SPECIFICITY OF 82.9% AND 75.4%, RESPECTIVELY IN DISTINGUISHING HCC FROM LC AND CHB. IN CONCLUSION, METHYLATION STATUS OF SERUM CDO1 GENE PROMOTER MAY BE HELPFUL IN THE DIAGNOSIS OF HCC AND THE ESTIMATION OF THE HCC STAGES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
17 3125  28 GHSR DNA HYPERMETHYLATION IS A COMMON EPIGENETIC ALTERATION OF HIGH DIAGNOSTIC VALUE IN A BROAD SPECTRUM OF CANCERS. IDENTIFICATION OF A SINGLE MOLECULAR TRAIT THAT IS DETERMINANT OF COMMON MALIGNANCIES MAY SERVE AS A POWERFUL DIAGNOSTIC SUPPLEMENT TO CANCER TYPE-SPECIFIC MARKERS. HERE, WE REPORT A DNA METHYLATION MARK THAT IS CHARACTERISTIC OF SEVEN STUDIED MALIGNANCIES, NAMELY CANCERS OF LUNG, BREAST, PROSTATE, PANCREAS, COLORECTUM, GLIOBLASTOMA AND B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) (N = 137). THIS MARK WAS DEFINED BY SUBSTANTIAL HYPERMETHYLATION AT THE PROMOTER AND FIRST EXON OF GROWTH HORMONE SECRETAGOUGE RECEPTOR (GHSR) THROUGH BISULFITE PYROSEQUENCING. THE DEGREE OF ABERRANT METHYLATION WAS CAPABLE OF ACCURATE DISCRIMINATION BETWEEN CANCER AND CONTROL SAMPLES. THE HIGHEST SENSITIVITY AND SPECIFICITY OF CANCER DETECTION WAS ACHIEVED FOR CANCERS OF PANCREAS, LUNG, BREAST AND CLL YIELDING THE AREA UNDER THE CURVE (AUC) VALUES OF 1.0000, 0.9952, 0.9800 AND 0.9400, RESPECTIVELY. NARROWING TO A SINGLE CPG SITE WITHIN THE GENE'S PROMOTER OR FOUR CONSECUTIVE CPG UNITS OF THE HIGHEST METHYLATION LEVELS WITHIN THE FIRST EXON IMPROVED THE DETECTION POWER. GHSR HYPERMETHYLATION WAS DETECTED ALREADY AT THE EARLY STAGE TUMORS. THE ACCURATE PERFORMANCE OF THIS MARKER WAS FURTHER REPLICATED IN AN INDEPENDENT SET OF PANCREATIC CANCER AND CONTROL SAMPLES (N = 78). THESE FINDINGS SUPPORT THE CANDIDATURE OF GHSR METHYLATION AS A HIGHLY ACCURATE PAN-CANCER MARKER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
18 1622  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
19 2761  34 EXPRESSION OF TESTIS-SPECIFIC GENES, TEX101 AND ODF4, IN CHRONIC MYELOID LEUKEMIA AND EVALUATION OF TEX101 IMMUNOGENICITY. BACKGROUND AND OBJECTIVES: CANCER-TESTIS (CT) ANTIGENS ARE A GROUP OF ANTIGENS WITH A RESTRICTED EXPRESSION IN NORMAL TISSUES, EXCEPT TESTIS, AND THEY HAVE ABERRANT EXPRESSION IN DIFFERENT TUMORS. THIS PATTERN OF EXPRESSION HAS MADE THEM PROMISING TARGETS FOR IMMUNOTHERAPY AND CANCER DETECTION. OUR AIM WAS TO FIND NEW MEMBERS OF THIS GROUP THAT MIGHT BE USEFUL AS MARKERS IN THE DETECTION OF CANCER AND IMMUNOTHERAPY. DESIGN AND SETTING: A DESCRIPTIVE STUDY CONDUCTED IN REFERRAL CENTERS OF TEHRAN UNIVERSITY OF MEDICAL SCIENCE FROM JANUARY 2008 TO JANUARY 2009. PATIENTS AND METHODS: WE ANALYZED THE EXPRESSION OF TWO TESTIS-SPECIFIC GENES NAMED ODF4 (OUTER DENSE FIBER OF SPERM TAILS 4) AND TEX101 (TESTIS EXPRESSED 101) IN 20 CHRONIC MYELOID LEUKEMIA (CML) AND 20 NORMAL SAMPLES BY REVERSE TRANSCRIPTION-POLYMERASE CHAIN REACTION AND SEQUENCING. IMMUNOGENICITY OF TEX101 WAS EVALUATED BY MEANS OF ENZYME-LINKED IMMUNOSORBENT ASSAY. RESULTS: THESE TWO GENES WERE EXPRESSED IN 30% OF CML PATIENTS BUT NOT IN ANY OF THE HEALTHY DONORS. HUMORAL RESPONSE AGAINST TEX101 WAS NOT DETECTED IN ANY SAMPLES. CONCLUSIONS: TEX101 AND ODF4 ARE CT GENES USEFUL FOR DETECTION OF CML. UNLIKE MANY CT GENES, OVEREXPRESSION OF TEX101 WAS NOT SHOWN TO INDUCE IMMUNOLOGIC RESPONSES IN THESE SAMPLES. ACCORDING TO THE PREVIOUS STUDIES, OVEREXPRESSION OF TEX101 LEADS TO SUPPRESSION OF CANCER INVASION AND METASTASIS; THUS, THE INDUCTION OF THE EXPRESSION OF TEX101 IN CANCER BY EPIGENETIC MECHANISMS MAY BE A TREATMENT STRATEGY.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
20 4225  30 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