1 1322 147 DEMONSTRATION OF THE USEFULNESS OF EPIGENETIC CANCER RISK PREDICTION BY A MULTICENTRE PROSPECTIVE COHORT STUDY. BACKGROUND: EPIGENETIC ALTERATIONS ACCUMULATE IN NORMAL-APPEARING TISSUES OF PATIENTS WITH CANCER, PRODUCING AN EPIGENETIC FIELD DEFECT. CROSS-SECTIONAL STUDIES SHOW THAT THE DEGREE OF THE DEFECT MAY BE ASSOCIATED WITH RISK IN SOME TYPES OF CANCER, ESPECIALLY CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION. OBJECTIVE: TO DEMONSTRATE, BY A MULTICENTRE PROSPECTIVE COHORT STUDY, THAT THE RISK OF METACHRONOUS GASTRIC CANCER AFTER ENDOSCOPIC RESECTION (ER) CAN BE PREDICTED BY ASSESSMENT OF THE EPIGENETIC FIELD DEFECT USING METHYLATION LEVELS. DESIGN: PATIENTS WITH EARLY GASTRIC CANCER, AGED 40-80 YEARS, WHO PLANNED TO HAVE, OR HAD UNDERGONE, ER, WERE ENROLLED AT LEAST 6 MONTHS AFTER HELICOBACTER PYLORI INFECTION DISCONTINUED. METHYLATION LEVELS OF THREE PRESELECTED GENES (MIR-124A-3, EMX1 AND NKX6-1) WERE MEASURED BY QUANTITATIVE METHYLATION-SPECIFIC PCR. PATIENTS WERE FOLLOWED UP ANNUALLY BY ENDOSCOPY, AND THE PRIMARY ENDPOINT WAS DEFINED AS DETECTION OF A METACHRONOUS GASTRIC CANCER. AUTHENTIC METACHRONOUS GASTRIC CANCERS WERE DEFINED AS CANCERS EXCLUDING THOSE DETECTED WITHIN 1 YEAR AFTER THE ENROLMENT. RESULTS: AMONG 826 PATIENTS ENROLLED, 782 PATIENTS HAD AT LEAST ONE FOLLOW-UP, WITH A MEDIAN FOLLOW-UP OF 2.97 YEARS. AUTHENTIC METACHRONOUS GASTRIC CANCERS DEVELOPED IN 66 PATIENTS: 29, 16 AND 21 PATIENTS AT 1-2, 2-3 AND >/=3 YEARS AFTER THE ENROLMENT, RESPECTIVELY. THE HIGHEST QUARTILE OF THE MIR-124A-3 METHYLATION LEVEL HAD A SIGNIFICANT UNIVARIATE HR (95% CI) (2.17 (1.07 TO 4.41); P=0.032) AND A MULTIVARIATE-ADJUSTED HR (2.30 (1.03 TO 5.10); P=0.042) OF DEVELOPING AUTHENTIC METACHRONOUS GASTRIC CANCERS. SIMILAR TRENDS WERE SEEN FOR EMX1 AND NKX6-1. CONCLUSIONS: ASSESSMENT OF THE DEGREE OF AN EPIGENETIC FIELD DEFECT IS A PROMISING CANCER RISK MARKER THAT TAKES ACCOUNT OF LIFE HISTORY. 2015 2 3125 32 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 3 5027 35 PERSONALIZED RISK ASSESSMENT FOR DYNAMIC TRANSITION OF GASTRIC NEOPLASMS. BACKGROUND: TO DEVELOP AN INDIVIDUALLY-TAILORED DYNAMIC RISK ASSESSMENT MODEL FOLLOWING A MULTISTEP, MULTIFACTORIAL PROCESS OF THE CORREA'S GASTRIC CANCER MODEL. METHODS: FIRST, WE ESTIMATED THE STATE-TO-STATE TRANSITION RATES FOLLOWING CORREA'S FIVE-STEP CARCINOGENIC MODEL AND ASSESSED THE EFFECT OF RISK FACTORS, INCLUDING HELICOBACTER PYLORI INFECTION, HISTORY OF UPPER GASTROINTESTINAL DISEASE, LIFESTYLE, AND DIETARY HABITS, ON THE STEP-BY-STEP TRANSITION RATES USING DATA FROM A HIGH-RISK POPULATION IN MATSU ISLANDS, TAIWAN. SECOND, WE INCORPORATED INFORMATION ON THE GASTRIC CANCER CARCINOGENESIS AFFECTED BY GENOMIC RISK FACTORS (INCLUDING INHERITED SUSCEPTIBILITY AND IRREVERSIBLE GENOMIC CHANGES) BASED ON LITERATURE TO GENERATE A GENETIC AND EPIGENETIC RISK ASSESSMENT MODEL BY USING A SIMULATED COHORT IDENTICAL TO THE MATSU POPULATION. THE COMBINATION OF CONVENTIONAL AND GENOMIC RISK FACTORS ENABLES US TO DEVELOP THE PERSONALIZED TRANSITION RISK SCORES AND COMPOSITE SCORES. RESULTS: THE STATE-BY-STATE TRANSITION RATES PER YEAR WERE 0.0053, 0.7523, 0.1750, AND 0.0121 PER YEAR FROM NORMAL MUCOSA TO CHRONIC ACTIVE GASTRITIS, CHRONIC ACTIVE GASTRITIS TO ATROPHIC GASTRITIS, ATROPHIC GASTRITIS TO INTESTINAL METAPLASIA, AND INTESTINAL METAPLASIA TO GASTRIC CANCER, RESPECTIVELY. COMPARED WITH THE MEDIAN RISK GROUP, THE MOST RISKY DECILE HAD A 5.22-FOLD RISK OF DEVELOPING GASTRIC CANCER, AND THE LEAST RISKY DECILE AROUND ONE-TWELFTH OF THE RISK. THE MEDIAN 10-YEAR RISK FOR GASTRIC CANCER INCIDENCE WAS 0.77%. THE MEDIAN LIFETIME RISK FOR GASTRIC CANCER INCIDENCE WAS 5.43%. BY DECILE, THE 10-YEAR RISK RANGED FROM 0.06 TO 4.04% AND THE LIFETIME RISK RANGED FROM 0.42 TO 21.04%. CONCLUSIONS: WE DEMONSTRATE HOW TO DEVELOP A PERSONALIZED DYNAMIC RISK ASSESSMENT MODEL WITH THE UNDERPINNING OF CORREA'S CASCADE TO STRATIFY THE POPULATION ACCORDING TO THEIR RISK FOR PROGRESSION TO GASTRIC CANCER. SUCH A RISK ASSESSMENT MODEL NOT ONLY FACILITATES THE DEVELOPMENT OF AN INDIVIDUALLY-TAILORED PREVENTIVE STRATEGY WITH TREATMENT FOR H. PYLORI INFECTION AND ENDOSCOPIC SCREENING BUT ALSO PROVIDES SHORT-TERM AND LONG-TERM INDICATORS TO EVALUATE THE PROGRAM EFFECTIVENESS. 2018 4 1355 36 DEVELOPMENT AND VALIDATION OF A SIMPLE GENERAL POPULATION LUNG CANCER RISK MODEL INCLUDING AHRR-METHYLATION. INTRODUCTION: SCREENING REDUCES LUNG CANCER MORTALITY OF HIGH-RISK POPULATIONS. CURRENTLY PROPOSED SCREENING ELIGIBILITY CRITERIA ONLY IDENTIFY HALF OF THOSE INDIVIDUALS, WHO LATER DEVELOP LUNG CANCER. THIS STUDY AIMED TO DEVELOP AND VALIDATE A SENSITIVE AND SIMPLE MODEL FOR PREDICTING 10-YEAR LUNG CANCER RISK. METHODS: USING THE 1991-94 EXAMINATION OF THE COPENHAGEN CITY HEART STUDY IN DENMARK, 6,820 FORMER OR CURRENT SMOKERS FROM THE GENERAL POPULATION WERE FOLLOWED FOR LUNG CANCER WITHIN 10 YEARS AFTER EXAMINATION. LOGISTIC REGRESSION OF BASELINE VARIABLES (AGE, SEX, EDUCATION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, FAMILY HISTORY OF LUNG CANCER, SMOKING STATUS AND CUMULATIVE SMOKING, SECONDHAND SMOKING, OCCUPATIONAL EXPOSURES TO DUST AND FUME, BODY MASS INDEX, LUNG FUNCTION, PLASMA C-REACTIVE PROTEIN, AND AHRR(CG05575921) METHYLATION) IDENTIFIED THE BEST PREDICTIVE MODEL. THE MODEL WAS VALIDATED AMONG 3,740 FORMER OR CURRENT SMOKERS FROM THE 2001-03 EXAMINATION, ALSO FOLLOWED FOR 10 YEARS. A SIMPLE RISK CHART WAS DEVELOPED WITH POISSON REGRESSION. RESULTS: AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION IDENTIFIED 65 OF 88 INDIVIDUALS WHO DEVELOPED LUNG CANCER IN THE VALIDATION COHORT. THE HIGHEST RISK GROUP, CONSISTING OF LESS EDUCATED MEN AGED >65 WITH CURRENT SMOKING STATUS AND CUMULATIVE SMOKING >20 PACK-YEARS, HAD ABSOLUTE 10-YEAR RISKS VARYING FROM 4% TO 16% BY AHRR(CG05575921) METHYLATION. CONCLUSION: A SIMPLE RISK CHART INCLUDING AGE, SEX, EDUCATION, SMOKING STATUS, CUMULATIVE SMOKING, AND AHRR(CG05575921) METHYLATION, IDENTIFIES INDIVIDUALS WITH 10-YEAR LUNG CANCER RISK FROM BELOW 1% TO 16%. INCLUDING AHRR(CG05575921) METHYLATION IN THE ELIGIBILITY CRITERIA FOR SCREENING IDENTIFIES SMOKERS WHO WOULD BENEFIT THE MOST FROM SCREENING. 2023 5 11 35 15Q12 VARIANTS, SPUTUM GENE PROMOTER HYPERMETHYLATION, AND LUNG CANCER RISK: A GWAS IN SMOKERS. BACKGROUND: LUNG CANCER IS THE LEADING CAUSE OF CANCER-RELATED MORTALITY WORLDWIDE. DETECTION OF PROMOTER HYPERMETHYLATION OF TUMOR SUPPRESSOR GENES IN EXFOLIATED CELLS FROM THE LUNG PROVIDES AN ASSESSMENT OF FIELD CANCERIZATION THAT IN TURN PREDICTS LUNG CANCER. THE IDENTIFICATION OF GENETIC DETERMINANTS FOR THIS VALIDATED CANCER BIOMARKER SHOULD PROVIDE NOVEL INSIGHTS INTO MECHANISMS UNDERLYING EPIGENETIC REPROGRAMMING DURING LUNG CARCINOGENESIS. METHODS: A GENOME-WIDE ASSOCIATION STUDY USING GENERALIZED ESTIMATING EQUATIONS AND LOGISTIC REGRESSION MODELS WAS CONDUCTED IN TWO GEOGRAPHICALLY INDEPENDENT SMOKER COHORTS TO IDENTIFY LOCI AFFECTING THE PROPENSITY FOR CANCER-RELATED GENE METHYLATION THAT WAS ASSESSED BY A 12-GENE PANEL INTERROGATED IN SPUTUM. ALL STATISTICAL TESTS WERE TWO-SIDED. RESULTS: TWO SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) AT 15Q12 (RS73371737 AND RS7179575) THAT DROVE GENE METHYLATION WERE DISCOVERED AND REPLICATED WITH RS73371737 REACHING GENOME-WIDE SIGNIFICANCE (P = 3.3X10(-8)). A HAPLOTYPE CARRYING RISK ALLELES FROM THE TWO 15Q12 SNPS CONFERRED 57% INCREASED RISK FOR GENE METHYLATION (P = 2.5X10(-9)). RS73371737 REDUCED GABRB3 EXPRESSION IN LUNG CELLS AND INCREASED RISK FOR SMOKING-INDUCED CHRONIC MUCOUS HYPERSECRETION. FURTHERMORE, SUBJECTS WITH VARIANT HOMOZYGOTE OF RS73371737 HAD A TWO-FOLD INCREASE IN RISK FOR LUNG CANCER (P = .0043). PATHWAY ANALYSIS IDENTIFIED DNA DOUBLE-STRAND BREAK REPAIR BY HOMOLOGOUS RECOMBINATION (DSBR-HR) AS A MAJOR PATHWAY AFFECTING SUSCEPTIBILITY FOR GENE METHYLATION THAT WAS VALIDATED BY MEASURING CHROMATID BREAKS IN LYMPHOCYTES CHALLENGED BY BLEOMYCIN. CONCLUSIONS: A FUNCTIONAL 15Q12 VARIANT WAS IDENTIFIED AS A RISK FACTOR FOR GENE METHYLATION AND LUNG CANCER. THE ASSOCIATIONS COULD BE MEDIATED BY GABAERGIC SIGNALING THAT DRIVES THE SMOKING-INDUCED MUCOUS CELL METAPLASIA. OUR FINDINGS ALSO SUBSTANTIATE DSBR-HR AS A CRITICAL PATHWAY DRIVING EPIGENETIC GENE SILENCING. 2015 6 3568 39 IMPACT OF INFLAMMATION ON EPIGENETIC DNA METHYLATION - A NOVEL RISK FACTOR FOR CARDIOVASCULAR DISEASE? OBJECTIVE: THE LIFESPAN OF DIALYSIS PATIENTS IS AS SHORT AS IN PATIENTS WITH METASTATIC CANCER DISEASE, MAINLY DUE TO CARDIOVASCULAR DISEASE (CVD). DNA METHYLATION IS AN IMPORTANT CELLULAR MECHANISM MODULATING GENE EXPRESSION ASSOCIATED WITH AGEING, INFLAMMATION AND ATHEROSCLEROTIC PROCESSES. DESIGN: DNA METHYLATION WAS ANALYSED IN PERIPHERAL BLOOD LEUCOCYTES FROM THREE DIFFERENT GROUPS OF CHRONIC KIDNEY DISEASE (CKD) POPULATIONS (37 CKD STAGES 3 AND 4 PATIENTS, 98 CKD STAGE 5 PATIENTS AND 20 PREVALENT HAEMODIALYSIS PATIENTS). THIRTY-SIX HEALTHY SUBJECTS SERVED AS CONTROLS. CLINICAL CHARACTERISTICS (DIABETES MELLITUS, NUTRITIONAL STATUS AND PRESENCE OF CLINICAL CVD), INFLAMMATION AND OXIDATIVE STRESS BIOMARKERS, HOMOCYSTEINE AND GLOBAL DNA METHYLATION IN PERIPHERAL BLOOD LEUCOCYTES (DEFINED AS HPAII/MSPI RATIO BY THE LUMINOMETRIC METHYLATION ASSAY METHOD) WERE EVALUATED. CKD STAGE 5 PATIENTS (N=98) STARTING DIALYSIS TREATMENT WERE FOLLOWED FOR A PERIOD OF 36 +/- 2 MONTHS. RESULTS: INFLAMED PATIENTS HAD LOWER RATIOS OF HPAII/MSPI, INDICATING GLOBAL DNA HYPERMETHYLATION. ANALYSIS BY THE COX REGRESSION MODEL DEMONSTRATED THAT DNA HYPERMETHYLATION (HPAII/MSPI RATIO 485,000 CPG SITES THROUGHOUT THE GENOME USING THE INFINIUM HUMANMETHYLATION450 BEADCHIP. OVER THE COURSE OF THE 8-WEEK SUPPLEMENTATION, 6746 AND 7513 CPG SITES CHANGED (P < 0.05) IN WHOLE BLOOD AND CD16+ NEUTROPHILS, RESPECTIVELY. DNA METHYLATION DECREASED IN 68.4% (WHOLE BLOOD) AND 71.8% (CD16+ NEUTROPHILS) OF THESE SITES. THERE WERE ONLY 182 CPG SITES THAT CHANGED IN BOTH THE WHOLE BLOOD AND CD16+ NEUTROPHILS, 139 OF WHICH CHANGED IN THE SAME DIRECTION. THESE RESULTS SUGGEST THAT THE GENOME-WIDE DNA METHYLATION RESPONSE TO CHRONIC FOLIC ACID SUPPLEMENTATION IS DIFFERENT BETWEEN WHOLE BLOOD AND CD16+ NEUTROPHILS AND THAT A SINGLE WHITE BLOOD CELL TYPE MAY FUNCTION AS A MORE SPECIFIC EPIGENETIC REPORTER OF FOLATE STATUS THAN WHOLE BLOOD. 2017 11 4986 35 PATIENT-REPORTED SYMPTOM OUTCOMES AND MICROSATELLITE INSTABILITY IN PATIENTS WITH METASTATIC COLORECTAL CANCER. BACKGROUND: THE SURVIVAL OF PATIENTS WITH METASTATIC COLORECTAL CANCER (MCRC) IS INFLUENCED BY THE GENETIC AND EPIGENETIC CHANGES THAT MIGHT INFLUENCE THE PATIENT EXPERIENCE OF SYMPTOM BURDEN. UNDERSTANDING THE ASSOCIATION OF MOLECULAR CHANGES WITH THE SYMPTOM BURDEN COULD HELP CLINICIANS GAIN INSIGHT INTO THE MOLECULAR BASIS OF SYMPTOM BURDEN AND IMPROVE TREATMENT TOLERANCE. TO DATE, NO STUDIES HAVE COMPARED THE PATIENT-REPORTED SYMPTOM BURDEN WITH THESE MOLECULAR SUBSETS AMONG PATIENTS WITH MCRC. PATIENTS AND METHODS: WE RECRUITED PATIENTS WITH MCRC THAT WAS REFRACTORY TO >/= 1 LINE OF THERAPY WHO HAD BEEN ENROLLED IN THE ASSESSMENT OF TARGETED THERAPIES AGAINST COLORECTAL CANCER TRIAL AT THE UNIVERSITY OF TEXAS MD ANDERSON CANCER CENTER. ALL PATIENTS COMPLETED A BASELINE GASTROINTESTINAL SYMPTOM INVENTORY (MD ANDERSON SYMPTOM INVENTORY, GASTROINTESTINAL). THE SYMPTOM BURDEN ACROSS KEY DEMOGRAPHIC VARIABLES AND MOLECULAR CHANGES, INCLUDING CRC-ASSOCIATED MUTATIONS, MICROSATELLITE INSTABILITY (MSI) STATUS, AND THE CPG ISLAND METHYLATOR PHENOTYPE (CIMP) WERE COMPARED USING CHI(2) TESTS. ASSOCIATION OF THE SYMPTOM BURDEN WITH OVERALL SURVIVAL WAS EXAMINED USING COX REGRESSION MODELS. RESULTS: PATIENTS WITH AN MSI-HIGH (MSI-H) PHENOTYPE REPORTED GREATER PAIN (ODDS RATIO [OR], 3.06; 95% CONFIDENCE INTERVAL [CI], 1.61-5.84), FATIGUE (OR, 2.78; 95% CI, 1.41-5.49), SLEEP (OR, 2.52; 95% CI, 1.32-4.08); AND DROWSINESS (OR, 2.51; 95% CI, 1.32-4.78) COMPARED WITH MICROSATELLITE STABLE PATIENTS. PATIENTS WITH AN MSI-H PHENOTYPE ALSO HAD GREATER ODDS OF OVERALL SYMPTOM BURDEN (OR, 2.48; 95% CI, 1.29-4.74) COMPARED WITH MICROSATELLITE STABLE PATIENTS. THE CIMP-HIGH PATIENTS EXPERIENCED GREATER ODDS OF PAIN COMPARED WITH THE CIMP-NEGATIVE PATIENTS (OR, 1.72; 95% CI, 1.06-2.80). A GREATER OVERALL SYMPTOM BURDEN WAS ASSOCIATED WITH POOR OVERALL SURVIVAL (HAZARD RATIO, 1.42; 95% CI, 0.98-2.06]), ALTHOUGH THE DIFFERENCE WAS NOT SIGNIFICANT (P = .06). CONCLUSION: CORRELATION OF MSI-H-ASSOCIATED TUMOR FEATURES WITH THE SYMPTOM BURDEN COULD HELP PROVIDE A BETTER UNDERSTANDING OF UNDERLYING MECHANISMS ASSOCIATED WITH OUR FINDINGS. 2020 12 1846 34 EFFECTS OF TWO TYPES OF ENERGY RESTRICTION ON METHYLATION LEVELS OF ADIPONECTIN RECEPTOR 1 AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT IN A MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA BREAST CANCER MOUSE MODEL. THE ROLE OF ADIPONECTIN AND LEPTIN SIGNALLING PATHWAYS HAS BEEN SUGGESTED TO PLAY IMPORTANT ROLES IN THE PROTECTIVE EFFECTS OF ENERGY RESTRICTION (ER) ON MAMMARY TUMOUR (MT) DEVELOPMENT. TO STUDY THE EFFECTS OF ER ON THE METHYLATION LEVELS IN ADIPONECTIN RECEPTOR 1 (ADIPOR1) AND LEPTIN RECEPTOR OVERLAPPING TRANSCRIPT (LEPROT) GENES USING THE PYROSEQUENCING METHOD IN MAMMARY FAT PAD TISSUE, MOUSE MAMMARY TUMOUR VIRUS-TRANSFORMING GROWTH FACTOR-ALPHA (MMTV-TGF-ALPHA) FEMALE MICE WERE RANDOMLY ASSIGNED TO AD LIBITUM (AL), CHRONIC ER (CER, 15 % ER) OR INTERMITTENT ER (3 WEEKS AL AND 1 WEEK 60 % ER IN CYCLIC PERIODS) GROUPS AT 10 WEEKS OF AGE UNTIL 82 WEEKS OF AGE. THE METHYLATION LEVELS OF ADIPOR1 IN THE CER GROUP WERE HIGHER THAN THOSE IN THE AL GROUP AT WEEK 49/50 (P < 0.05), WHILE THE LEVELS OF METHYLATION FOR ADIPOR1 AND LEPROT GENES WERE SIMILAR AMONG THE OTHER GROUPS. ALSO, THE METHYLATION LEVELS AT CPG2 AND CPG3 REGIONS OF THE PROMOTER REGION OF THE ADIPOR1 GENE IN THE CER GROUP WERE THREE TIMES HIGHER (P < 0.05), WHILE CPG1 ISLAND OF LEPROT METHYLATION WAS SIGNIFICANTLY LOWER COMPARED WITH THE OTHER GROUPS (P < 0.05). ADIPONECTIN AND LEPTIN GENE EXPRESSION LEVELS WERE CONSISTENT WITH THE METHYLATION LEVELS. WE ALSO OBSERVED A CHANGE WITH AGEING IN METHYLATION LEVELS OF THESE GENES. THESE RESULTS INDICATE THAT DIFFERENT TYPES OF ER MODIFY METHYLATION LEVELS OF ADIPOR1 AND LEPROT IN DIFFERENT WAYS AND CER HAD A MORE SIGNIFICANT EFFECT ON METHYLATION LEVELS OF BOTH GENES. EPIGENETIC REGULATION OF THESE GENES MAY PLAY IMPORTANT ROLES IN THE PREVENTIVE EFFECTS OF ER AGAINST MT DEVELOPMENT AND AGEING PROCESSES. 2021 13 1023 41 CIRCULATING MICRORNA PROFILES FOR PREMATURE CARDIOVASCULAR DEATH IN PATIENTS WITH KIDNEY FAILURE WITH REPLACEMENT THERAPY. INTRODUCTION: PATIENTS WITH KIDNEY FAILURE WITH REPLACEMENT THERAPY (KFRT) SUFFER FROM A DISPROPORTIONATELY HIGH CARDIOVASCULAR DISEASE BURDEN. CIRCULATING SMALL NON-CODING RNAS (C-SNCRNAS) HAVE EMERGED AS NOVEL EPIGENETIC REGULATORS AND ARE SUGGESTED AS NOVEL BIOMARKERS AND THERAPEUTIC TARGETS FOR CARDIOVASCULAR DISEASE; HOWEVER, LITTLE IS KNOWN ABOUT THE ASSOCIATIONS OF C-SNCRNAS WITH PREMATURE CARDIOVASCULAR DEATH IN KFRT. METHODS: IN A PILOT CASE-CONTROL STUDY OF 50 HEMODIALYSIS PATIENTS WHO DIED OF CARDIOVASCULAR EVENTS AS CASES, AND 50 MATCHED HEMODIALYSIS CONTROLS WHO REMAINED ALIVE DURING A MEDIAN FOLLOW-UP OF 2.0 YEARS, WE PERFORMED C-SNCRNAS PROFILES USING NEXT-GENERATION SEQUENCING TO IDENTIFY DIFFERENTIALLY EXPRESSED CIRCULATING MICRORNAS (C-MIRNAS) BETWEEN THE PLASMA OF CASES AND THAT OF CONTROLS. MRNA TARGET PREDICTION AND PATHWAY ENRICHMENT ANALYSIS WERE PERFORMED TO EXAMINE THE FUNCTIONAL RELEVANCE OF DIFFERENTIALLY EXPRESSED C-MIRNAS TO CARDIOVASCULAR PATHOPHYSIOLOGY. THE ASSOCIATION OF DIFFERENTIALLY EXPRESSED C-MIRNAS WITH CARDIOVASCULAR MORTALITY WAS EXAMINED USING MULTIVARIABLE CONDITIONAL LOGISTIC REGRESSION. RESULTS: THE PATIENT CHARACTERISTICS WERE SIMILAR BETWEEN CASES AND CONTROLS, WITH A MEAN AGE OF 63 YEARS, 48% MALE, AND 54% AFRICAN AMERICAN IN BOTH GROUPS. WE DETECTED A TOTAL OF 613 MIRNAS IN THE PLASMA, AMONG WHICH FIVE MIRNAS (I.E., MIR-129-1-5P, MIR-500B-3P, MIR-125B-1-3P, MIR-3648-2-5P, AND MIR-3150B-3P) WERE IDENTIFIED TO BE DIFFERENTIALLY EXPRESSED BETWEEN CASES AND CONTROLS WITH CUT-OFFS OF P < 0.05 AND LOG2 FOLD-CHANGE (LOG2FC) > 1. WHEN USING MORE STRINGENT CUT-OFFS OF P-ADJUSTED < 0.05 AND LOG2FC > 1, ONLY MIR-129-1-5P REMAINED SIGNIFICANTLY DIFFERENTIALLY EXPRESSED, WITH HIGHER LEVELS OF MIR-129-1-5P IN THE CASES THAN IN THE CONTROLS. THE PATHWAY ENRICHMENT ANALYSIS USING PREDICTED MIR-129-1-5P MRNA TARGETS DEMONSTRATED ENRICHMENT IN ADRENERGIC SIGNALING IN CARDIOMYOCYTES, ARRHYTHMOGENIC RIGHT VENTRICULAR CARDIOMYOPATHY, AND OXYTOCIN SIGNALING PATHWAYS. IN PARALLEL, THE CIRCULATING MIR-129-1-5P LEVELS WERE SIGNIFICANTLY ASSOCIATED WITH THE RISK OF CARDIOVASCULAR DEATH (ADJUSTED OR [95% CI], 1.68 [1.01-2.81] FOR ONE INCREASE IN LOG-TRANSFORMED MIR-129-1-5P COUNTS), INDEPENDENT OF POTENTIAL CONFOUNDERS. CONCLUSIONS: CIRCULATING MIR-129-1-5P MAY SERVE AS A NOVEL BIOMARKER FOR PREMATURE CARDIOVASCULAR DEATH IN KFRT. 2023 14 546 33 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT. 2023 15 3310 37 HIGHER ORDER GENES INTERACTION IN DNA REPAIR AND CYTOKINE GENES POLYMORPHISM AND RISK TO LUNG CANCER IN NORTH INDIANS. CONTEXT: LUNG CANCER PATHOLOGICAL PROCESS INVOLVES CUMULATIVE EFFECTS EXERTED BY GENE POLYMORPHISM(S), EPIGENETIC MODIFICATIONS, AND ALTERATIONS IN DNA REPAIR MACHINERY. FURTHER, DNA DAMAGE DUE TO OXIDATIVE STRESS, CHRONIC INFLAMMATION, AND THE INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS IS ALSO AN ETIOLOGIC MILIEU OF THIS MALIGNANT DISEASE. AIMS: THE PRESENT STUDY AIMS TO ASSESS THE PROGNOSTIC VALUE OF DNA REPAIR, CYTOKINES, AND GST GENE POLYMORPHISM IN LUNG CANCER PATIENTS WHO HAD NOT RECEIVED ANY NEOADJUVANT THERAPY. MATERIALS AND METHODS: IN THIS CASE-CONTROL STUDY, 127 CASES AND 120 CONTROLS WERE ENROLLED. DNA FROM THE BLOOD SAMPLES OF BOTH PATIENTS AND CONTROLS WAS USED TO GENOTYPE XRCC1ARG399GLN, XPDLYS751GLN, AND INTERLEUKIN-1 (IL-1BETA) GENES BY POLYMERASE CHAIN REACTION (PCR)-RESTRICTION FRAGMENT LENGTH POLYMORPHISM METHOD, WHEREAS MULTIPLEX PCR WAS PERFORMED TO GENOTYPE GSTT1 AND GSTM1. RESULTS: BINARY LOGISTIC REGRESSION ANALYSIS SHOWED THAT XRCC1ARG399GLN-MUTANT GENOTYPE (GLN/GLN, ODDS RATIO [OR] = 4.6, 95% CONFIDENCE INTERVAL [CI]: 2.2-9.6) AND GSTT1 NULL (OR = 2.7, 95% CI: 1.6-4.5) WERE LINKED TO CANCER SUSCEPTIBILITY. GENERALIZED MULTIDIMENSIONAL REDUCTION ANALYSIS OF HIGHER ORDER GENE-GENE INTERACTION USING CROSS-VALIDATION TESTING (CVT) ACCURACY SHOWED THAT GSTT1 (CVT 0.62, P = 0.001), XPD751 AND IL-1BETA (CVT 0.6, P = 0.001), AND XRCC1399, XPD751, AND INTERLEUKIN-1 RECEPTOR ANTAGONISTS (IL-1RN) (CVT 0.98, P = 0.001) WERE SINGLE-, TWO-, AND THREE-FACTOR BEST MODEL PREDICTED, RESPECTIVELY, FOR LUNG CANCER RISK. CLASSIFICATION AND REGRESSION TREE ANALYSIS RESULTS SHOWED THAT TERMINAL NODES WHICH CONTAIN XRCC1399-MUTANT GENOTYPE (AA) HAD INCREASED THE RISK TO LUNG CANCER. CONCLUSION: THE PRESENT STUDY DEMONSTRATED THAT XRCC1399 (GLN/GLN), GSTT1, AND IL-1RN ALLELE I, I/II SERVED AS THE RISK GENOTYPES. THESE GENES COULD SERVE AS THE BIOMARKERS TO PREDICT LUNG CANCER RISK. 2022 16 2048 34 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 17 2637 37 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 18 6190 34 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 19 2037 33 EPIGENETIC CHANGES OF TIMP-3, GSTP-1 AND 14-3-3 SIGMA GENES AS INDICATION OF STATUS OF CHRONIC INFLAMMATION AND CANCER. OBJECTIVES: THIS STUDY AIMED TO COMPARE THE EPIGENETIC CHANGES VIA HYPERMETHYLATION STATUS OF TIMP-3, GSTP-1 AND 14-3-3SIGMA GENES, BETWEEN HEALTHY SUBJECTS AND PATIENTS WITH REVERSIBLE CHRONIC INFLAMMATORY DISEASE, AND BETWEEN HEALTHY SUBJECTS AND PATIENTS WITH IRREVERSIBLE MALIGNANT DISEASE, TO HIGHLIGHT THE GENETIC CHANGES THAT OCCUR IN THE PROGRESSION FROM AN INFLAMMATORY CONDITION TO IRREVERSIBLE GENETIC CHANGES COMMONLY OBSERVED IN CANCER PATIENTS. METHODS: DNA WAS EXTRACTED FROM THE BLOOD OF 680 HEALTHY SUBJECTS, AND TISSUES AND BLOOD OF 110 PATIENTS WITH CHRONIC INFLAMMATION DISEASE OF THE GUMS, AS WELL AS NEOPLASTIC TISSUES OF 108 BREAST CANCER PATIENTS. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR) FOR TIMP-3, GSTP-1 AND 14-3-3SIGMA WAS PERFORMED, AND HYPERMETHYLATION STATUS WAS ANALYZED AND COMPARED BETWEEN THE 3 GROUPS. RESULTS: THE HYPERMETHYLATION FREQUENCIES OF TIMP-3 AND GSTP-1 OF REVERSIBLE CHRONIC INFLAMMATORY GUM DISEASE AND THE CONTROL GROUP WERE SIMILAR, BUT BOTH WERE SIGNIFICANTLY LOWER THAN THOSE FOR MALIGNANT DISEASE PATIENTS (P<0.0001). THE METHYLATION FREQUENCY OF 14-3-3SIGMA IN CHRONIC INFLAMMATORY GUM DISEASE WAS HIGHER THAN IN THE CANCER AND CONTROL GROUPS (P<0.0001). THE METHYLATION OF CPG ISLANDS IN TIMP-3 AND GSTP-1 IN CHRONIC INFLAMMATION PATIENTS OCCURRED AS FREQUENTLY AS IN THE CONTROL GROUP, BUT LESS FREQUENTLY THAN IN BREAST CANCER PATIENTS. HOWEVER, THE EPIGENETIC SILENCING OF 14-3-3SIGMA OCCURRED MORE FREQUENTLY IN THE CHRONIC INFLAMMATION GROUP THAN IN CANCER PATIENTS AND HEALTHY CONTROLS. CONCLUSIONS: THE EPIGENETIC SILENCING OF 14-3-3SIGMA MIGHT BE ESSENTIAL FOR CHRONIC INFLAMMATORY GUM DISEASE. THE EPIGENETIC CHANGES PRESENTED IN CHRONIC INFLAMMATION PATIENTS MIGHT DEMONSTRATE AN IRREVERSIBLE DESTRUCTION IN THE TISSUES OR ORGANS SIMILAR TO CANCER. 2014 20 1138 25 COMPUTATIONAL METHODS FOR DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING KERNEL DISTANCE AND SCAN STATISTICS. MOTIVATION: RESEARCHERS IN GENOMICS ARE INCREASINGLY INTERESTED IN EPIGENETIC FACTORS SUCH AS DNA METHYLATION BECAUSE THEY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION WITHOUT CHANGES IN THE SEQUENCE OF DNA. ABNORMAL DNA METHYLATION IS ASSOCIATED WITH MANY HUMAN DISEASES. RESULTS: WE PROPOSE TWO DIFFERENT APPROACHES TO TEST FOR DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH COMPLEX TRAITS, WHILE ACCOUNTING FOR CORRELATIONS AMONG CPG SITES IN THE DMRS. THE FIRST APPROACH IS A NONPARAMETRIC METHOD USING A KERNEL DISTANCE STATISTIC AND THE SECOND ONE IS A LIKELIHOOD-BASED METHOD USING A BINOMIAL SPATIAL SCAN STATISTIC. THE KERNEL DISTANCE METHOD USES THE KERNEL FUNCTION, WHILE THE BINOMIAL SCAN STATISTIC APPROACH USES A MIXED-EFFECTS MODEL TO INCORPORATE CORRELATIONS AMONG CPG SITES. EXTENSIVE SIMULATIONS SHOW THAT BOTH APPROACHES HAVE EXCELLENT CONTROL OF TYPE I ERROR, AND BOTH HAVE REASONABLE STATISTICAL POWER. THE BINOMIAL SCAN STATISTIC APPROACH APPEARS TO HAVE HIGHER POWER, WHILE THE KERNEL DISTANCE METHOD IS COMPUTATIONALLY FASTER. THE PROPOSED METHODS ARE DEMONSTRATED USING DATA FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY. 2019