1   401 153 ANALYSIS OF ABERRANT METHYLATION ON PROMOTER SEQUENCES OF TUMOR SUPPRESSOR GENES AND TOTAL DNA IN SPUTUM SAMPLES: A PROMISING TOOL FOR EARLY DETECTION OF COPD AND LUNG CANCER IN SMOKERS. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A DISORDER ASSOCIATED TO CIGARETTE SMOKE AND LUNG CANCER (LC). SINCE EPIGENETIC CHANGES IN ONCOGENES AND TUMOR SUPPRESSOR GENES (TSGS) ARE CLEARLY IMPORTANT IN THE DEVELOPMENT OF LC. IN THIS STUDY, WE HYPOTHESIZE THAT TOBACCO SMOKERS ARE SUSCEPTIBLE FOR METHYLATION IN THE PROMOTER REGION OF TSGS IN AIRWAY EPITHELIAL CELLS WHEN COMPARED WITH NON-SMOKER SUBJECTS. THE PURPOSE OF THIS STUDY WAS TO INVESTIGATE THE USEFULNESS OF DETECTION OF GENES PROMOTER METHYLATION IN SPUTUM SPECIMENS, AS A COMPLEMENTARY TOOL TO IDENTIFY LC BIOMARKERS AMONG SMOKERS WITH EARLY COPD. METHODS: WE DETERMINED THE AMOUNT OF DNA IN INDUCED SPUTUM FROM PATIENTS WITH COPD (N = 23), LC (N = 26), AS WELL AS IN HEALTHY SUBJECTS (CTR) (N = 33), USING A COMMERCIAL KIT FOR DNA PURIFICATION, FOLLOWED BY ABSORBANCE MEASUREMENT AT 260 NM. THE FREQUENCY OF CDKN2A, CDH1 AND MGMT PROMOTER METHYLATION IN THE SAME GROUPS WAS DETERMINED BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP). THE FISHER'S EXACT TEST WAS EMPLOYED TO COMPARE FREQUENCY OF RESULTS BETWEEN DIFFERENT GROUPS. RESULTS: DNA CONCENTRATION WAS 7.4 AND 5.8 TIMES HIGHER IN LC AND COPD COMPARED TO THE (CTR) (P < 0.0001), RESPECTIVELY. METHYLATION STATUS OF CDKN2A AND MGMT WAS SIGNIFICANTLY HIGHER IN COPD AND LC PATIENTS COMPARED WITH CTR GROUP (P < 0.0001). FREQUENCY OF CDH1 METHYLATION ONLY SHOWED A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN LC PATIENTS AND CTR GROUP (P < 0.05). CONCLUSIONS: WE PROVIDE EVIDENCE THAT ABERRANT METHYLATION OF TSGS IN SAMPLES OF INDUCED SPUTUM IS A USEFUL TOOL FOR EARLY DIAGNOSTIC OF LUNG DISEASES (LC AND COPD) IN SMOKER SUBJECTS. VIRTUAL SLIDES: THE ABSTRACT MUST FINISH WITH THE FOLLOWING TEXT: VIRTUAL SLIDES THE VIRTUAL SLIDE(S) FOR THIS ARTICLE CAN BE FOUND HERE: HTTP://WWW.DIAGNOSTICPATHOLOGY.DIAGNOMX.EU/VS/1127865005664160.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2   700  23 BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4): A KEY PLAYER IN INFLAMMATORY BOWEL DISEASE AND POTENTIAL TO INSPIRE EPIGENETIC THERAPEUTICS. INTRODUCTION: INFLAMMATORY BOWEL DISEASES (IBDS) ARE DEBILITATING CHRONIC INFLAMMATORY DISORDERS WITH INCREASING PREVALENCE WORLDWIDE. EPIGENETIC REGULATOR BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4) IS CRITICAL IN CONTROLLING GENE EXPRESSION OF IBD-ASSOCIATED INFLAMMATORY CYTOKINE NETWORKS. BRD4 AS A PROMISING THERAPEUTIC TARGET IS ALSO TIGHTLY ASSOCIATED WITH MANY OTHER DISEASES, SUCH AS AIRWAY INFLAMMATION AND FIBROSIS, CANCERS, INFECTIOUS DISEASES AND CENTRAL NERVOUS SYSTEM DISORDERS. AREAS COVERED: THIS REVIEW BRIEFLY SUMMARIZED THE CRITICAL ROLE OF BRD4 IN THE PATHOGENESIS OF IBDS AND THE CURRENT CLINICAL LANDSCAPE OF DEVELOPING BROMODOMAIN AND EXTRA TERMINAL DOMAIN (BET) INHIBITORS. THE CHALLENGES AND OPPORTUNITIES AS WELL AS FUTURE DIRECTIONS OF TARGETING BRD4 INHIBITION FOR POTENTIAL IBD MEDICATIONS WERE ALSO DISCUSSED. EXPERT OPINION: TARGETING BRD4 WITH POTENT AND SPECIFIC INHIBITORS MAY OFFER NOVEL EFFECTIVE THERAPEUTICS FOR IBD PATIENTS, PARTICULARLY THOSE WHO ARE REFRACTORY TO ANTI-TNFALPHA THERAPY AND IBD-RELATED PROFIBROTIC. DEVELOPING HIGHLY SPECIFIC BRD4 INHIBITORS FOR IBD MEDICATIONS MAY HELP ERASE THE DRAWBACKS OF MOST CURRENT PAN-BET/BRD4 INHIBITORS, SUCH AS OFF-TARGET EFFECTS, POOR ORAL BIOAVAILABILITY, AND LOW GUT MUCOSAL ABSORBANCE. NOVEL STRATEGIES SUCH AS COMBINATORIAL THERAPY, BRD4-BASED DUAL INHIBITORS AND PROTEOLYSIS TARGETING CHIMERAS (PROTACS) MAY ALSO HAVE GREAT POTENTIAL TO MITIGATE SIDE EFFECTS AND OVERCOME DRUG RESISTANCE DURING IBD TREATMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
3  2018  50 EPIGENETIC CHANGE (GATA-4 GENE METHYLATION) IS ASSOCIATED WITH HEALTH STATUS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. GENE METHYLATION IS AN EPIGENETIC CHANGE THAT INVOLVES A HERITABLE MODIFICATION OF CHROMATIN STRUCTURE THAT ALTERS GENE EXPRESSION WITHOUT A CHANGE IN DNA SEQUENCE. IT HAS PREVIOUSLY BEEN SHOWN THAT METHYLATION OF THE GATA-4 GENE PROMOTER REGION IN SPUTUM DNA IS ASSOCIATED WITH LOW LUNG FUNCTION AND INCREASED ODDS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AMONG SMOKERS. GIVEN THESE FINDINGS, WE HYPOTHESIZED THAT GATA-4 GENE METHYLATION IN SPUTUM DNA WOULD BE ASSOCIATED WITH LOW HEALTH STATUS, AS MEASURED BY THE ST. GEORGE'S RESPIRATORY QUESTIONNAIRE (SGRQ), IN SUBJECTS WITH COPD. SELF-REPORTED SGRQ, SPIROMETRY, AND INDUCED SPUTUM SAMPLES WERE OBTAINED FROM 168 COPD SUBJECTS FROM THE LOVELACE SMOKERS COHORT. GATA-4 GENE METHYLATION WAS EVALUATED IN SPUTUM DNA USING NESTED METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) ASSAYS. USING GENERAL LINEAR MODEL WITH POISSON REGRESSION, WE FOUND THAT GATA-4 GENE METHYLATION WAS SIGNIFICANTLY ASSOCIATED WITH OVERALL LOWER SGRQ HEALTH STATUS (PARAMETER ESTIMATE = .296, P < .001). THIS FINDING REMAINED SIGNIFICANT EVEN AFTER CONTROLLING FOR AGE, LUNG FUNCTION, AND OTHER COVARIATES. IN AN ADDITIONAL ANALYSIS USING LOGISTIC REGRESSION AND COMPARING EXTREME TERTILES OF OVERALL SGRQ SCORE, WE CONFIRMED THAT GATA-4 GENE METHYLATION WAS ASSOCIATED WITH A 3-FOLD INCREASE IN RISK OF POOR HEALTH STATUS (OR 2.95 AND P = .028). THE UNEXPLORED LINKS BETWEEN EPIGENETIC CHANGES AND PSYCHOSOCIAL FACTORS SUCH AS HEALTH STATUS ARE CRITICAL GAPS IN THE LITERATURE. THIS STUDY IS THE FIRST TO SUGGEST THAT AIRWAY GATA-4 GENE METHYLATION STATUS MAY INDEPENDENTLY PREDICT HEALTH STATUS IN INDIVIDUALS WITH COPD.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
4  3294  39 HIGH INCIDENCE OF MGMT AND RARBETA PROMOTER METHYLATION IN PRIMARY GLIOBLASTOMAS: ASSOCIATION WITH HISTOPATHOLOGICAL CHARACTERISTICS, INFLAMMATORY MEDIATORS AND CLINICAL OUTCOME. GLIOBLASTOMAS, THE MOST FREQUENT PRIMARY BRAIN TUMORS IN ADULTS, ARE CHARACTERIZED BY A HIGHLY AGGRESSIVE, INFLAMMATORY AND ANGIOGENIC PHENOTYPE. METHYLATION OF CPG ISLANDS IN CANCER-RELATED GENES MAY SERVE AS AN EPIGENETIC BIOMARKER FOR GLIOBLASTOMA DIAGNOSIS AND PROGNOSIS. THE AIM OF THIS STUDY WAS TO ANALYZE THE METHYLATION STATUS OF FOUR CRITICAL TUMOR-ASSOCIATED GENES (MGMT, RARBETA, RASSF1A, CDH13), AND INVESTIGATE POSSIBLE LINKS WITH INFLAMMATORY (INTERLEUKIN [IL]-6, IL-8) AND ANGIOGENIC MEDIATORS (VASCULAR ENDOTHELIAL GROWTH FACTOR [VEGF], CYCLOOXYGENASE [COX]-2) AND CLINICAL OUTCOME IN 23 GLIOMA SAMPLES (6 GRADE II ASTROCYTOMAS, 17 GRADE IV GLIOBLASTOMAS). RARBETA AND MGMT GENES WERE MORE FREQUENTLY METHYLATED IN 70.58% AND 58.8% OF GLIOBLASTOMAS, RESPECTIVELY. RASSF1A AND CDH13 DISPLAYED A SIMILAR METHYLATION FREQUENCY (23.52%) IN GLIOBLASTOMAS. NO GENE METHYLATION WAS OBSERVED IN GRADE II ASTROCYTOMAS. TUMOR GRADE CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION (P = 0.005 AND P = 0.019, RESPECTIVELY) AND THE EXTENT OF NECROSIS (P = 0.001 AND P = 0.003). INTERESTINGLY, THE MARKER OF CHRONIC INFLAMMATION, IL-6, WAS POSITIVELY ASSOCIATED WITH METHYLATION OF MGMT (P = 0.004), RARBETA (P = 0.002), AND RASSF1A (P = 0.0081) AS WELL AS THE TOTAL NUMBER OF METHYLATED GENES (P < 0.0001), INDICATING THE IMPORTANT ROLE OF IL-6 IN MAINTAINING PROMOTER METHYLATION OF THESE GENES. VEGF EXPRESSION CORRELATED POSITIVELY WITH MGMT AND RARBETA METHYLATION ALTHOUGH THESE RELATIONSHIPS WERE OF MARGINAL SIGNIFICANCE (P = 0.0679 AND P = 0.0757). KAPLAN-MEIER UNIVARIATE SURVIVAL ANALYSIS INDICATED AN UNFAVORABLE SURVIVAL PERIOD IN PATIENTS WITH MGMT METHYLATION COMPARED WITH THOSE WITHOUT METHYLATION (P = 0.0474). OUR STUDY HIGHLIGHTS THE IMPLICATION OF MGMT AND RARBETA METHYLATION IN THE AGGRESSIVE PHENOTYPE OF PRIMARY GLIOBLASTOMAS. THE ASSOCIATION OF MGMT METHYLATION WITH CLINICAL OUTCOME INDICATES ITS POTENTIAL PROGNOSTIC VALUE.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
5  3497  59 IDENTIFICATION OF NOVEL EPIGENETIC ABNORMALITIES AS SPUTUM BIOMARKERS FOR LUNG CANCER RISK AMONG SMOKERS AND COPD PATIENTS. OBJECTIVES: SMOKING IS A COMMON RISK FACTOR FOR CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. ALTHOUGH COPD PATIENTS HAVE HIGHER RISK OF LUNG CANCER COMPARED TO NON-COPD SMOKERS, THE MOLECULAR LINKS BETWEEN THESE DISEASES ARE NOT WELL-DEFINED. THIS STUDY AIMS TO IDENTIFY GENES THAT ARE DOWNREGULATED BY CIGARETTE SMOKE AND COMMONLY REPRESSED IN COPD AND LUNG CANCER. MATERIALS AND METHODS: PRIMARY HUMAN AIRWAY EPITHELIAL CELLS (HAEC) WERE EXPOSED TO CIGARETTE-SMOKE-EXTRACT (CSE) FOR 10-WEEKS AND SIGNIFICANTLY SUPPRESSED GENES WERE IDENTIFIED BY TRANSCRIPTOME ARRAY. EPIGENETIC ABNORMALITIES OF THESE GENES IN LUNG ADENOCARCINOMA (LUAD) FROM PATIENTS WITH OR WITHOUT COPD WERE DETERMINED USING GENOME-WIDE AND GENE-SPECIFIC ASSAYS AND BY IN VITRO TREATMENT OF CELL LINES WITH TRICHOSTATIN-A OR 5-AZA-2-DEOXYCYTIDINE. RESULTS: THE TEN MOST COMMONLY DOWNREGULATED GENES FOLLOWING CHRONIC CSE EXPOSURE OF HAEC AND SHOW PROMOTER HYPERMETHYLATION IN LUAD WERE SELECTED. AMONG THESE, EXPRESSION OF CCNA1, SNCA, AND ZNF549 WAS SIGNIFICANTLY REDUCED IN LUNG TISSUES FROM COPD COMPARED WITH NON-COPD CASES WHILE EXPRESSION OF CCNA1 AND SNCA WAS FURTHER DOWNREGULATED IN TUMORS WITH COPD. THE PROMOTER REGIONS OF ALL THREE GENES WERE HYPERMETHYLATED IN LUAD BUT NOT NORMAL OR COPD LUNGS. THE REDUCED EXPRESSION AND ABERRANT PROMOTER HYPERMETHYLATION OF THESE GENES IN LUAD WERE INDEPENDENTLY VALIDATED USING DATA FROM THE CANCER GENOME ATLAS PROJECT. IMPORTANTLY, SNCA AND ZNF549 METHYLATION DETECTED IN SPUTUM DNA FROM LUAD (52% AND 38%) CASES WERE MORE PREVALENT COMPARED TO CANCER-FREE SMOKERS (26% AND 15%), RESPECTIVELY (P < 0.02). CONCLUSIONS: OUR DATA SHOW THAT SUPPRESSION OF CCNA1, SNCA, AND ZNF549 IN LUNG CANCER AND COPD OCCURS WITH OR WITHOUT PROMOTER HYPERMETHYLATION, RESPECTIVELY. DETECTING METHYLATION OF THESE AND PREVIOUSLY IDENTIFIED GENES IN SPUTUM OF CANCER-FREE SMOKERS MAY SERVE AS NON-INVASIVE BIOMARKERS FOR EARLY DETECTION OF LUNG CANCER AMONG HIGH RISK SMOKERS INCLUDING COPD PATIENTS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
6   672  39 BRAF, KRAS AND HELICOBACTER PYLORI EPIGENETIC CHANGES-ASSOCIATED CHRONIC GASTRITIS IN EGYPTIAN PATIENTS WITH AND WITHOUT GASTRIC CANCER. WE AIMED TO STUDY MLH1 AND MGMT METHYLATION STATUS IN HELICOBACTER PYLORI-ASSOCIATED CHRONIC GASTRITIS IN EGYPTIAN PATIENTS WITH AND WITHOUT GASTRIC CANCER. 39 PATIENTS WERE INCLUDED IN OUR STUDY. THEY WERE DIVIDED INTO 2 GROUPS; PATIENTS WITHOUT (GROUP I) AND WITH GASTRIC ADENOCARCINOMA (GROUP II). PATIENTS WERE SUBJECTED TO CLINICAL EXAMINATION, ABDOMINAL ULTRASOUND AND UPPER ENDOSCOPY FOR GASTRIC BIOPSY. BIOPSIES WERE SUBJECTED TO UREASE TEST, HISTOLOGICAL EXAMINATION, AND DNA PURIFICATION. H. PYLORI, BRAF, KRAS, MLH1 AND MGMT METHYLATION WERE ASSESSED BY QUANTITATIVE PCR. DNA SEQUENCING WAS PERFORMED TO ASSESS BRAF AND KRAS GENES MUTATION. QPCR OF H. PYLORI WAS SIGNIFICANTLY HIGHER IN PATIENTS WITH ADENOCARCINOMA (GROUP II) THAN THOSE WITHOUT ADENOCARCINOMA (GROUP I); WITH A P < 0.001 AS WELL AS IN PATIENTS WITH AGE ABOVE 50 YEARS WITH A P VALUE = 0.008. BY APPLYING LOGISTIC REGRESSION ANALYSIS IT WAS REPORTED THAT THE H. PYLORI QPCR IS A SIGNIFICANT PREDICTOR TO THE ADENOCARCINOMA WITH OR = 1.025 (95 % CI: 1. 002-1.048), WITH SENSITIVITY OF 90 % AND SPECIFICITY OF 100 %. ADENOCARCINOMA PATIENTS HAD A SIGNIFICANTLY HIGHER MEAN AGE AND LEVELS OF H. PYLORI, BRAF, K-RAS, METHYLATED MGMT AND METHYLATED MLH1 THAN THOSE OF GASTRITIS PATIENTS. DNA SEQUENCE ANALYSIS OF BRAF (CODON 12) AND KRAS (CODON 600) HAD GENES MUTATION IN GASTRIC ADENOCARCINOMA VERSUS CHRONIC GASTRITIS. CONCLUSION: H. PYLORI MAY CAUSE EPIGENETIC CHANGES PREDISPOSING THE PATIENTS TO CANCER STOMACH. ESTIMATION OF H. PYLORI BY QPCR CAN BE A GOOD PREDICTOR TO ADENOCARCINOMA. BRAF AND KRAS GENES MUTATION WERE REVELED IN GASTRITIS AND ADENOCARCINOMA PATIENTS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
7   158  34 ABERRANT P16 PROMOTER METHYLATION AMONG GREEK LUNG CANCER PATIENTS AND SMOKERS: CORRELATION WITH SMOKING. GENETIC AND ENVIRONMENTAL FACTORS (DIETARY AND SMOKING) INFLUENCE LUNG CANCER EPIDEMIOLOGY AND INDUCE EPIGENETIC MODIFICATIONS THAT SHOULD BE ASSESSED IN INDIVIDUAL POPULATIONS. WE ANALYZED P16 METHYLATION AMONG GREEK NON-SMALL CELL LUNG CARCINOMA PATIENTS AND SMOKERS USING TWO-STAGE METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. ONE HUNDRED AND FIFTY SPECIMENS FROM CANCEROUS AND ADJACENT NON-CANCEROUS TISSUE, BRONCHIAL WASHINGS AND SPUTUM FROM PATIENTS AND 48 SPECIMENS, MOSTLY SPUTUM, FROM DISEASE-FREE SMOKERS WERE INCLUDED. P16 METHYLATION WAS VERY FREQUENT IN BIOPSIES (82.85%) AND BRONCHIAL WASHINGS (NON-SMALL CELL LUNG CARCINOMA, 80.35%; SMALL CELL LUNG CARCINOMA, 16.66%) FROM PATIENTS, BUT ALSO IN ADJACENT NON-CANCEROUS TISSUE (45.71%). CONCORDANCE OF P16 METHYLATION AND POSITIVITY BY CYTOLOGICAL EXAMINATION WAS 51.78%. METHYLATION WAS ALSO OBSERVED IN SPUTUM FROM ASYMPTOMATIC CYTOLOGY-NEGATIVE SMOKERS (22.5%) AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE PATIENTS (THREE OF EIGHT). AMONG DISEASE-FREE INDIVIDUALS, METHYLATION CORRELATED ONLY WITH HEAVY SMOKING (>50 PACK-YEARS, P<0.001) AND DIFFERED AMONG MALE AND FEMALE DISEASE-FREE SMOKERS. IN SUMMARY, P16 METHYLATION IS VERY FREQUENT AMONG NON-SMALL CELL LUNG CARCINOMA PATIENTS, AND CORRELATES WITH HEAVY CIGARETTE CONSUMPTION ONLY IN DISEASE-FREE SMOKERS.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
8  6314  39 THE RELATIONSHIP BETWEEN THE EPIGENETIC AGING BIOMARKER "GRIMAGE" AND LUNG FUNCTION IN BOTH THE AIRWAY AND BLOOD OF PEOPLE LIVING WITH HIV: AN OBSERVATIONAL COHORT STUDY. BACKGROUND: AGE-RELATED COMORBIDITIES SUCH AS CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) ARE COMMON IN PEOPLE LIVING WITH HUMAN IMMUNODEFICIENCY VIRUS (PLWH). WE INVESTIGATED THE RELATIONSHIP BETWEEN COPD AND THE EPIGENETIC AGE OF THE AIRWAY EPITHELIUM AND PERIPHERAL BLOOD OF PLWH. METHODS: AIRWAY EPITHELIAL BRUSHINGS FROM 34 PLWH ENROLLED IN THE ST. PAUL'S HOSPITAL HIV BRONCHOSCOPY COHORT AND PERIPHERAL BLOOD FROM 378 PLWH ENROLLED IN THE STRATEGIC TIMING OF ANTIRETROVIRAL TREATMENT (START) STUDY WERE PROFILED FOR DNA METHYLATION. THE DNA METHYLATION BIOMARKER OF AGE AND HEALTHSPAN, GRIMAGE, WAS CALCULATED IN BOTH TISSUE COMPARTMENTS. WE TESTED THE ASSOCIATION OF GRIMAGE WITH COPD IN THE AIRWAY EPITHELIUM AND AIRFLOW OBSTRUCTION AS DEFINED BY AN FEV(1)/FVC<0.70, AND FEV(1) DECLINE OVER 6 YEARS IN BLOOD. FINDINGS: THE AIRWAY EPITHELIUM OF PLWH WITH COPD WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS COMPARED TO PLWH WITHOUT COPD (BETA=3.18, 95%CI=1.06-5.31, P=0.005). IN BLOOD, FEV(1)/FVC<LLN WAS ASSOCIATED WITH GREATER GRIMAGE RESIDUALS (BETA=1.74, 95%CI=0.37-3.24, P=0.019). FEV(1) DECLINE WAS INVERSELY CORRELATED WITH GRIMAGE RESIDUALS IN BLOOD (R=-0.13, P=0.012). PLWH WHO HAD NORMAL LUNG FUNCTION BUT WHO SUBSEQUENTLY DEVELOPED AN FEV(1)/FVC<0.70 OVER THE COURSE OF 6 YEARS HAD HIGHER GRIMAGE RESIDUALS AT BASELINE (BETA=2.33, 95%CI=0.23-4.44, P=0.031). INTERPRETATION: GRIMAGE MAY REFLECT LUNG AND SYSTEMIC EPIGENETIC CHANGES THAT OCCUR WITH ADVANCED AIRFLOW OBSTRUCTION AND MAY HELP TO IDENTIFY PLWH WITH A HIGHER RISK OF DEVELOPING COPD. FUNDING: CANADIAN INSTITUTES OF HEALTH RESEARCH AND THE BRITISH COLUMBIA LUNG ASSOCIATION. THE START SUBSTUDY WAS FUNDED BY NIH GRANTS: UM1-AI068641, UM1-AI120197, AND RO1HL096453.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
9  5005  33 PERIPHERAL BLOOD DNA METHYLATION-BASED MACHINE LEARNING MODELS FOR PREDICTION OF KNEE OSTEOARTHRITIS PROGRESSION: BIOLOGIC SPECIMENS AND DATA FROM THE OSTEOARTHRITIS INITIATIVE AND JOHNSTON COUNTY OSTEOARTHRITIS PROJECT. OBJECTIVE: THE LACK OF ACCURATE BIOMARKERS TO PREDICT KNEE OSTEOARTHRITIS (OA) PROGRESSION IS A KEY UNMET NEED IN OA CLINICAL RESEARCH. THE OBJECTIVE OF THIS STUDY WAS TO DEVELOP BASELINE PERIPHERAL BLOOD EPIGENETIC BIOMARKER MODELS TO PREDICT KNEE OA PROGRESSION. METHODS: GENOME-WIDE BUFFY COAT DNA METHYLATION PATTERNS FROM 554 INDIVIDUALS FROM THE OSTEOARTHRITIS BIOMARKERS CONSORTIUM (OABC) WERE DETERMINED USING ILLUMINA INFINIUM METHYLATIONEPIC 850K ARRAYS. DATA WERE DIVIDED INTO MODEL DEVELOPMENT AND VALIDATION SETS, AND MACHINE LEARNING MODELS WERE TRAINED TO CLASSIFY FUTURE OA PROGRESSION BY KNEE PAIN, RADIOGRAPHIC IMAGING, KNEE PAIN PLUS RADIOGRAPHIC IMAGING, AND ANY PROGRESSION (PAIN, RADIOGRAPHIC, OR BOTH). PARSIMONIOUS MODELS USING THE TOP 13 CPG SITES MOST FREQUENTLY SELECTED DURING DEVELOPMENT WERE TESTED ON INDEPENDENT SAMPLES FROM PARTICIPANTS IN THE JOHNSTON COUNTY OSTEOARTHRITIS (JOCO OA) PROJECT (N = 128) AND A PREVIOUSLY PUBLISHED OSTEOARTHRITIS INITIATIVE (OAI) DATA SET (N = 55). RESULTS: FULL MODELS ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC-ONLY PROGRESSION (MEAN +/- SEM ACCURACY 87 +/- 0.8%, AREA UNDER THE CURVE [AUC] 0.94 +/- 0.004), PAIN-ONLY PROGRESSION (ACCURACY 89 +/- 0.9%, AUC 0.97 +/- 0.004), PAIN PLUS RADIOGRAPHIC PROGRESSION (ACCURACY 72 +/- 0.7%, AUC 0.79 +/- 0.006), AND ANY PROGRESSION (ACCURACY 78 +/- 0.4%, AUC 0.86 +/- 0.004). PAIN-ONLY AND RADIOGRAPHIC-ONLY PROGRESSORS WERE NOT DISTINGUISHABLE (MEAN +/- SEM ACCURACY 58 +/- 1%, AUC 0.62 +/- 0.001). PARSIMONIOUS MODELS SHOWED SIMILAR PERFORMANCE AND ACCURATELY CLASSIFIED FUTURE RADIOGRAPHIC PROGRESSORS IN THE OABC COHORT AND IN BOTH VALIDATION COHORTS (MEAN +/- SEM ACCURACY 80 +/- 0.3%, AUC 0.88 +/- 0.003 [USING JOCO OA PROJECT DATA], ACCURACY 80 +/- 0.8%, AUC 0.89 +/- 0.002 [USING PREVIOUS OAI DATA]). CONCLUSION: OUR DATA SUGGEST THAT PAIN AND STRUCTURAL PROGRESSION SHARE SIMILAR EARLY SYSTEMIC IMMUNE EPIGENOTYPES. FURTHER STUDIES SHOULD FOCUS ON EVALUATING THE PATHOPHYSIOLOGIC CONSEQUENCES OF DIFFERENTIAL DNA METHYLATION AND PERIPHERAL BLOOD CELL EPIGENOTYPES IN INDIVIDUALS WITH KNEE OA.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
10  1194  50 CORRELATION OF EPIGENETIC CHANGE AND IDENTIFICATION OF RISK FACTORS FOR ORAL SUBMUCOUS FIBROSIS. BACKGROUND: DNA METHYLATION OF CERTAIN GENES IS AN EPIGENETIC CHANGE THAT IS ESSENTIAL FOR TUMORIGENESIS. ORAL SUBMUCOUS FIBROSIS (OSF) IS A PRECANCEROUS CONDITION OF ORAL MUCOSA WITH INFLAMMATION AND PROGRESSIVE FIBROSIS OF THE LAMINA PROPRIA AND DEEPER CONNECTIVE TISSUE. THE HYPERMETHYLATION OF E-CADHERIN AND CYCLOOXYGENASE 2 (COX-2) IN CHRONIC INFLAMMATION MAY DEMONSTRATE A MILD LESION/MUTATION AT EPIGENETIC LEVELS. THIS STUDY COMPARES THE HYPERMETHYLATION STATUS OF E-CADHERIN AND COX-2 GENES IN PATIENTS WITH ORAL CANCER AND PATIENTS WITH OSF AND ALSO AIMS TO IDENTIFY RISK FACTORS FOR THE DEVELOPMENT OF OSF. METHODS: DNA WAS EXTRACTED FROM BLOOD SAMPLES OF 50 HEALTHY SUBJECTS, 50 PATIENTS WITH OSF AND 60 PATIENTS WITH ORAL CANCER. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION FOR E-CADHERIN AND COX-2 WAS PERFORMED ON THESE SAMPLES AND THE PRODUCTS WERE ANALYZED ON 2% AGAROSE GEL. SURVEYS ABOUT ORAL HEALTH HABITS AND CLINICAL PERIODONTAL EXAMINATIONS IN PATIENTS WITH OSF AND HEALTHY SUBJECTS WERE ALSO CONDUCTED BY WELL-TRAINED DENTISTS, AND LOGISTIC REGRESSION WAS PERFORMED TO IDENTIFY RISK FACTORS FOR OSF. RESULTS: HYPERMETHYLATION OF E-CADHERIN AND COX-2 WAS OBSERVED IN 36% AND 22% OF ORAL CANCER SAMPLES, RESPECTIVELY. IN PATIENTS WITH OSF, THE RATES WERE 52% AND 30%, AND IN HEALTHY CONTROLS THE RATES WERE 4% AND 6%. HYPERMETHYLATION WAS SHOWN TO BE CORRELATED BETWEEN THE 3 GROUPS WITH STATISTICAL SIGNIFICANCE (P<0.01). METHYLATION OF CPG ISLANDS IN E-CADHERIN AND COX-2 OCCURRED MORE FREQUENTLY IN PATIENTS WITH OSF THAN IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN PATIENTS WITH ORAL CANCER. IN THE LOGISTIC REGRESSION ANALYSIS, SMOKING, BRUSHING MORE THAN TWICE DAILY, PERIODONTAL PROBING DEPTH AND PLAQUE INDEX WERE IDENTIFIED AS 4 MAJOR RISK FACTORS FOR OSF. CONCLUSIONS: THESE DATA CONFIRM THAT E-CADHERIN AND COX-2 EXPRESSIONS ARE RELATED TO OSF. THE EPIGENETIC CHANGES PRESENTED IN PATIENTS WITH CHRONIC INFLAMMATION MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO THE EFFECTS OF CANCER. CHRONIC OSF WAS SIGNIFICANTLY ASSOCIATED WITH HYPERMETHYLATION, A CANCER RISK FACTOR.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
11  3460  38 HYPOMETHYLATION OF THE IL8 PROMOTER IN NASAL EPITHELIAL CELLS OF PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS. BACKGROUND: IL-8 IS AN IMPORTANT CHEMOKINE IMPLICATED IN THE PATHOGENESIS OF CHRONIC RHINOSINUSITIS (CRS), BUT LITTLE IS KNOWN ABOUT EPIGENETIC REGULATION OF IL8 IN THE PATHOGENESIS OF CRS. OBJECTIVE: WE SOUGHT TO INVESTIGATE THE RELATIONSHIP BETWEEN THE DNA METHYLATION LEVEL IN THE IL8 PROXIMAL PROMOTER AND CRS IN HAN CHINESE SUBJECTS. METHODS: PATIENTS WITH CHRONIC RHINOSINUSITIS WITH NASAL POLYPS (CRSWNP; N = 187), PATIENTS WITH CHRONIC RHINOSINUSITIS WITHOUT NASAL POLYPS (CRSSNP; N = 89), AND CONTROL SUBJECTS (N = 57) WERE ENROLLED IN 2 INDEPENDENT COHORTS. PURIFIED HUMAN NASAL EPITHELIAL CELLS FROM EACH PARTICIPANT WERE ASSESSED FOR PERCENTAGE DNA METHYLATION OF CPG SITES IN THE IL8 PROXIMAL PROMOTER BY USING BISULFITE PYROSEQUENCING AND FOR FUNCTIONAL ASPECTS OF METHYLATION STATUS BY USING IN VITRO ASSAYS. RESULTS: DNA METHYLATION OF CPG SITES 1, 2, AND 3, RESPECTIVELY, IN THE IL8 PROXIMAL PROMOTER WAS SIGNIFICANTLY DECREASED IN HUMAN NASAL EPITHELIAL CELLS OF PATIENTS WITH CRSWNP COMPARED WITH THAT IN PATIENTS WITH CRSSNP (P < .001) AND CONTROL SUBJECTS (P < .001). PERCENTAGE OF DNA METHYLATION OF THE CPG3 SITE WAS CORRELATED NEGATIVELY WITH BOTH TISSUE EOSINOPHILIC CATIONIC PROTEIN (P < .01) AND MYELOPEROXIDASE (P < .05) LEVELS. IL-1BETA (P < .001) AND TNF-ALPHA (P < .01) SIGNIFICANTLY INCREASED IL8 EXPRESSION ACCOMPANIED BY A REDUCTION IN METHYLATION AT THE CPG3 SITE (P < .001). ELECTROPHORETIC MOBILITY SHIFT ASSAYS DEMONSTRATED THAT METHYLATION STATUS OF CPG3 CHANGED THE BINDING OF OCTAMER-BINDING TRANSCRIPTION FACTOR 1 AND NUCLEAR FACTOR KAPPAB. CONCLUSION: DECREASED DNA METHYLATION OF PARTICULARLY CPG SITES IN THE IL8 PROXIMAL PROMOTER MIGHT PLAY A ROLE IN THE PATHOGENESIS OF CRSWNP.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
12   502  45 ASSOCIATION OF ARSENIC EXPOSURE WITH WHOLE BLOOD DNA METHYLATION: AN EPIGENOME-WIDE STUDY OF BANGLADESHI ADULTS. BACKGROUND: ARSENIC EXPOSURE AFFECTS [FORMULA: SEE TEXT] PEOPLE WORLDWIDE, INCLUDING [FORMULA: SEE TEXT] IN BANGLADESH. ARSENIC EXPOSURE INCREASES THE RISK OF CANCER AND OTHER CHRONIC DISEASES, AND ONE POTENTIAL MECHANISM OF ARSENIC TOXICITY IS EPIGENETIC DYSREGULATION. OBJECTIVE: WE ASSESSED ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND GENOME-WIDE DNA METHYLATION MEASURED AT BASELINE AMONG 396 BANGLADESHI ADULTS PARTICIPATING IN THE HEALTH EFFECTS OF ARSENIC LONGITUDINAL STUDY (HEALS) WHO WERE EXPOSED BY DRINKING NATURALLY CONTAMINATED WELL WATER. METHODS: METHYLATION IN WHOLE BLOOD DNA WAS MEASURED AT [FORMULA: SEE TEXT] USING THE ILLUMINA INFINIUMMETHYLATIONEPIC (EPIC) ARRAY. TO ASSESS ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND CPG METHYLATION, WE USED LINEAR REGRESSION MODELS ADJUSTED FOR COVARIATES AND SURROGATE VARIABLES (SVS) (CAPTURING UNKNOWN TECHNICAL AND BIOLOGIC FACTORS). WE ATTEMPTED REPLICATION AND CONDUCTED A META-ANALYSIS USING AN INDEPENDENT DATASET OF [FORMULA: SEE TEXT] FROM 400 BANGLADESHI INDIVIDUALS WITH ARSENICAL SKIN LESIONS. RESULTS: WE IDENTIFIED 34 CPGS ASSOCIATED WITH [FORMULA: SEE TEXT] CREATININE-ADJUSTED URINARY ARSENIC [[FORMULA: SEE TEXT]]. SIXTEEN OF THESE CPGS ANNOTATED TO THE [FORMULA: SEE TEXT] ARRAY, AND 10 ASSOCIATIONS WERE REPLICATED ([FORMULA: SEE TEXT]). THE TOP TWO CPGS ANNOTATED UPSTREAM OF THE ABR GENE (CG01912040, CG10003262 ). ALL URINARY ARSENIC-ASSOCIATED CPGS WERE ALSO ASSOCIATED WITH ARSENIC CONCENTRATION MEASURED IN DRINKING WATER ([FORMULA: SEE TEXT]). META-ANALYSIS ([FORMULA: SEE TEXT] SAMPLES) IDENTIFIED 221 URINARY ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]). THE ARSENIC-ASSOCIATED CPGS FROM THE META-ANALYSIS WERE ENRICHED IN NON-CPG ISLANDS AND SHORES ([FORMULA: SEE TEXT]) AND DEPLETED IN PROMOTER REGIONS ([FORMULA: SEE TEXT]). AMONG THE ARSENIC-ASSOCIATED CPGS ([FORMULA: SEE TEXT]), WE OBSERVED SIGNIFICANT ENRICHMENT OF GENES ANNOTATING TO THE REACTIVE OXYGEN SPECIES PATHWAY, INFLAMMATORY RESPONSE, AND TUMOR NECROSIS FACTOR [FORMULA: SEE TEXT] ([FORMULA: SEE TEXT]) SIGNALING VIA NUCLEAR FACTOR KAPPA-B ([FORMULA: SEE TEXT]) HALLMARKS ([FORMULA: SEE TEXT]). CONCLUSIONS: THE NOVEL AND REPLICABLE ASSOCIATIONS BETWEEN ARSENIC EXPOSURE AND DNA METHYLATION AT SPECIFIC CPGS OBSERVED IN THIS WORK SUGGEST THAT EPIGENETIC ALTERATIONS SHOULD BE FURTHER INVESTIGATED AS POTENTIAL MEDIATORS IN ARSENIC TOXICITY AND AS BIOMARKERS OF EXPOSURE AND EFFECT IN EXPOSED POPULATIONS. HTTPS://DOI.ORG/10.1289/EHP3849.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
13  1431  44 DIFFERENTIAL FREQUENCIES OF P16(INK4A) PROMOTER HYPERMETHYLATION, P53 MUTATION, AND K-RAS MUTATION IN EXFOLIATIVE MATERIAL MARK THE DEVELOPMENT OF LUNG CANCER IN SYMPTOMATIC CHRONIC SMOKERS. PURPOSE: THE AIM OF THIS STUDY WAS TO INVESTIGATE THE FREQUENCY OF THREE (EPI)GENETIC ALTERATIONS (P53 AND K-RAS MUTATIONS AND P16(INK4A) PROMOTER HYPERMETHYLATION) IN SYMPTOMATIC CHRONIC SMOKERS COMPARED WITH PATIENTS WITH LUNG CANCER AND TO EVALUATE THE USE OF EXFOLIATIVE MATERIAL FOR SUCH ANALYSES. PATIENTS AND METHODS: FIFTY-ONE PATIENTS WITH HISTOLOGICALLY CONFIRMED LUNG CANCER AND 25 CHRONIC SMOKERS (> 20 PACK-YEARS) WERE INVESTIGATED FOR MUTATIONS IN THE K-RAS (CODON 12) AND P53 (CODONS 248, 249, AND 273) GENES AND FOR ALLELIC HYPERMETHYLATION OF THE P16(INK4A) GENE. DNA WAS ISOLATED FROM SPUTUM AND BILATERAL BRONCHIAL LAVAGE, AND BRUSHINGS WERE TAKEN AT BRONCHOSCOPY. RESULTS: FORTY-ONE GENETIC LESIONS WERE DETECTED WITHIN EXFOLIATIVE MATERIAL FROM THE GROUP OF 51 PATIENTS WITH LUNG CANCER AND 10 LESIONS IN THE CHRONIC SMOKER GROUP. K-RAS MUTATIONS OCCURRED EXCLUSIVELY IN THE LUNG CANCER GROUP, WHEREAS P53 MUTATIONS AND P16(INK4A) PROMOTER HYPERMETHYLATION WERE ALSO FOUND IN CHRONIC SMOKERS. THREE OF EIGHT CHRONIC SMOKERS WHO HARBORED AN (EPI)GENETIC ALTERATION WERE SUBSEQUENTLY DIAGNOSED WITH LUNG CANCER. ANALYSIS OF SPUTUM YIELDED INFORMATION EQUIVALENT TO THAT OF SAMPLES OBTAINED DURING BRONCHOSCOPY. CONCLUSION: P16(INK4A) PROMOTER HYPERMETHYLATION AND P53 MUTATIONS CAN OCCUR IN CHRONIC SMOKERS BEFORE ANY CLINICAL EVIDENCE OF NEOPLASIA AND MAY BE INDICATIVE OF AN INCREASED RISK OF DEVELOPING LUNG CANCER OR OF EARLY DISEASE. K-RAS MUTATIONS OCCUR EXCLUSIVELY IN THE PRESENCE OF CLINICALLY DETECTABLE NEOPLASTIC TRANSFORMATION. MOLECULAR ANALYSIS OF SPUTUM FOR SUCH MARKERS MAY PROVIDE AN EFFECTIVE MEANS OF SCREENING CHRONIC SMOKERS TO ENABLE EARLIER DETECTION AND THERAPEUTIC INTERVENTION OF LUNG CANCER.	2000	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
14  1956  41 EPIGENETIC AGE IN PERIPHERAL BLOOD AMONG CHILDREN, ADOLESCENT, AND ADULT SURVIVORS OF CHILDHOOD CANCER. IMPORTANCE: CERTAIN CANCER THERAPIES ARE RISK FACTORS FOR EPIGENETIC AGE ACCELERATION (EAA) AMONG SURVIVORS OF CHILDHOOD CANCER, AND EAA IS ASSOCIATED WITH CHRONIC HEALTH CONDITIONS (CHCS). HOWEVER, SMALL NUMBERS OF YOUNGER SURVIVORS (AGED <20 YEARS) PREVIOUSLY EVALUATED HAVE LIMITED THE ABILITY TO CALCULATE EAA AMONG THIS AGE GROUP. OBJECTIVE: TO EVALUATE THE CHANGE RATE OF EPIGENETIC AGE (EA) AND EAA IN YOUNGER COMPARED WITH OLDER SURVIVORS AND THE POSSIBLE ASSOCIATION OF EAA WITH EARLY-ONSET OBESITY (AGED <20 YEARS), SEVERITY/BURDEN OF CHCS, AND LATE MORTALITY (>5 YEARS FROM CANCER DIAGNOSIS). DESIGN, SETTING, AND PARTICIPANTS: STUDY PARTICIPANTS WERE FROM THE ST JUDE LIFETIME COHORT, INITIATED IN 2007 WITH ONGOING FOLLOW-UP. THE PRESENT STUDY WAS CONDUCTED FROM APRIL 17, 2022, TO MARCH 23, 2023. SURVIVORS IN THIS COHORT OF EUROPEAN ANCESTRY WITH DNA METHYLATION DATA WERE INCLUDED. CROSS-SECTIONAL ANNUAL CHANGES IN EA AND EAA WERE COMPARED ACROSS 5 DIFFERENT CHRONOLOGIC AGE GROUPS: AGE 0 TO 9 (CHILDREN), 10 TO 19 (ADOLESCENTS), 20 TO 34 (YOUNGER ADULTS), 35 TO 49 (MIDDLE-AGED ADULTS), AND GREATER THAN OR EQUAL TO 50 (OLDER ADULTS) YEARS. LOGISTIC REGRESSION EVALUATED THE ASSOCIATION BETWEEN EAA AND EARLY-ONSET OBESITY OR SEVERITY/BURDEN OF CHCS. COX PROPORTIONAL HAZARDS REGRESSION ASSESSED THE ASSOCIATION BETWEEN EAA AND LATE MORTALITY. MAIN OUTCOMES AND MEASURES: EARLY-ONSET OBESITY, SEVERITY/BURDEN OF CHCS (GRADED USING THE COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (GRADE 1, MILD; 2, MODERATE; 3, SEVERE/DISABLING; 4, LIFE-THREATENING) AND WERE COMBINED INTO HIGH VS LOW SEVERITY/BURDEN BASED ON FREQUENCY AND GRADE), AND LATE MORTALITY WERE THE OUTCOMES BASED ON FOLLOW-UP UNTIL APRIL 2020. EXPANDED DNA METHYLATION PROFILING INCREASED THE NUMBER OF SURVIVORS YOUNGER THAN 20 YEARS (N = 690). EPIGENETIC AGE WAS CALCULATED PRIMARILY USING THE LEVINE CLOCK, AND EAA WAS DERIVED FROM LEAST SQUARES REGRESSION OF EA AGAINST CHRONOLOGIC AGE AND WAS STANDARDIZED TO A Z SCORE (LEVINE EEA). RESULTS: AMONG 2846 PARTICIPANTS (MEDIAN AGE, 30.3 [IQR, 9.3-41.5] YEARS; 53% MALES), THE CROSS-SECTIONAL ANNUAL CHANGE IN EA_LEVINE WAS HIGHER IN CHILDREN (1.63 YEARS) AND ADOLESCENTS (1.14 YEARS), AND THE ADJUSTED LEAST-SQUARES MEAN OF LEVINE EEA WAS LOWER IN CHILDREN (-0.22 YEARS) AND OLDER ADULTS (-1.70 YEARS). EACH 1-SD INCREASE IN LEVINE EEA WAS ASSOCIATED WITH INCREASED RISK OF DEVELOPING EARLY-ONSET OBESITY (ODDS RATIO [OR], 1.46; 95% CI, 1.19-1.78), HIGH SEVERITY/BURDEN OF CHCS (OR, 1.13; 95% CI, 1.03-1.24), AND LATE MORTALITY (HAZARD RATIO, 1.75; 95% CI, 1.35-2.26). CONCLUSIONS AND RELEVANCE: THE FINDINGS OF THIS STUDY SUGGEST THAT EAA MEASURED IN CHILDREN AND ADOLESCENT SURVIVORS OF CHILDHOOD CANCER IS ASSOCIATED WITH EARLY-ONSET OBESITY, SEVERITY/BURDEN OF ALL CHCS, AND LATE MORTALITY. EVALUATING EAA MAY HELP IDENTIFY SURVIVORS OF CHILDHOOD CANCER AT INCREASED RISK FOR EARLY-ONSET OBESITY, MORBIDITY IN GENERAL, AND MORTALITY.	2023	

15  2147  44 EPIGENETIC MARKER OF TELOMERIC AGE IS ASSOCIATED WITH EXACERBATIONS AND HOSPITALIZATIONS IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. BACKGROUND: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS AN AGE-RELATED CONDITION THAT HAS BEEN ASSOCIATED WITH EARLY TELOMERE ATTRITION; THE CLINICAL IMPLICATIONS OF TELOMERE SHORTENING IN COPD ARE NOT WELL KNOWN. IN THIS STUDY WE AIMED TO DETERMINE THE RELATIONSHIP OF THE EPIGENETIC REGULATION OF TELOMERIC LENGTH IN PERIPHERAL BLOOD WITH THE RISK OF EXACERBATIONS AND HOSPITALIZATION IN PATIENTS WITH COPD. METHODS: BLOOD DNA METHYLATION PROFILES WERE OBTAINED FROM 292 PATIENTS WITH COPD ENROLLED IN THE PLACEBO ARM OF THE MACROLIDE AZITHROMYCIN TO PREVENT RAPID WORSENING OF SYMPTOMS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (MACRO) STUDY AND WHO WERE FOLLOWED FOR 1-YEAR. WE CALCULATED TELOMERE LENGTH BASED ON DNA METHYLATION MARKERS (DNAMTL) AND RELATED THIS BIOMARKER TO THE RISK OF EXACERBATION AND HOSPITALIZATION AND HEALTH STATUS (ST. GEORGE RESPIRATORY QUESTIONNAIRE [SGRQ]) SCORE OVER TIME USING A COX PROPORTIONAL HAZARDS MODEL. WE ALSO USED LINEAR MODELS TO INVESTIGATE THE ASSOCIATIONS OF DNAMTL WITH THE RATES OF EXACERBATION AND HOSPITALIZATION (ADJUSTED FOR CHRONOLOGICAL AGE, LUNG FUNCTION, RACE, SEX, SMOKING, BODY MASS INDEX AND CELL COMPOSITION). RESULTS: PARTICIPANTS WITH SHORT DNAMTL DEMONSTRATED INCREASED RISK OF EXACERBATION (P = 0.02) AND HOSPITALIZATION (P = 0.03) COMPARED TO THOSE WITH LONGER DNAMTL. DNAMTL AGE ACCELERATION WAS ASSOCIATED WITH HIGHER RATES OF EXACERBATION (P = 1.35 X 10(-04)) AND HOSPITALIZATION (P = 5.21 X 10(-03)) AND POOR HEALTH STATUS (LOWER SGRQ SCORES) INDEPENDENT OF CHRONOLOGICAL AGE (P = 0.03). CONCLUSION: TELOMERIC AGE BASED ON BLOOD DNA METHYLATION IS ASSOCIATED WITH COPD EXACERBATION AND HOSPITALIZATION AND THUS A PROMISING BIOMARKER FOR POOR OUTCOMES IN COPD.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16  3445  45 HYPERMETHYLATION OF ITGA4, TFPI2 AND VIMENTIN PROMOTERS IS INCREASED IN INFLAMED COLON TISSUE: PUTATIVE RISK MARKERS FOR COLITIS-ASSOCIATED CANCER. PURPOSE: EPIGENETIC SILENCING OF TUMOR SUPPRESSOR GENES IS INVOLVED IN EARLY TRANSFORMING EVENTS AND HAS A HIGH IMPACT ON COLORECTAL CARCINOGENESIS. LIKEWISE, COLON CANCERS THAT DERIVE FROM CHRONICALLY INFLAMED BOWEL DISEASES FREQUENTLY EXHIBIT EPIGENETIC CHANGES. BUT THERE IS LITTLE DATA ABOUT EPIGENETIC ABERRATIONS CAUSING COLORECTAL CANCER IN CHRONICALLY INFLAMED TISSUE. THE AIM OF THE PRESENT STUDY WAS TO EVALUATE THE ABERRANT GAIN OF METHYLATION IN THE GENE PROMOTERS OF VIM, TFPI2 AND ITGA4 AS PUTATIVE EARLY MARKERS IN THE DEVELOPMENT FROM INFLAMED TISSUE VIA PRECANCEROUS LESIONS TOWARD COLORECTAL CANCER. METHODS: INITIAL SCREENING OF DIFFERENT CANCER CELL LINES BY USING METHYLATION-SPECIFIC PCR REVEALED A PUTATIVE COLON CANCER-SPECIFIC METHYLATION PATTERN. ADDITIONALLY, A DEMETHYLATION ASSAY WAS PERFORMED TO INVESTIGATE THE METHYLATION-DEPENDENT GENE SILENCING OF ITGA4. THE CANDIDATE MARKERS WERE ANALYZED IN COLONIC TISSUE SPECIMENS FROM PATIENTS WITH COLORECTAL CANCER (N = 15), ADENOMAS (N = 76), SERRATED LESIONS (N = 13), CHRONIC INFLAMMATION (N = 10) AND NORMAL MUCOSAL SAMPLES (N = 9). RESULTS: A HIGH METHYLATION FREQUENCY OF VIM (55.6 %) WAS OBSERVED IN NORMAL COLON TISSUE, WHEREAS ITGA4 AND TFPI2 WERE COMPLETELY UNMETHYLATED IN CONTROLS. A SIGNIFICANT GAIN OF METHYLATION FREQUENCY WITH PROGRESSION OF DISEASE AS WELL AS AN AGE-DEPENDENT EFFECT WAS DETECTABLE FOR TFPI2. ITGA4 METHYLATION FREQUENCY WAS HIGH IN PRECANCEROUS AND CANCEROUS TISSUES AS WELL AS IN INFLAMMATORY BOWEL DISEASES (IBD). CONCLUSION: THE ALREADY ESTABLISHED METHYLATION MARKER VIM DOES NOT PERMIT A SPECIFIC AND SENSITIVE DISCRIMINATION OF HEALTHY AND NEOPLASTIC TISSUE. THE METHYLATION MARKERS ITGA4 AND TFPI2 SEEM TO BE SUITABLE RISK MARKERS FOR INFLAMMATION-ASSOCIATED COLON CANCER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                   
17   779  37 CELL-FREE DNA PROMOTER HYPERMETHYLATION AS A DIAGNOSTIC MARKER FOR PANCREATIC DUCTAL ADENOCARCINOMA - AN EXTERNAL VALIDATION STUDY. BACKGROUND: WE RECENTLY IDENTIFIED A DIAGNOSTIC PREDICTION MODEL BASED ON PROMOTER HYPERMETHYLATION OF EIGHT SELECTED GENES IN PLASMA CELL-FREE (CF) DNA, WHICH SHOWED PROMISING RESULTS AS A DIAGNOSTIC BIOMARKER FOR PANCREATIC DUCTAL ADENOCARCINOMA (PDAC). THE AIM OF THE PRESENT STUDY WAS TO VALIDATE THIS BIOMARKER PROFILE IN AN EXTERNAL PATIENT COHORT AND EXAMINE ANY ADDITIONAL EFFECT OF SERUM CA 19-9. METHODS: PATIENTS WITH PDAC (N = 346, STAGE I-IV) AND CHRONIC PANCREATITIS (N = 25) WERE INCLUDED. METHYLATION-SPECIFIC PCR OF A 28-GENE PANEL WAS PERFORMED ON SERUM CFDNA SAMPLES. THE PREVIOUSLY DEVELOPED DIAGNOSTIC PREDICTION MODEL (AGE>65 YEARS, BMP3, RASSF1A, BNC1, MESTV2, TFPI2, APC, SFRP1 AND SFRP2) WAS VALIDATED ALONE AND IN COMBINATION WITH SERUM CA 19-9 IN THIS EXTERNAL PATIENT COHORT. RESULTS: PATIENTS WITH PDAC HAD A HIGHER NUMBER OF HYPERMETHYLATED GENES (MEAN 8.11, 95% CI 7.70-8.52) THAN PATIENTS WITH CHRONIC PANCREATITIS (MEAN 5.60, 95% CI 4.42-6.78, P = 0.011). VALIDATION OF THE DIAGNOSTIC PREDICTION MODEL YIELDED AN AUC OF 0.77 (95% CI 0.69-0.84). THE COMBINATION OF SERUM CA 19-9 AND OUR TEST HAD AN AUC OF 0.93 (95% CI 0.89-0.96) IN THE PRIMARY STUDY AND 0.85 (95% CI 0.79-0.91) IN THE VALIDATION STUDY. CONCLUSION: IN THIS VALIDATION STUDY, PDAC WAS ASSOCIATED WITH A HIGHER NUMBER OF HYPERMETHYLATED GENES IN SERUM CFDNA THAN CHRONIC PANCREATITIS. OUR DIAGNOSTIC TEST WAS SUPERIOR TO THE PREDICTIVE VALUE OF SERUM CA 19-9 ALONE IN BOTH THE PRIMARY AND THE VALIDATION STUDY. THE COMBINATION OF OUR TEST WITH CA 19-9 MAY SERVE AS A CLINICALLY USEFUL DIAGNOSTIC BIOMARKER FOR PDAC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
18  4248  46 METHYLATION STATUS, MRNA AND PROTEIN EXPRESSION OF THE SMAD4 GENE IN PATIENTS WITH NON-MELANOCYTIC SKIN CANCERS. BACKGROUND: SMAD4 IS A POTENT TUMOR SUPPRESSOR. SMAD4 LOSS INCREASES GENOMIC INSTABILITY AND PLAYS A CRITICAL ROLE IN THE DNA DAMAGE RESPONSE THAT LEADS TO SKIN CANCER DEVELOPMENT. WE AIMED TO INVESTIGATE SMAD4 METHYLATION EFFECTS ON MRNA AND PROTEIN EXPRESSION OF SMAD4 IN CANCER AND HEALTHY TISSUES FROM PATIENTS WITH BASAL CELL CARCINOMA (BCC), CUTANEOUS SQUAMOUS CELL CARCINOMA (CSCC), AND BASOSQUAMOUS SKIN CANCER (BSC). METHODS AND RESULTS: THE STUDY INCLUDED 17 BCC, 24 CSCC AND NINE BSC PATIENTS. DNA AND RNA WERE ISOLATED FROM CANCEROUS AND HEALTHY TISSUES FOLLOWING PUNCH BIOPSY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) AND REAL-TIME QUANTITATIVE PCR METHODS WERE USED TO EXAMINE SMAD4 PROMOTER METHYLATION AND SMAD4 MRNA LEVELS, RESPECTIVELY. THE PERCENTAGE AND INTENSITY OF STAINING OF THE SMAD4 PROTEIN WERE DETERMINED BY IMMUNOHISTOCHEMISTRY. THE PERCENTAGE OF SMAD4 METHYLATION WAS INCREASED IN THE PATIENTS WITH BCC (P = 0.007), CSCC (P = 0.004), AND BSC (P = 0.018) COMPARED TO THE HEALTHY TISSUE. SMAD4 MRNA EXPRESSION WAS DECREASED IN THE PATIENTS WITH BCC (P<0.001), CSCC (P<0.001), AND BSC (P = 0.008). THE STAINING CHARACTERISTIC OF SMAD4 PROTEIN WAS NEGATIVE IN THE CANCER TISSUES OF THE PATIENTS WITH CSCC (P = 0.00). LOWER SMAD4 MRNA LEVELS WERE OBSERVED IN THE POORLY DIFFERENTIATED CSCC PATIENTS (P = 0.001). THE STAINING CHARACTERISTICS OF THE SMAD4 PROTEIN WERE RELATED TO AGE AND CHRONIC SUN EXPOSURE. CONCLUSIONS: HYPERMETHYLATION OF SMAD4 AND REDUCED SMAD4 MRNA EXPRESSION WERE FOUND TO PLAY A ROLE IN THE PATHOGENESIS OF BCC, CSCC, AND BSC. A DECREASE IN SMAD4 PROTEIN EXPRESSION LEVEL WAS OBSERVED ONLY IN CSCC PATIENTS. THIS SUGGESTS THAT EPIGENETIC ALTERATIONS TO THE SMAD4 GENE ARE ASSOCIATED WITH CSCC. TRIAL REGISTRATION: THE NAME OF THE TRIAL REGISTER: SMAD4 METHYLATION AND EXPRESSION LEVELS IN NON-MELANOCYTIC SKIN CANCERS; SMAD4 PROTEIN POSITIVITY. THE REGISTRATION NUMBER: NCT04759261 ( HTTPS://CLINICALTRIALS.GOV/CT2/RESULTS?TERM=NCT04759261 ).	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
19  4249  38 METHYLATION-BASED BIOLOGICAL AGE AND BREAST CANCER RISK. BACKGROUND: AGE IS ONE OF THE STRONGEST PREDICTORS OF CANCER, CHRONIC DISEASE, AND MORTALITY, BUT BIOLOGICAL RESPONSES TO AGING DIFFER AMONG PEOPLE. EPIGENETIC DNA MODIFICATIONS HAVE BEEN USED TO ESTIMATE "BIOLOGICAL AGE," WHICH MAY BE A USEFUL PREDICTOR OF DISEASE RISK. WE TESTED THIS HYPOTHESIS FOR BREAST CANCER. METHODS: USING A CASE-COHORT APPROACH, WE MEASURED BASELINE BLOOD DNA METHYLATION OF 2764 WOMEN ENROLLED IN THE SISTER STUDY, 1566 OF WHOM SUBSEQUENTLY DEVELOPED BREAST CANCER AFTER AN AVERAGE OF 6 YEARS. USING THREE PREVIOUSLY ESTABLISHED METHYLATION-BASED "CLOCKS" (HANNUM, HORVATH, AND LEVINE), WE DEFINED BIOLOGICAL AGE ACCELERATION FOR EACH WOMAN BY COMPARING HER ESTIMATED BIOLOGICAL AGE WITH HER CHRONOLOGICAL AGE. HAZARD RATIOS AND 95% CONFIDENCE INTERVALS FOR BREAST CANCER RISK WERE ESTIMATED USING COX REGRESSION MODELS. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: EACH OF THE THREE CLOCKS SHOWED THAT BIOLOGICAL AGE ACCELERATION WAS STATISTICALLY SIGNIFICANTLY ASSOCIATED WITH INCREASED RISK OF DEVELOPING BREAST CANCER (5-YEAR AGE ACCELERATION, HANNUM'S CLOCK: HAZARD RATIO [HR] = 1.10, 95% CONFIDENCE INTERVAL [CI] = 1.00 TO 1.21, P = .04; HORVATH'S CLOCK: HR = 1.08, 95% CI = 1.00 TO 1.17, P = .04; LEVINE'S CLOCK: HR = 1.15, 95% CI = 1.07 TO 1.23, P < .001). FOR LEVINE'S CLOCK, EACH 5-YEAR ACCELERATION IN BIOLOGICAL AGE CORRESPONDED WITH A 15% INCREASE IN BREAST CANCER RISK. ALTHOUGH BIOLOGICAL AGE MAY ACCELERATE WITH MENOPAUSAL TRANSITION, AGE ACCELERATION IN PREMENOPAUSAL WOMEN INDEPENDENTLY PREDICTED BREAST CANCER. CASE-ONLY ANALYSIS SUGGESTED THAT, AMONG WOMEN WHO DEVELOP BREAST CANCER, INCREASED AGE ACCELERATION IS ASSOCIATED WITH INVASIVE CANCER (ODDS RATIO FOR INVASIVE = 1.09, 95% CI = 0.98 TO 1.22, P = .10). CONCLUSIONS: DNA METHYLATION-BASED MEASURES OF BIOLOGICAL AGE MAY BE IMPORTANT PREDICTORS OF BREAST CANCER RISK.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
20  3075  36 GENOME-WIDE EPIGENETIC STUDY OF CHRONIC RHINOSINUSITIS TISSUES REVEALS DYSREGULATED INFLAMMATORY, IMMUNOLOGIC AND REMODELING PATHWAYS. BACKGROUND: EPIGENETICS STUDIES MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS, AND ALTERNATIVE POLYADENYLATION THAT CAN MODIFY GENE ACTIVITY WITHOUT CHANGING THE UNDERLYING DNA NUCLEOTIDE BASE-PAIR STRUCTURE. BECAUSE THESE CHANGES ARE REVERSIBLE, THEY HAVE POTENTIAL IN DEVELOPING NOVEL THERAPEUTICS. CURRENTLY, SEVEN PHARMACEUTICAL AGENTS TARGETING EPIGENETIC CHANGES ARE FDA APPROVED AND COMMERCIALLY AVAILABLE FOR TREATMENT OF CERTAIN CANCERS. HOWEVER, STUDIES INVESTIGATING EPIGENETICS IN CHRONIC RHINOSINUSITIS (CRS) HAVE NOT BEEN UNDERTAKEN PREVIOUSLY IN THE UNITED STATES. OBJECTIVES: THE GOAL OF THIS STUDY WAS TO INVESTIGATE SINONASAL DNA METHYLATION PATTERNS IN CRS VERSUS CONTROLS, TO DISCERN ENVIRONMENTALLY-INDUCED EPIGENETIC CHANGES IMPACTING CRS SUBJECTS. METHODS AND RESULTS: ETHMOIDAL SAMPLES FROM CRS AND INFERIOR TURBINATE MUCOSAL TISSUE SAMPLES FROM CONTROLS WITHOUT CRS WERE STUDIED. DNA METHYLATION WAS STUDIED BY REDUCED REPRESENTATION BISULFITE SEQUENCING. RADMETH(R) BIOSTATISTICAL PACKAGE WAS USED TO IDENTIFY DIFFERENTIALLY METHYLATED REGIONS (DMRS) BETWEEN CRS AND CONTROLS. INGENUITY PATHWAY ANALYSIS OF DMRS WAS PERFORMED TO IDENTIFY TOP UPSTREAM REGULATORS AND CANONICAL PATHWAYS. NINETY-THREE SAMPLES FROM 64 CRS SUBJECTS (36 CRSWNP; 28 CRSSNP) AND 29 CONTROLS WERE STUDIED. CRS AND CONTROL SAMPLES DIFFERED IN 13 662 CPGS SITES AND 1381 DMRS. TOP UPSTREAM REGULATORS IDENTIFIED INCLUDED: 1. CRS VERSUS CONTROLS: TGFB1, TNF, TP53, DGCR8, AND BETA-ESTRADIOL. 2. CRSWNP VERSUS CONTROLS: TGFB1, CTNNB1, LIPOPOLYSACCHARIDE, ID2, AND TCF7L2. 3. CRSSNP VERSUS CONTROLS: MYOD1, ACETONE, ID2, ST8SIA4, AND LEPR. CONCLUSIONS: DIFFERENTIAL PATTERNS OF METHYLATION WERE IDENTIFIED BETWEEN CONTROLS AND CRS, CRSWNP, AND CRSSNP. EPIGENETIC, ENVIRONMENTALLY-INDUCED CHANGES RELATED TO NOVEL, INFLAMMATORY, IMMUNOLOGIC, AND REMODELING PATHWAYS APPEAR TO AFFECT EPITHELIAL INTEGRITY, CELL PROLIFERATION, HOMEOSTASIS, VASCULAR PERMEABILITY, AND OTHER YET UNCHARACTERIZED PATHWAYS AND GENES.	2023