1 2048 134 EPIGENETIC CLUSTERING OF LUNG ADENOCARCINOMAS BASED ON DNA METHYLATION PROFILES IN ADJACENT LUNG TISSUE: ITS CORRELATION WITH SMOKING HISTORY AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE. THE AIM OF THIS STUDY WAS TO CLARIFY THE SIGNIFICANCE OF DNA METHYLATION ALTERATIONS DURING LUNG CARCINOGENESIS. INFINIUM ASSAY WAS PERFORMED USING 139 PAIRED SAMPLES OF NON-CANCEROUS LUNG TISSUE (N) AND TUMOROUS TISSUE (T) FROM A LEARNING COHORT OF PATIENTS WITH LUNG ADENOCARCINOMAS (LADCS). FIFTY PAIRED N AND T SAMPLES FROM A VALIDATION COHORT WERE ALSO ANALYZED. DNA METHYLATION ALTERATIONS ON 1,928 PROBES OCCURRED IN N SAMPLES RELATIVE TO NORMAL LUNG TISSUE FROM PATIENTS WITHOUT PRIMARY LUNG TUMORS, AND WERE INHERITED BY, OR STRENGTHENED IN, T SAMPLES. UNSUPERVISED HIERARCHICAL CLUSTERING USING DNA METHYLATION LEVELS IN N SAMPLES ON ALL 26,447 PROBES SUBCLUSTERED PATIENTS INTO CLUSTER I (N = 32), CLUSTER II (N = 35) AND CLUSTER III (N = 72). LADCS IN CLUSTER I DEVELOPED FROM THE INFLAMMATORY BACKGROUND IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN HEAVY SMOKERS AND WERE LOCALLY INVASIVE. MOST PATIENTS IN CLUSTER II WERE NON-SMOKERS AND HAD A FAVORABLE OUTCOME. LADCS IN CLUSTER III DEVELOPED IN LIGHT SMOKERS WERE MOST AGGRESSIVE (FREQUENTLY SHOWING LYMPHATIC AND BLOOD VESSEL INVASION, LYMPH NODE METASTASIS AND AN ADVANCED PATHOLOGICAL STAGE), AND HAD A POOR OUTCOME. DNA METHYLATION LEVELS OF HALLMARK GENES FOR EACH CLUSTER, SUCH AS IRX2, HOXD8, SPARCL1, RGS5 AND EI24, WERE AGAIN CORRELATED WITH CLINICOPATHOLOGICAL CHARACTERISTICS IN THE VALIDATION COHORT. DNA METHYLATION PROFILES REFLECTING CARCINOGENETIC FACTORS SUCH AS SMOKING AND COPD APPEAR TO BE ESTABLISHED IN NON-CANCEROUS LUNG TISSUE FROM PATIENTS WITH LADCS AND MAY DETERMINE THE AGGRESSIVENESS OF TUMORS DEVELOPING IN INDIVIDUAL PATIENTS, AND THUS PATIENT OUTCOME.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
2 1591  43 DNA METHYLATION PROFILING IN PERIPHERAL LUNG TISSUES OF SMOKERS AND PATIENTS WITH COPD. BACKGROUND: EPIGENETICS CHANGES HAVE BEEN SHOWN TO BE AFFECTED BY CIGARETTE SMOKING. CIGARETTE SMOKE (CS)-MEDIATED DNA METHYLATION CAN POTENTIALLY AFFECT SEVERAL CELLULAR AND PATHOPHYSIOLOGICAL PROCESSES, ACUTE EXACERBATIONS, AND COMORBIDITY IN THE LUNGS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). WE SOUGHT TO DETERMINE WHETHER GENOME-WIDE LUNG DNA METHYLATION PROFILES OF SMOKERS AND PATIENTS WITH COPD WERE SIGNIFICANTLY DIFFERENT FROM NON-SMOKERS. WE ISOLATED DNA FROM PARENCHYMAL LUNG TISSUES OF PATIENTS INCLUDING EIGHT LIFELONG NON-SMOKERS, EIGHT CURRENT SMOKERS, AND EIGHT PATIENTS WITH COPD AND ANALYZED THE SAMPLES USING ILLUMINA'S INFINIUM HUMANMETHYLATION450 BEADCHIP. RESULTS: OUR DATA REVEALED THAT THE DIFFERENTIALLY METHYLATED GENES WERE RELATED TO TOP CANONICAL PATHWAYS (E.G., G BETA GAMMA SIGNALING, MECHANISMS OF CANCER, AND NNOS SIGNALING IN NEURONS), DISEASE AND DISORDERS (ORGANISMAL INJURY AND ABNORMALITIES, CANCER, AND RESPIRATORY DISEASE), AND MOLECULAR AND CELLULAR FUNCTIONS (CELL DEATH AND SURVIVAL, CELLULAR ASSEMBLY AND ORGANIZATION, CELLULAR FUNCTION AND MAINTENANCE) IN PATIENTS WITH COPD. THE GENOME-WIDE DNA METHYLATION ANALYSIS IDENTIFIED SUGGESTIVE GENES, SUCH AS NOS1AP, TNFAIP2, BID, GABRB1, ATXN7, AND THOC7 WITH DNA METHYLATION CHANGES IN COPD LUNG TISSUES THAT WERE FURTHER VALIDATED BY PYROSEQUENCING. PYROSEQUENCING VALIDATION CONFIRMED HYPER-METHYLATION IN SMOKERS AND PATIENTS WITH COPD AS COMPARED TO NON-SMOKERS. HOWEVER, WE DID NOT DETECT SIGNIFICANT DIFFERENCES IN DNA METHYLATION FOR TNFAIP2, ATXN7, AND THOC7 GENES IN SMOKERS AND COPD GROUPS DESPITE THE CHANGES OBSERVED IN THE GENOME-WIDE ANALYSIS. CONCLUSIONS: OUR STUDY SUGGESTS THAT DNA METHYLATION IN SUGGESTIVE GENES, SUCH AS NOS1AP, BID, AND GABRB1 MAY BE USED AS EPIGENETIC SIGNATURES IN SMOKERS AND PATIENTS WITH COPD IF THE SAME IS VALIDATED IN A LARGER COHORT. FUTURE STUDIES ARE REQUIRED TO CORRELATE DNA METHYLATION STATUS WITH TRANSCRIPTOMICS OF SELECTIVE GENES IDENTIFIED IN THIS STUDY AND ELUCIDATE THEIR ROLE AND INVOLVEMENT IN THE PROGRESSION OF COPD AND ITS EXACERBATIONS.	2017	
                                                                                                                
3 3954  30 LONG INTERSPERSED NUCLEAR ELEMENT-1 METHYLATION STATUS IN THE CIRCULATING DNA FROM BLOOD OF PATIENTS WITH MALIGNANT AND CHRONIC INFLAMMATORY LUNG DISEASES. ALONG WITH OTHER MALIGNANT DISEASES, LUNG CANCER ARISES FROM THE PRECANCEROUS LUNG TISSUE STATE. ABERRANT DNA METHYLATION (HYPERMETHYLATION OF CERTAIN GENES AND HYPOMETHYLATION OF RETROTRANSPOSONS) IS KNOWN AS ONE OF THE DRIVING FORCES OF MALIGNANT CELL TRANSFORMATION. EPIGENETIC CHANGES WERE SHOWN TO BE DETECTABLE IN DNA, CIRCULATING IN THE BLOOD (CIRDNA) OF CANCER PATIENTS, INDICATING THE POSSIBILITY TO USE THEM AS CANCER MARKERS. THE CURRENT STUDY IS THE FIRST TO COMPARE THE LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) METHYLATION LEVEL IN THE BLOOD FROM LUNG CANCER PATIENTS BEFORE TREATMENT VERSUS DIFFERENT CONTROL GROUPS AS HEALTHY SUBJECTS, PATIENTS WITH BRONCHITIS AND PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THE CONCENTRATION OF LINE-1 METHYLATED FRAGMENTS, REGION 1 (LINE-1 METHYLATED, LINE-1-MET) WAS ESTIMATED BY QUANTITATIVE METHYL-SPECIFIC PCR. THE TOTAL CONCENTRATION OF THE CIRCULATING LINE-1 COPIES WAS MEASURED BY QPCR SPECIFIC FOR LINE-1 REGION 2, WHICH WAS SELECTED DUE TO ITS CPG METHYLATION-INDEPENDENT SEQUENCE (LINE-1-IND). BOTH LINE-1 METHYLATION LEVEL AND LINE-1 METHYLATION INDEX (LINE-1-MET/LINE-1-IND RATIO) WAS DECREASED IN LUNG CANCER PATIENTS COMPARED WITH THE JOINT CONTROL GROUP (HEALTHY SUBJECTS + PATIENTS WITH BRONCHITIS + COPD PATIENTS) (MANN-WHITNEY U-TEST, P = 0.016). WE ALSO FOUND THAT THE TENDENCY OF LINE-1 METHYLATION INDEX DECREASES IN THE CIRDNA FROM LUNG CANCER PATIENTS VERSUS COPD PATIENTS (MANN-WHITNEY U-TEST, P = 0.07). OUR DATA INDICATE THAT THE QUANTITATIVE ANALYSIS OF THE LINE-1 METHYLATION LEVEL IN THE CIRDNA IS VALUABLE FOR DISCRIMINATION OF LUNG CANCER PATIENTS FROM PATIENTS WITH CHRONIC INFLAMMATORY LUNG DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
4 1590  30 DNA METHYLATION PROFILING IN HUMAN LUNG TISSUE IDENTIFIES GENES ASSOCIATED WITH COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A SMOKING-RELATED DISEASE CHARACTERIZED BY GENETIC AND PHENOTYPIC HETEROGENEITY. ALTHOUGH ASSOCIATION STUDIES HAVE IDENTIFIED MULTIPLE GENOMIC REGIONS WITH REPLICATED ASSOCIATIONS TO COPD, GENETIC VARIATION ONLY PARTIALLY EXPLAINS THE SUSCEPTIBILITY TO LUNG DISEASE, AND SUGGESTS THE RELEVANCE OF EPIGENETIC INVESTIGATIONS. WE PERFORMED GENOME-WIDE DNA METHYLATION PROFILING IN HOMOGENIZED LUNG TISSUE SAMPLES FROM 46 CONTROL SUBJECTS WITH NORMAL LUNG FUNCTION AND 114 SUBJECTS WITH COPD, ALL FORMER SMOKERS. THE DIFFERENTIALLY METHYLATED LOCI WERE INTEGRATED WITH PREVIOUS GENOME-WIDE ASSOCIATION STUDY RESULTS. THE TOP 535 DIFFERENTIALLY METHYLATED SITES, FILTERED FOR A MINIMUM MEAN METHYLATION DIFFERENCE OF 5% BETWEEN CASES AND CONTROLS, WERE ENRICHED FOR CPG SHELVES AND SHORES. PATHWAY ANALYSIS REVEALED ENRICHMENT FOR TRANSCRIPTION FACTORS. THE TOP DIFFERENTIALLY METHYLATED SITES FROM THE INTERSECTION WITH PREVIOUS GWAS WERE IN CHRM1, GLT1D1, AND C10ORF11; SORTED BY GWAS P-VALUE, THE TOP SITES INCLUDED FRMD4A, THSD4, AND C10ORF11. EPIGENETIC ASSOCIATION STUDIES COMPLEMENT GENETIC ASSOCIATION STUDIES TO IDENTIFY GENES POTENTIALLY INVOLVED IN COPD PATHOGENESIS. ENRICHMENT FOR GENES IMPLICATED IN ASTHMA AND LUNG FUNCTION AND FOR TRANSCRIPTION FACTORS SUGGESTS THE POTENTIAL PATHOGENIC RELEVANCE OF GENES IDENTIFIED THROUGH DIFFERENTIAL METHYLATION AND THE INTERSECTION WITH A BROADER RANGE OF GWAS ASSOCIATIONS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5 1607  29 DNA METHYLATION, COLON CANCER AND MEDITERRANEAN DIET: RESULTS FROM THE EPIC-ITALY COHORT. THE BIOLOGICAL MECHANISMS THROUGH WHICH ADHERENCE TO MEDITERRANEAN DIET (MD) PROTECTS AGAINST COLON CANCER (CC) ARE POORLY UNDERSTOOD. EVIDENCE SUGGESTS THAT CHRONIC INFLAMMATION MAY BE IMPLICATED IN THE PATHWAY. BOTH DIET AND CC ARE RELATED TO EPIGENETIC REGULATION. WE PERFORMED A NESTED CASE-CONTROL STUDY ON 161 PAIRS FROM THE ITALIAN COMPONENT OF THE EUROPEAN PROSPECTIVE INVESTIGATION INTO CANCER AND NUTRITION (EPIC) COHORT, IN WHICH WE LOOKED FOR THE METHYLATION SIGNALS IN DNA EXTRACTED FROM LEUCOCYTES ASSOCIATED WITH BOTH CC AND MD IN 995 CPGS LOCATED IN 48 INFLAMMATION GENES. THE DNA METHYLATION SIGNALS DETECTED IN THIS ANALYSIS WERE VALIDATED IN A SUBGROUP OF 47 CASE-CONTROL PAIRS AND FURTHER REPLICATED (WHERE VALIDATED) IN 95 NEW PAIRS BY MEANS OF PYROSEQUENCING. AMONG THE CPG SITES SELECTED A-PRIORI IN INFLAMMATION-RELATED GENES, SEVEN CPG SITES WERE FOUND TO BE ASSOCIATED WITH CC STATUS AND WITH MD, IN LINE WITH ITS PROTECTIVE EFFECT. ONLY TWO CPG SITES (CG17968347-SERPINE1 AND CG20674490-RUNX3) WERE VALIDATED USING BISULPHITE PYROSEQUENCING AND, AFTER REPLICATION, WE FOUND THAT DNA METHYLATION OF CG20674490-RUNX3 MAY BE A POTENTIAL MOLECULAR MEDIATOR EXPLAINING THE PROTECTIVE EFFECT OF MD ON CC ONSET. THE USE OF A 'MEET-IN-THE-MIDDLE' APPROACH TO IDENTIFY THE OVERLAP BETWEEN EXPOSURE AND PREDICTIVE MARKERS OF DISEASE IS INNOVATIVE IN STUDIES ON THE RELATIONSHIP BETWEEN DIET AND CANCER, IN WHICH EXPOSURE ASSESSMENT IS DIFFICULT AND THE MECHANISMS THROUGH WHICH THE NUTRIENTS EXERT THEIR PROTECTIVE EFFECT IS LARGELY UNKNOWN.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
6 1519  28 DNA METHYLATION AT ATP11A CG11702988 IS A BIOMARKER OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS: A LONGITUDINAL STUDY. CYSTIC FIBROSIS (CF) IS A CHRONIC GENETIC DISEASE THAT MAINLY AFFECTS THE RESPIRATORY AND GASTROINTESTINAL SYSTEMS. NO CURATIVE TREATMENTS ARE AVAILABLE, BUT THE FOLLOW-UP IN SPECIALIZED CENTERS HAS GREATLY IMPROVED THE PATIENT LIFE EXPECTANCY. ROBUST BIOMARKERS ARE REQUIRED TO MONITOR THE DISEASE, GUIDE TREATMENTS, STRATIFY PATIENTS, AND PROVIDE OUTCOME MEASURES IN CLINICAL TRIALS. IN THE PRESENT STUDY, WE OUTLINE A STRATEGY TO SELECT PUTATIVE DNA METHYLATION BIOMARKERS OF LUNG DISEASE SEVERITY IN CYSTIC FIBROSIS PATIENTS. IN THE DISCOVERY STEP, WE SELECTED SEVEN POTENTIAL BIOMARKERS USING A GENOME-WIDE DNA METHYLATION DATASET THAT WE GENERATED IN NASAL EPITHELIAL SAMPLES FROM THE METHYLCF COHORT. IN THE REPLICATION STEP, WE ASSESSED THE SAME BIOMARKERS USING SPUTUM CELL SAMPLES FROM THE METHYLBIOMARK COHORT. OF INTEREST, DNA METHYLATION AT THE CG11702988 SITE (ATP11A GENE) POSITIVELY CORRELATED WITH LUNG FUNCTION AND BMI, AND NEGATIVELY CORRELATED WITH LUNG DISEASE SEVERITY, P. AERUGINOSA CHRONIC INFECTION, AND THE NUMBER OF EXACERBATIONS. THESE RESULTS WERE REPLICATED IN PROSPECTIVE SPUTUM SAMPLES COLLECTED AT FOUR TIME POINTS WITHIN AN 18-MONTH PERIOD AND LONGITUDINALLY. TO CONCLUDE, (I) WE IDENTIFIED A DNA METHYLATION BIOMARKER THAT CORRELATES WITH CF SEVERITY, (II) WE PROVIDED A METHOD TO EASILY ASSESS THIS BIOMARKER, AND (III) WE CARRIED OUT THE FIRST LONGITUDINAL ANALYSIS OF DNA METHYLATION IN CF PATIENTS. THIS NEW EPIGENETIC BIOMARKER COULD BE USED TO STRATIFY CF PATIENTS IN CLINICAL TRIALS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
7 3125  27 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
8  158  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
9 6488  33 TP53 R72P POLYMORPHISM MODULATES DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS CHARACTERIZED BY WIDESPREAD EPIDEMIOLOGICAL AND MOLECULAR HETEROGENEITY. PREVIOUS WORK SHOWED THAT IN THE WESTERN PART OF NORTH AFRICA, A REGION OF LOW INCIDENCE OF HCC, MUTATIONS ARE SCARCE FOR THIS TUMOR TYPE. AS EPIGENETIC CHANGES ARE CONSIDERED POSSIBLE SURROGATES TO MUTATIONS IN HUMAN CANCERS, WE DECIDED, THUS, TO CHARACTERIZE DNA METHYLATION IN HCC FROM NORTH-AFRICAN PATIENTS. METHODS: A SET OF 11 LOCI WAS INVESTIGATED IN A SERIES OF 45 TUMOR SPECIMENS USING METHYLATION-SPECIFIC AND COMBINED-BISULFITE RESTRICTION ASSAY PCR. RESULTS OBTAINED ON CLINICAL SAMPLES WERE SUBSEQUENTLY VALIDATED IN LIVER CANCER CELL LINES. RESULTS: DNA METHYLATION AT TUMOR SUPPRESSOR LOCI IS SIGNIFICANTLY HIGHER IN SAMPLES DISPLAYING CHROMOSOME INSTABILITY. MORE IMPORTANTLY, DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN ARG/ARG WHEN COMPARED TO PRO/PRO GENOTYPE CARRIERS AT CODON 72 RS1042522 OF TP53 (65% VS 20% METHYLATED LOCI, P = 0.0006), A POLYMORPHISM ALREADY KNOWN TO AFFECT SOMATIC MUTATION RATE IN HUMAN CARCINOMAS. IN VITRO EXPERIMENTS IN CELL LINES INDICATED THAT ENZYMES CONTROLLING DNA METHYLATION WERE DIFFERENTIALLY REGULATED BY CODON 72 ARG OR PRO ISOFORMS OF P53. FURTHERMORE, THE ARG72-CARRYING VERSION OF P53 WAS SHOWN TO RE-METHYLATE DNA MORE RAPIDLY THAN THE PRO-HARBORING ISOFORM. FINALLY, PRO-CARRYING CELL LINES WERE SHOWN TO BE SIGNIFICANTLY MORE RESISTANT TO DECITABINE TREATMENT (TWO-FOLD, P = 0.005). CONCLUSIONS: OUR DATA SUGGEST THAT ARG72PRO POLYMORPHISM IN A WT P53 CONTEXT MAY ACT AS A PRIMARY DRIVER OF EPIGENETIC CHANGES IN HCC. IT SUGGESTS, IN ADDITION, THAT RS1042522 GENOTYPE MAY PREDICT SENSITIVITY TO EPIGENETIC-TARGETED THERAPY. THIS MODEL OF LIVER TUMORIGENESIS THAT ASSOCIATES LOW PENETRANCE GENETIC PREDISPOSITION TO EPIGENETIC CHANGES EMERGES FROM A REGION OF LOW HCC INCIDENCE AND IT MAY, THEREFORE, APPLY ESSENTIALLY TO POPULATION LIVING IN SIMILAR AREAS. SURVEYS ON POPULATIONS SUBMITTED TO HIGHLY MUTAGENIC CONDITIONS AS PERINATALLY-ACQUIRED CHRONIC HEPATITIS B OR AFLATOXIN B1 EXPOSURE REMAINED TO BE CONDUCTED TO VALIDATE OUR OBSERVATIONS AS A GENERAL MODEL.	2015	
                                                                                          
10 1909  36 ENRICHMENT OF GENOMIC PATHWAYS BASED ON DIFFERENTIAL DNA METHYLATION PROFILES ASSOCIATED WITH CHRONIC MUSCULOSKELETAL PAIN IN OLDER ADULTS: AN EXPLORATORY STUDY. OUR STUDY AIMED TO IDENTIFY DIFFERENTIALLY METHYLATED CPGS/REGIONS AND THEIR ENRICHED GENOMIC PATHWAYS ASSOCIATED WITH UNDERLYING CHRONIC MUSCULOSKELETAL PAIN IN OLDER INDIVIDUALS. WE RECRUITED COGNITIVELY HEALTHY OLDER ADULTS WITH (N = 20) AND WITHOUT (N = 9) SELF-REPORTED MUSCULOSKELETAL PAIN AND COLLECTED DNA FROM PERIPHERAL BLOOD THAT WAS ANALYZED USING METHYLATIONEPIC ARRAYS. WE IDENTIFIED 31,739 HYPERMETHYLATED CPG AND 10,811 HYPOMETHYLATED CPG PROBES (PS </= 0.05). ALL CPG PROBES WERE CLUSTERED INTO 5966 REGIONS, AMONG WHICH 600 REGIONS WERE DIFFERENTIALLY METHYLATED AT P </= 0.05 LEVEL, INCLUDING 294 HYPERMETHYLATED REGIONS AND 306 HYPOMETHYLATED REGIONS (DIFFERENTIALLY METHYLATED REGIONS). INGENUITY PATHWAY ENRICHMENT ANALYSIS REVEALED THAT THE PAIN-RELATED DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED ACROSS MULTIPLE PATHWAYS. THE TOP 10 CANONICAL PATHWAYS WERE LINKED TO CELLULAR SIGNALING PROCESSES RELATED TO IMMUNE RESPONSES (I.E. ANTIGEN PRESENTATION, PROGRAMED CELL DEATH 1 RECEPTOR/PD-1 LIGAND 1, INTERLEUKIN-4, OX40 SIGNALING, T CELL EXHAUSTION, AND APOPTOSIS) AND GAMMA-AMINOBUTYRIC ACID RECEPTOR SIGNALING. FURTHER, WEIGHTED GENE CORRELATION NETWORK ANALYSIS REVEALED A COMETHYLATION NETWORK MODULE IN THE PAIN GROUP THAT WAS NOT PRESERVED IN THE CONTROL GROUP, WHERE THE HUB GENE WAS THE CYCLIC ADENOSINE MONOPHOSPHATE-DEPENDENT TRANSCRIPTION FACTOR ATF-2. OUR PRELIMINARY FINDINGS PROVIDE NEW EPIGENETIC INSIGHTS INTO THE ROLE OF ABERRANT IMMUNE SIGNALING IN MUSCULOSKELETAL PAIN IN OLDER ADULTS WHILE FURTHER SUPPORTING INVOLVEMENT OF DYSFUNCTIONAL GABAERGIC SIGNALING MECHANISMS IN CHRONIC PAIN. OUR FINDINGS NEED TO BE URGENTLY REPLICATED IN LARGER COHORTS AS THEY MAY SERVE AS A BASIS FOR DEVELOPING AND TARGETING FUTURE INTERVENTIONS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                        
11 1739  35 EARLY DNA METHYLATION CHANGES IN CHILDREN DEVELOPING BETA CELL AUTOIMMUNITY AT A YOUNG AGE. AIMS/HYPOTHESIS: TYPE 1 DIABETES IS A CHRONIC AUTOIMMUNE DISEASE OF COMPLEX AETIOLOGY, INCLUDING A POTENTIAL ROLE FOR EPIGENETIC REGULATION. PREVIOUS EPIGENOMIC STUDIES FOCUSED MAINLY ON CLINICALLY DIAGNOSED INDIVIDUALS. THE AIM OF THE STUDY WAS TO ASSESS EARLY DNA METHYLATION CHANGES ASSOCIATED WITH TYPE 1 DIABETES ALREADY BEFORE THE DIAGNOSIS OR EVEN BEFORE THE APPEARANCE OF AUTOANTIBODIES. METHODS: REDUCED REPRESENTATION BISULPHITE SEQUENCING (RRBS) WAS APPLIED TO STUDY DNA METHYLATION IN PURIFIED CD4(+) T CELL, CD8(+) T CELL AND CD4(-)CD8(-) CELL FRACTIONS OF 226 PERIPHERAL BLOOD MONONUCLEAR CELL SAMPLES LONGITUDINALLY COLLECTED FROM SEVEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL INDIVIDUALS MATCHED FOR AGE, SEX, HLA RISK AND PLACE OF BIRTH. WE ALSO EXPLORED CORRELATIONS BETWEEN DNA METHYLATION AND GENE EXPRESSION USING RNA SEQUENCING DATA FROM THE SAME SAMPLES. TECHNICAL VALIDATION OF RRBS RESULTS WAS PERFORMED USING PYROSEQUENCING. RESULTS: WE IDENTIFIED 79, 56 AND 45 DIFFERENTIALLY METHYLATED REGIONS IN CD4(+) T CELLS, CD8(+) T CELLS AND CD4(-)CD8(-) CELL FRACTIONS, RESPECTIVELY, BETWEEN TYPE 1 DIABETES-SPECIFIC AUTOANTIBODY-POSITIVE INDIVIDUALS AND CONTROL PARTICIPANTS. THE ANALYSIS OF PRE-SEROCONVERSION SAMPLES IDENTIFIED DNA METHYLATION SIGNATURES AT THE VERY EARLY STAGE OF DISEASE, INCLUDING DIFFERENTIAL METHYLATION AT THE PROMOTER OF IRF5 IN CD4(+) T CELLS. FURTHER, WE VALIDATED RRBS RESULTS USING PYROSEQUENCING AT THE FOLLOWING CPG SITES: CHR19:18118304 IN THE PROMOTER OF ARRDC2; CHR21:47307815 IN THE INTRON OF PCBP3; AND CHR14:81128398 IN THE INTERGENIC REGION NEAR TRAF3 IN CD4(+) T CELLS. CONCLUSIONS/INTERPRETATION: THESE PRELIMINARY RESULTS PROVIDE NOVEL INSIGHTS INTO CELL TYPE-SPECIFIC DIFFERENTIAL EPIGENETIC REGULATION OF GENES, WHICH MAY CONTRIBUTE TO TYPE 1 DIABETES PATHOGENESIS AT THE VERY EARLY STAGE OF DISEASE DEVELOPMENT. SHOULD THESE FINDINGS BE VALIDATED, THEY MAY SERVE AS A POTENTIAL SIGNATURE USEFUL FOR DISEASE PREDICTION AND MANAGEMENT.	2022	
                                                                                                                                                                                                
12 5673  37 SHARED EPIGENETIC ALTERATIONS BETWEEN ORAL CANCER AND PERIODONTITIS: A PRELIMINARY STUDY. INTRODUCTION: WE RECENTLY DEVELOPED A NON-INVASIVE SAMPLING PROCEDURE FOR ORAL SQUAMOUS CELL CARCINOMA (OSCC) DETECTION BASED ON DNA METHYLATION ANALYSIS OF A PANEL OF 13 GENES. ORAL CANCER, AS WELL AS ACUTE AND CHRONIC INFLAMMATORY DISEASES, MAY INFLUENCE THE METHYLATION LEVEL OF SEVERAL GENES IN THE ORAL CAVITY. IN THE PRESENT STUDY, WE EVALUATED THE PRESENCE OF PERIODONTAL DISEASE (PD) AND THE METHYLATION STATUS USING OUR 13-GENE PANEL. METHODS: ORAL BRUSHING SPECIMENS WERE COLLECTED FROM THREE DIFFERENT PATIENT GROUPS: 23 GINGIVAL OSCC PATIENTS, 15 PATIENTS AFFECTED BY PD, AND 15 HEALTHY VOLUNTEERS LACKING EVIDENCE OF PD. DNA METHYLATION ANALYSIS WAS PERFORMED AND EACH SAMPLE WAS DETERMINED TO BE POSITIVE OR NEGATIVE BASED ON A PREDEFINED CUT-OFF VALUE. RESULTS: POSITIVE RESULTS WERE FOUND FOR 23/23 OSCC PATIENTS, 3/15 PD PATIENTS, AND 0/15 SAMPLES FROM HEALTHY VOLUNTEERS. THE GP1BB AND MIR193 GENES IN THE PD GROUP EXHIBITED MEAN METHYLATION LEVELS SIMILAR TO OSCC PATIENTS. ZAP70 SHOWED DIFFERENT METHYLATION LEVELS AMONG THREE GROUPS. CONCLUSION: PRELIMINARY DATA IDENTIFIED SHARED EPIGENETIC ALTERATIONS BETWEEN PD AND OSCC PATIENTS IN TWO INFLAMMATORY GENES (GP1BB AND MIR193). THIS STUDY MAY HELP TO IDENTIFY POTENTIAL LINKS BETWEEN THE TWO DISEASES AND SERVE AS A STARTING POINT FOR THE FUTURE RESEARCH FOCUSED ON PATHOGENESIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
13 6190  36 THE IMPACT OF METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ON ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES. BACKGROUND: METHYLATION QUANTITATIVE TRAIT LOCI (MQTLS) ARE THE GENETIC VARIANTS THAT MAY AFFECT THE DNA METHYLATION PATTERNS OF CPG SITES. HOWEVER, THEIR ROLES IN INFLUENCING THE DISTURBANCES OF SMOKING-RELATED EPIGENETIC CHANGES HAVE NOT BEEN WELL ESTABLISHED. THIS STUDY WAS CONDUCTED TO ADDRESS WHETHER MQTLS EXIST IN THE VICINITY OF SMOKING-RELATED CPG SITES (+/- 50 KB) AND TO EXAMINE THEIR ASSOCIATIONS WITH SMOKING EXPOSURE AND ALL-CAUSE MORTALITY IN OLDER ADULTS. RESULTS: WE OBTAINED DNA METHYLATION PROFILES IN WHOLE BLOOD SAMPLES BY ILLUMINA INFINIUM HUMAN METHYLATION 450 BEADCHIP ARRAY OF TWO INDEPENDENT SUBSAMPLES OF THE ESTHER STUDY (DISCOVERY SET, N = 581; VALIDATION SET, N = 368) AND THEIR CORRESPONDING GENOTYPING DATA USING THE ILLUMINA INFINIUM ONCOARRAY BEADCHIP. AFTER CORRECTION FOR MULTIPLE TESTING (FDR), WE SUCCESSFULLY IDENTIFIED THAT 70 OUT OF 151 PREVIOUSLY REPORTED SMOKING-RELATED CPG SITES WERE SIGNIFICANTLY ASSOCIATED WITH 192 SNPS WITHIN THE 50 KB SEARCH WINDOW OF EACH LOCUS. THE 192 MQTLS SIGNIFICANTLY INFLUENCED THE ACTIVE SMOKING-RELATED DNA METHYLATION CHANGES, WITH PERCENTAGE CHANGES RANGING FROM 0.01 TO 18.96%, ESPECIALLY FOR THE WEAKLY/MODERATELY SMOKING-RELATED CPG SITES. HOWEVER, THESE IDENTIFIED MQTLS WERE NOT DIRECTLY ASSOCIATED WITH ACTIVE SMOKING EXPOSURE OR ALL-CAUSE MORTALITY. CONCLUSIONS: OUR FINDINGS CLEARLY DEMONSTRATED THAT IF NOT DEALT WITH PROPERLY, THE MQTLS MIGHT IMPAIR THE POWER OF EPIGENETIC-BASED MODELS OF SMOKING EXPOSURE TO A CERTAIN EXTENT. IN ADDITION, SUCH GENETIC VARIANTS COULD BE THE KEY FACTOR TO DISTINGUISH BETWEEN THE HERITABLE AND SMOKING-INDUCED IMPACT ON EPIGENOME DISPARITIES. THESE MQTLS ARE OF SPECIAL IMPORTANCE WHEN DNA METHYLATION MARKERS MEASURED BY ILLUMINA INFINIUM ASSAY ARE USED FOR ANY COMPARATIVE POPULATION STUDIES RELATED TO SMOKING-RELATED CANCERS AND CHRONIC DISEASES.	2017	
                                                                                                                                                                                                                                                                                                                                          
14 2653  35 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008	
                                                                                                                                                                                                                                                                                     
15 6080  31 THE EFFECT OF DNA METHYLATION IN THE DEVELOPMENT AND PROGRESSION OF CHRONIC KIDNEY DISEASE IN THE GENERAL POPULATION: AN EPIGENOME-WIDE ASSOCIATION STUDY USING THE KOREAN GENOME AND EPIDEMIOLOGY STUDY DATABASE. BACKGROUND: ALTHOUGH KNOWLEDGE OF THE GENETIC FACTORS INFLUENCING KIDNEY DISEASE IS INCREASING, EPIGENETIC PROFILES, WHICH ARE ASSOCIATED WITH CHRONIC KIDNEY DISEASE (CKD), HAVE NOT BEEN FULLY ELUCIDATED. WE SOUGHT TO IDENTIFY THE DNA METHYLATION STATUS OF CPG SITES ASSOCIATED WITH REDUCED KIDNEY FUNCTION AND EXAMINE WHETHER THE IDENTIFIED CPG SITES ARE ASSOCIATED WITH CKD DEVELOPMENT. METHOD: WE ANALYZED DNA METHYLATION PATTERNS OF 440 PARTICIPANTS IN THE KOREAN GENOME AND EPIDEMIOLOGY STUDY (KOGES) WITH ESTIMATED GLOMERULAR FILTRATION RATES (EGFRS) >/= 60 ML/MIN/1.73 M(2) AT BASELINE. CKD DEVELOPMENT WAS DEFINED AS A DECREASE IN THE EGFR OF <60 AT ANY TIME DURING AN 8-YEAR FOLLOW-UP PERIOD ("CKD PREDICTION" ANALYSIS). IN ADDITION, AMONG THE 440 PARTICIPANTS, 49 PARTICIPANTS WHO UNDERWENT A SECOND METHYLATION PROFILING WERE ASSESSED FOR AN ASSOCIATION BETWEEN A DECLINE IN KIDNEY FUNCTION AND CHANGES IN THE DEGREE OF METHYLATION OF CPG SITES DURING THE 8 YEARS ("KIDNEY FUNCTION SLOPE" ANALYSIS). RESULTS: IN THE CKD PREDICTION ANALYSIS, METHYLATION PROFILES OF A TOTAL OF 403,129 CPG SITES WERE EVALUATED AT BASELINE IN 440 PARTICIPANTS, AND INCREASED AND DECREASED METHYLATION OF 268 AND 189 CPG SITES, RESPECTIVELY, WERE SIGNIFICANTLY CORRELATED WITH THE DEVELOPMENT OF CKD IN MULTIVARIABLE LOGISTIC REGRESSION. DURING KIDNEY FUNCTION SLOPE ANALYSIS USING FOLLOW-UP METHYLATION PROFILES OF 49 PARTICIPANTS, THE PERCENT METHYLATION CHANGES IN 913 CPG SITES SHOWED A LINEAR RELATIONSHIP WITH THE PERCENT CHANGE IN EGFR DURING 8 YEARS. DURING FUNCTIONAL ENRICHMENT ANALYSES FOR SIGNIFICANT CPG SITES FOUND IN THE CKD PREDICTION AND KIDNEY FUNCTION SLOPE ANALYSES, WE FOUND THAT THOSE CPG SITES REPRESENTED MAPK, PI3K/AKT, AND RAP1 PATHWAYS. IN ADDITION, THREE CPG SITES FROM THREE GENES, NPHS2, CHCHD4, AND AHR, WERE FOUND TO BE SIGNIFICANT IN THE CKD PREDICTION ANALYSIS AND RELATED TO A DECLINE IN KIDNEY FUNCTION. CONCLUSION: IT IS SUGGESTED THAT DNA METHYLATION ON SPECIFIC GENES IS ASSOCIATED WITH THE DEVELOPMENT OF CKD AND THE DETERIORATION OF KIDNEY FUNCTION.	2023	
                     
16 1587  32 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
17 6691  33 VARIABLE DNA METHYLATION IS ASSOCIATED WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE AND LUNG FUNCTION. RATIONALE: CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS ASSOCIATED WITH LOCAL (LUNG) AND SYSTEMIC (BLOOD) INFLAMMATION AND MANIFESTATIONS. DNA METHYLATION IS AN IMPORTANT REGULATOR OF GENE TRANSCRIPTION, AND GLOBAL AND SPECIFIC GENE METHYLATION MARKS MAY VARY WITH CIGARETTE SMOKE EXPOSURE. OBJECTIVES: TO PERFORM A COMPREHENSIVE ASSESSMENT OF METHYLATION MARKS IN DNA FROM SUBJECTS WELL PHENOTYPED FOR NONNEOPLASTIC LUNG DISEASE. METHODS: WE CONDUCTED ARRAY-BASED METHYLATION SCREENS, USING A TEST-REPLICATION APPROACH, IN TWO FAMILY-BASED COHORTS (N = 1,085 AND 369 SUBJECTS). MEASUREMENTS AND MAIN RESULTS: WE OBSERVED 349 CPG SITES SIGNIFICANTLY ASSOCIATED WITH THE PRESENCE AND SEVERITY OF COPD IN BOTH COHORTS. SEVENTY PERCENT OF THE ASSOCIATED CPG SITES WERE OUTSIDE OF CPG ISLANDS, WITH THE MAJORITY OF CPG SITES RELATIVELY HYPOMETHYLATED. GENE ONTOLOGY ANALYSIS BASED ON THESE 349 CPGS (330 GENES) SUGGESTED THE INVOLVEMENT OF A NUMBER OF GENES RESPONSIBLE FOR IMMUNE AND INFLAMMATORY SYSTEM PATHWAYS, RESPONSES TO STRESS AND EXTERNAL STIMULI, AS WELL AS WOUND HEALING AND COAGULATION CASCADES. INTERESTINGLY, OUR OBSERVATIONS INCLUDE SIGNIFICANT, REPLICABLE ASSOCIATIONS BETWEEN SERPINA1 HYPOMETHYLATION AND COPD AND LOWER AVERAGE LUNG FUNCTION PHENOTYPES (COMBINED P VALUES: COPD, 1.5 X 10(-23); FEV(1)/FVC, 1.5 X 10(-35); FEV(1), 2.2 X 10(-40)). CONCLUSIONS: GENETIC AND EPIGENETIC PATHWAYS MAY BOTH CONTRIBUTE TO COPD. MANY OF THE TOP ASSOCIATIONS BETWEEN COPD AND DNA METHYLATION OCCUR IN BIOLOGICALLY PLAUSIBLE PATHWAYS. THIS LARGE-SCALE ANALYSIS SUGGESTS THAT DNA METHYLATION MAY BE A BIOMARKER OF COPD AND MAY HIGHLIGHT NEW PATHWAYS OF COPD PATHOGENESIS.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
18   57  39 A GENOME-WIDE ASSOCIATION STUDY OF QUANTITATIVE COMPUTED TOMOGRAPHIC EMPHYSEMA IN KOREAN POPULATIONS. EMPHYSEMA IS AN IMPORTANT FEATURE OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). GENETIC FACTORS LIKELY AFFECT EMPHYSEMA PATHOGENESIS, BUT THIS QUESTION HAS PREDOMINANTLY BEEN STUDIED IN THOSE OF EUROPEAN ANCESTRY. IN THIS STUDY, WE SOUGHT TO DETERMINE GENETIC COMPONENTS OF EMPHYSEMA SEVERITY AND CHARACTERIZE THE POTENTIAL FUNCTION OF THE ASSOCIATED LOCI IN KOREAN POPULATION. WE PERFORMED A GENOME-WIDE ASSOCIATION STUDY (GWAS) ON QUANTITATIVE EMPHYSEMA IN SUBJECTS WITH OR WITHOUT COPD FROM TWO KOREAN COPD COHORTS. WE INVESTIGATED THE FUNCTIONAL CONSEQUENCES OF THE LOCI USING EPIGENETIC ANNOTATION AND GENE EXPRESSION DATA. WE ALSO COMPARED OUR GWAS RESULTS WITH AN EPIGENOME-WIDE ASSOCIATION STUDY AND PREVIOUS DIFFERENTIAL GENE EXPRESSION ANALYSIS. IN TOTAL, 548 SUBJECTS (476 [86.9%] MALE) INCLUDING 514 COPD PATIENTS WERE EVALUATED. WE IDENTIFIED ONE GENOME-WIDE SIGNIFICANT SNP (P < 5.0 X 10(-8)), RS117084279, NEAR PIBF1. WE IDENTIFIED AN ADDITIONAL 57 SNPS (P < 5.0 X 10(-6)) ASSOCIATED WITH EMPHYSEMA IN ALL SUBJECTS, AND 106 SNPS (P < 5.0 X 10(-6)) IN COPD PATIENTS. OF THESE CANDIDATE SNPS, 2 (RS12459249, RS11667314) NEAR CYP2A6 WERE EXPRESSION QUANTITATIVE TRAIT LOCI IN LUNG TISSUE AND A SNP (RS11214944) NEAR NNMT WAS AN EXPRESSION QUANTITATIVE TRAIT LOCUS IN WHOLE BLOOD. OF NOTE, RS11214944 WAS IN LINKAGE DISEQUILIBRIUM WITH VARIANTS IN ENHANCER HISTONE MARKS IN LUNG TISSUE. SEVERAL GENES NEAR ADDITIONAL SNPS WERE IDENTIFIED IN OUR PREVIOUS EWAS STUDY WITH NOMINAL LEVEL OF SIGNIFICANCE. WE IDENTIFIED A NOVEL SNP ASSOCIATED WITH QUANTITATIVE EMPHYSEMA ON CT. INCLUDING THE NOVEL SNP, SEVERAL CANDIDATE SNPS IN OUR STUDY MAY PROVIDE CLUES TO THE GENETIC ETIOLOGY OF EMPHYSEMA IN ASIAN POPULATIONS. FURTHER RESEARCH AND VALIDATION OF THE LOCI WILL HELP DETERMINE THE GENETIC FACTORS FOR THE DEVELOPMENT OF EMPHYSEMA.	2021	
                                                                                                                                                                                                                                                                                                                                                                                 
19 2637  32 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY.	2022	

20 5883  29 SYSTEMIC AND AIRWAY EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH HEALTH STATUS IN COPD. EPIGENETIC MODIFICATIONS ARE COMMON IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD); HOWEVER, THEIR CLINICAL RELEVANCE IS LARGELY UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC DISRUPTIONS ARE ASSOCIATED WITH SYMPTOMS AND HEALTH STATUS IN COPD. WE PROFILED THE BLOOD (N = 57) AND AIRWAYS (N = 62) OF COPD PATIENTS FOR DNA METHYLATION (N = 55 PAIRED). THE PATIENTS' HEALTH STATUS WAS ASSESSED USING THE ST. GEORGE'S RESPIRATORY QUESTIONNAIRE (SGRQ). WE CONDUCTED DIFFERENTIAL METHYLATION ANALYSES AND IDENTIFIED PATHWAYS CHARACTERIZED BY EPIGENETIC DISRUPTIONS ASSOCIATED WITH SGRQ SCORES AND ITS INDIVIDUAL DOMAINS. 29,211 AND 5044 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) WERE ASSOCIATED WITH TOTAL SGRQ SCORES IN BLOOD AND AIRWAY SAMPLES, RESPECTIVELY. THE ACTIVITY, IMPACT, AND SYMPTOM DOMAINS WERE ASSOCIATED WITH 9161, 25,689 AND 17,293 DMPS IN BLOOD, RESPECTIVELY; AND 4674, 3730 AND 5063 DMPS IN AIRWAYS, RESPECTIVELY. THERE WAS A SUBSTANTIAL OVERLAP OF DMPS BETWEEN AIRWAY AND BLOOD. DMPS WERE ENRICHED FOR PATHWAYS RELATED TO COMMON CO-MORBIDITIES OF COPD (E.G., AGEING, CANCER AND NEUROLOGICAL) IN BOTH TISSUES. HEALTH STATUS IN COPD IS ASSOCIATED WITH AIRWAY AND SYSTEMIC EPIGENETIC CHANGES ESPECIALLY IN PATHWAYS RELATED TO CO-MORBIDITIES OF COPD. THERE ARE MORE BLOOD DMPS THAN IN THE AIRWAYS SUGGESTING THAT BLOOD EPIGENOME IS A PROMISING SOURCE TO DISCOVER BIOMARKERS FOR CLINICAL OUTCOMES IN COPD.	2023