1 3796 139 INTERLEUKIN-6 PROMOTES TUMORIGENESIS BY ALTERING DNA METHYLATION IN ORAL CANCER CELLS. WORLDWIDE ORAL SQUAMOUS CELL CARCINOMA (OSCC) ACCOUNTS FOR MORE THAN 100,000 DEATHS EACH YEAR. CHRONIC INFLAMMATION CONSTITUTES ONE OF THE KEY RISK FACTORS FOR OSCC. ACCUMULATING EVIDENCE SUGGESTS THAT ABERRANT DNA METHYLATION MAY CONTRIBUTE TO OSCC TUMORIGENESIS. THIS STUDY INVESTIGATED WHETHER CHRONIC INFLAMMATION ALTERS DNA METHYLATION AND EXPRESSION OF CANCER-ASSOCIATED GENES IN OSCC. WE ESTABLISHED AN IN VITRO MODEL OF INTERLEUKIN (IL)-6 MEDIATING CHRONIC INFLAMMATION IN OSCC CELL LINES. THEREAFTER, WE MEASURED THE ABILITY OF IL-6 TO INDUCE GLOBAL HYPOMETHYLATION OF LONG INTERSPERSED NUCLEAR ELEMENT-1 (LINE-1) SEQUENCES, AS WELL AS CPG METHYLATION CHANGES USING MULTIPLE METHODOLOGIES INCLUDING QUANTITATIVE PYROSEQUENCING, METHYLATION-SPECIFIC MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION AND SENSITIVE MELTING ANALYSIS AFTER REAL-TIME-METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (PCR). GENE EXPRESSION WAS INVESTIGATED BY QUANTITATIVE REVERSE TRANSCRIPTASE-PCR. IL-6 INDUCED SIGNIFICANT GLOBAL LINE-1 HYPOMETHYLATION (P=0.016) IN OUR IN VITRO MODEL OF INFLAMMATORY STRESS IN OSCC CELL LINES. SIMULTANEOUSLY, IL-6 INDUCED CPG PROMOTER METHYLATION CHANGES IN SEVERAL IMPORTANT PUTATIVE TUMOR SUPPRESSOR GENES INCLUDING CHFR, GATA5 AND PAX6. METHYLATION CHANGES CORRELATED INVERSELY WITH THE CHANGES IN THE EXPRESSION OF CORRESPONDING GENES. OUR RESULTS INDICATE THAT IL-6-INDUCED INFLAMMATION PROMOTES TUMORIGENESIS IN THE ORAL CAVITY BY ALTERING GLOBAL LINE-1 HYPOMETHYLATION. IN ADDITION, CONCURRENT HYPERMETHYLATION OF MULTIPLE TUMOR SUPPRESSOR GENES BY IL-6 SUGGESTS THAT EPIGENETIC GENE SILENCING MAY BE AN IMPORTANT CONSEQUENCE OF CHRONIC INFLAMMATION IN THE ORAL CAVITY. THESE FINDINGS HAVE CLINICAL RELEVANCE, AS BOTH METHYLATION AND INFLAMMATION ARE SUITABLE TARGETS FOR DEVELOPING NOVEL PREVENTIVE AND THERAPEUTIC MEASURES. 2011 2 5157 32 PRE-NEOPLASTIC EPIGENETIC DISRUPTION OF TRANSCRIPTIONAL ENHANCERS IN CHRONIC INFLAMMATION. CHRONIC PERIODONTITIS (CP) IS A CHRONIC INFLAMMATORY DISEASE INDEPENDENTLY ASSOCIATED WITH HIGHER INCIDENCE OF ORAL CAVITY SQUAMOUS CELL CARCINOMA (OSCC). HOWEVER, THE MOLECULAR MECHANISM RESPONSIBLE FOR THIS INCREASED INCIDENCE IS UNKNOWN. HERE WE PROFILED THE DNA METHYLOME OF CP PATIENTS AND HEALTHY CONTROLS AND COMPARED TO A LARGE SET OF OSCC SAMPLES FROM TCGA. WE OBSERVED A SIGNIFICANT OVERLAP BETWEEN THE ALTERED DNA METHYLATION PATTERNS IN CP AND IN OSCC, SUGGESTING AN EMERGENCE OF A PRE-NEOPLASTIC EPIGENOME IN CP. REMARKABLY, THE HYPERMETHYLATED CPGS IN CP WERE SIGNIFICANTLY ENRICHED FOR ENHANCER ELEMENTS. THIS ABERRANT ENHANCER METHYLATION IS FUNCTIONAL AND ABLE TO DISRUPT ENHANCER ACTIVITY BY PREVENTING THE BINDING OF CHROMATIN LOOPING FACTORS. THIS STUDY PROVIDES NEW INSIGHTS ON THE MOLECULAR MECHANISMS LINKING CHRONIC INFLAMMATION AND TUMOR PREDISPOSITION, HIGHLIGHTING THE ROLE OF EPIGENETIC DISRUPTION OF TRANSCRIPTIONAL ENHANCERS. 2016 3 2771 42 EXTENSIVE PROMOTER DNA HYPERMETHYLATION AND HYPOMETHYLATION IS ASSOCIATED WITH ABERRANT MICRORNA EXPRESSION IN CHRONIC LYMPHOCYTIC LEUKEMIA. DYSREGULATED MICRORNA (MIRNA) EXPRESSION CONTRIBUTES TO THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES, INCLUDING CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). HOWEVER, AN UNDERSTANDING OF THE MECHANISMS THAT CAUSE ABERRANT MIRNA TRANSCRIPTIONAL CONTROL IS LACKING. IN THIS STUDY, WE COMPREHENSIVELY INVESTIGATED THE ROLE AND EXTENT OF MIRNA EPIGENETIC REGULATION IN CLL. GENOME-WIDE PROFILING CONDUCTED ON 24 CLL AND 10 HEALTHY B CELL SAMPLES REVEALED GLOBAL DNA METHYLATION PATTERNS UPSTREAM OF MIRNA SEQUENCES THAT DISTINGUISHED MALIGNANT FROM HEALTHY CELLS AND IDENTIFIED PUTATIVE MIRNA PROMOTERS. INTEGRATION OF DNA METHYLATION AND MIRNA PROMOTER DATA LED TO THE IDENTIFICATION OF 128 RECURRENT MIRNA TARGETS FOR ABERRANT PROMOTER DNA METHYLATION. DNA HYPOMETHYLATION ACCOUNTED FOR MORE THAN 60% OF ALL ABERRANT PROMOTER-ASSOCIATED DNA METHYLATION IN CLL, AND PROMOTER DNA HYPOMETHYLATION WAS RESTRICTED TO WELL-DEFINED REGIONS. INDIVIDUAL HYPER- AND HYPOMETHYLATED PROMOTERS ALLOWED DISCRIMINATION OF CLL SAMPLES FROM HEALTHY CONTROLS. PROMOTER DNA METHYLATION PATTERNS WERE CONFIRMED IN AN INDEPENDENT PATIENT COHORT, WITH 11 MIRNAS CONSISTENTLY SHOWING AN INVERSE CORRELATION BETWEEN DNA METHYLATION STATUS AND EXPRESSION LEVEL. TOGETHER, OUR FINDINGS CHARACTERIZE THE ROLE OF EPIGENETIC CHANGES IN THE REGULATION OF MIRNA TRANSCRIPTION AND CREATE A REPOSITORY OF DISEASE-SPECIFIC PROMOTER REGIONS THAT MAY PROVIDE ADDITIONAL INSIGHTS INTO THE PATHOGENESIS OF CLL. 2012 4 3795 42 INTERLEUKIN-6 CONTRIBUTES TO GROWTH IN CHOLANGIOCARCINOMA CELLS BY ABERRANT PROMOTER METHYLATION AND GENE EXPRESSION. THE ASSOCIATION BETWEEN CHRONIC INFLAMMATION AND THE DEVELOPMENT AND PROGRESSION OF MALIGNANCY IS EXEMPLIFIED IN THE BILIARY TRACT WHERE PERSISTENT INFLAMMATION STRONGLY PREDISPOSES TO CHOLANGIOCARCINOMA. THE INFLAMMATORY CYTOKINE INTERLEUKIN-6 (IL-6) ENHANCES TUMOR GROWTH IN CHOLANGIOCARCINOMA BY ALTERED GENE EXPRESSION VIA AUTOCRINE MECHANISMS. IL-6 CAN REGULATE THE ACTIVITY OF DNA METHYLTRANSFERASES, AND MOREOVER, ABERRANT DNA METHYLATION CAN CONTRIBUTE TO CARCINOGENESIS. WE THEREFORE INVESTIGATED THE EFFECT OF CHRONIC EXPOSURE TO IL-6 ON METHYLATION-DEPENDENT GENE EXPRESSION AND TRANSFORMED CELL GROWTH IN HUMAN CHOLANGIOCARCINOMA. THE RELATIONSHIP BETWEEN AUTOCRINE IL-6 PATHWAYS, DNA METHYLATION, AND TRANSFORMED CELL GROWTH WAS ASSESSED USING MALIGNANT CHOLANGIOCYTES STABLY TRANSFECTED TO OVEREXPRESS IL-6. TREATMENT WITH THE DNA METHYLATION INHIBITOR 5-AZA-2'-DEOXYCYTIDINE DECREASED CELL PROLIFERATION, GROWTH IN SOFT AGAR, AND METHYLCYTOSINE CONTENT OF MALIGNANT CHOLANGIOCYTES. HOWEVER, THIS EFFECT WAS NOT OBSERVED IN IL-6-OVEREXPRESSING CELLS. IL-6 OVEREXPRESSION RESULTED IN THE ALTERED EXPRESSION AND PROMOTER METHYLATION OF SEVERAL GENES, INCLUDING THE EPIDERMAL GROWTH FACTOR RECEPTOR (EGFR). EGFR PROMOTER METHYLATION WAS DECREASED AND GENE AND PROTEIN EXPRESSION WAS INCREASED BY IL-6. THUS, EPIGENETIC REGULATION OF GENE EXPRESSION BY IL-6 CAN CONTRIBUTE TO TUMOR PROGRESSION BY ALTERING PROMOTER METHYLATION AND GENE EXPRESSION OF GROWTH-REGULATORY PATHWAYS, SUCH AS THOSE INVOLVING EGFR. MOREOVER, ENHANCED IL-6 EXPRESSION MAY DECREASE THE SENSITIVITY OF TUMOR CELLS TO THERAPEUTIC TREATMENTS USING METHYLATION INHIBITORS. THESE OBSERVATIONS HAVE IMPORTANT IMPLICATIONS FOR CANCER TREATMENT AND PROVIDE A MECHANISM BY WHICH PERSISTENT CYTOKINE STIMULATION CAN PROMOTE TUMOR GROWTH. 2006 5 3686 31 INFLAMMATION-RELATED ABERRANT PATTERNS OF DNA METHYLATION: DETECTION AND ROLE IN EPIGENETIC DEREGULATION OF CANCER CELL TRANSCRIPTOME. IT IS NOW APPARENT THAT EPIGENETIC ABNORMALITIES, IN PARTICULAR ALTERED DNA METHYLATION, PLAY A CRUCIAL ROLE IN THE DEVELOPMENT AND PROGRESSION OF HUMAN CANCERS. DNA HYPERMETHYLATION AT PROMOTER CPG ISLANDS IS NOW RECOGNIZED AS A THIRD MECHANISM BY WHICH INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS. ABERRANT CPG ISLAND HYPERMETHYLATION IS ALSO FREQUENTLY OBSERVED IN CHRONIC INFLAMMATION AND PRECANCEROUS LESIONS, WHICH SUGGESTS THAT IT IS AN EARLY EVENT IN TUMORIGENESIS THAT COULD SERVE AS A USEFUL TUMOR MARKER. A VARIETY OF SCREENING TECHNIQUES HAVE BEEN DEVELOPED FOR GENOME-WIDE SCREENING OF METHYLATION STATUS. OF THOSE, TRANSCRIPTOME ANALYSIS COUPLED WITH PHARMACOLOGICAL UNMASKING HAS EMERGED AS A POWERFUL TOOL FOR REVEALING DNA METHYLATION PATTERNS IN CANCER CELLS AND IDENTIFYING NEW TUMOR MARKER CANDIDATES. 2009 6 3440 34 HYPERMETHYLATION AND LOW TRANSCRIPTION OF TLR2 GENE IN CHRONIC PERIODONTITIS. PERIODONTITIS IS AN INFLAMMATORY DISORDER CHARACTERIZED BY INTERACTIONS BETWEEN PERIODONTAL PATHOGENS AND HOST'S IMMUNE RESPONSE. EPIGENETIC MAY CONTRIBUTE TO DISEASE DEVELOPMENT AND OUTCOME BY INFLUENCING THE EXPRESSION OF GENES INVOLVED IN THE IMMUNE RESPONSE. IT HAS BEEN SHOWN THAT TOLL-LIKE RECEPTORS (TLR) PLAY AN IMPORTANT ROLE IN THE RESPONSE TO PERIODONTOPATHIC BACTERIA. THE AIM OF STUDY WAS TO EVALUATE THE METHYLATION STATUS AND THE EXPRESSION OF TLR2 GENE IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH AND WITHOUT PERIODONTITIS. DNA WAS ANALYZED USING THE METHYL PROFILER DNA METHYLATION QPCR ASSAY. DNA METHYLATION AND TRANSCRIPT LEVELS WERE EVALUATED BY REAL-TIME POLYMERASE CHAIN REACTION. THE PERIODONTITIS GROUP SHOWED A HYPERMETHYLATED PROFILE AND A LOW EXPRESSION OF GENE. POSITIVE CORRELATION BETWEEN THE TLR2 METHYLATION FREQUENCY AND PROBING DEPTH WAS OBSERVED. THIS STUDY GIVES THE FIRST EVIDENCE OF METHYLATION FREQUENCY IN INFLAMED PERIODONTAL TISSUES AND OF THE POSSIBLE PARTICIPATION OF METHYLATION IN THE DEVELOPMENT OF PERIODONTITIS. 2013 7 342 39 ALTERATIONS OF DNA METHYLATION ASSOCIATED WITH ABNORMALITIES OF DNA METHYLTRANSFERASES IN HUMAN CANCERS DURING TRANSITION FROM A PRECANCEROUS TO A MALIGNANT STATE. ALTERATIONS OF DNA METHYLATION ARE ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN HUMAN CANCERS. HUMAN CANCERS GENERALLY SHOW GLOBAL DNA HYPOMETHYLATION ACCOMPANIED BY REGION-SPECIFIC HYPERMETHYLATION. ALTERATIONS OF DNA METHYLATION MAY RESULT IN CHROMOSOMAL INSTABILITY AS A RESULT OF CHANGES IN CHROMATIN STRUCTURE. DNA HYPERMETHYLATION OF CPG ISLANDS SILENCES VARIOUS TUMOR-RELATED GENES. ALTERATIONS OF DNA METHYLATION ARE FREQUENTLY OBSERVED IN CANCERS ASSOCIATED WITH CHRONIC INFLAMMATION AND/OR PERSISTENT INFECTION WITH VIRUSES OR OTHER PATHOGENIC MICROORGANISMS, SUCH AS HEPATITIS B OR C VIRUSES, EPSTEIN-BARR VIRUS, HUMAN PAPILLOMAVIRUS AND HELICOBACTER PYLORI, OR WITH CIGARETTE SMOKING. ACCUMULATING EVIDENCE SUGGESTS THAT ALTERATIONS OF DNA METHYLATION ARE INVOLVED EVEN IN THE EARLY AND PRECANCEROUS STAGES. ON THE OTHER HAND, IN PATIENTS WITH CANCERS, ABERRANT DNA METHYLATION IS SIGNIFICANTLY ASSOCIATED WITH POORER TUMOR DIFFERENTIATION, TUMOR AGGRESSIVENESS AND POOR PROGNOSIS. PRECANCEROUS CONDITIONS SHOWING ALTERATIONS OF DNA METHYLATION MAY PROGRESS RAPIDLY AND GENERATE MORE MALIGNANT CANCERS. DNA METHYLTRANSFERASE (DNMT) 1 OVER-EXPRESSION IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY BUT IS SIGNIFICANTLY CORRELATED WITH THE CPG ISLAND METHYLATOR PHENOTYPE, WHICH IS DEFINED AS FREQUENT DNA HYPERMETHYLATION OF C-TYPE CPG ISLANDS THAT ARE USUALLY METHYLATED IN A CANCER-SPECIFIC (NOT AGE-DEPENDENT) MANNER. SPLICING ALTERATION OF DNMT3B MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION OF PERICENTROMERIC SATELLITE REGIONS. ALTERATION OF DNA METHYLATION MAY BECOME AN INDICATOR FOR CARCINOGENETIC RISK ESTIMATION AND EARLY DIAGNOSIS OF CANCERS AND A BIOLOGICAL PREDICTOR OF POOR PROGNOSIS IN PATIENTS WITH CANCERS. CORRECTION OF DNA METHYLATION STATUS MAY OFFER A NEW STRATEGY FOR PREVENTION AND THERAPY OF CANCERS. 2007 8 1500 45 DNA METHYLATION ANALYSIS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABERRANT CROSS-TALK BETWEEN KERATINOCYTES AND IMMUNE CELLS SUCH AS CD4+ T CELLS, RESULTING IN KERATINOCYTE HYPERPROLIFERATION IN THE EPIDERMIS. DNA METHYLATION, ONE OF SEVERAL EPIGENETIC MECHANISMS, PLAYS AN IMPORTANT ROLE IN GENE EXPRESSION WITHOUT CHANGING THE DNA SEQUENCE. SEVERAL STUDIES HAVE SUGGESTED THE INVOLVEMENT OF EPIGENETIC REGULATION IN SKIN LESIONS FROM PATIENTS WITH PSORIASIS. IN THIS STUDY, WE INVESTIGATED THE GENOME-WIDE DNA METHYLATION STATUS OF CD4+ T CELLS IN PATIENTS WITH PSORIASIS COMPARED WITH HEALTHY SUBJECTS USING METHYLATED DNA IMMUNOPRECIPITATION SEQUENCING (MEDIP-SEQ). THE RESULTS OF MEDIP-SEQ SHOWED THAT THE GLOBAL METHYLATION VALUES OF CD4+ T CELLS ARE HIGHER IN PATIENTS WITH PSORIASIS THAN IN HEALTHY CONTROLS, PARTICULARLY IN THE PROMOTER REGIONS. AMONG THE MOST HYPERMETHYLATED GENES IN THE PROMOTER REGIONS, WE SELECTED THE GENES WHOSE EXPRESSION IS SIGNIFICANTLY REDUCED IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. STUDIES USING THE METHYLATION INHIBITOR 5-AZACYTIDINE IN VITRO METHYLATION ASSAYS HAVE SHOWN THAT THE DIFFERENTIAL EXPRESSION LEVELS WERE ASSOCIATED WITH THE METHYLATION STATUS OF EACH GENE. BISULFITE SEQUENCING OF THE TRANSCRIPTION START REGION OF PHOSPHATIDIC ACID PHOSPHATASE TYPE 2 DOMAIN CONTAINING 3 (PPAPDC3), ONE OF THE SELECTED GENES, SHOWED HYPERMETHYLATION IN THE CD4+ T CELLS OF PSORIASIS PATIENTS. THESE RESULTS SUGGESTED THAT THE METHYLATION STATUS, WHICH IS IDENTIFIED BY MEDIP-SEQ OF THE GENES, WAS CORRELATED WITH THE MRNA EXPRESSION LEVEL OF THE GENES. COLLECTIVELY, THE DNA METHYLATION STATUS IN CD4+ T CELLS MIGHT BE ASSOCIATED WITH THE PATHOGENESIS OF PSORIASIS. 2014 9 3067 36 GENOME-WIDE DNA METHYLATION PROFILES IN PRECANCEROUS CONDITIONS AND CANCERS. ALTERATIONS OF DNA METHYLATION, WHICH RESULT IN CHROMOSOMAL INSTABILITY AND SILENCING OF TUMOR-RELATED GENES, ARE AMONG THE MOST CONSISTENT EPIGENETIC CHANGES OBSERVED IN HUMAN CANCERS. ANALYSIS OF TISSUE SPECIMENS HAS REVEALED THAT DNA METHYLATION ALTERATIONS PARTICIPATE IN MULTISTAGE CARCINOGENESIS, EVEN FROM THE EARLY AND PRECANCEROUS STAGES, ESPECIALLY IN ASSOCIATION WITH CHRONIC INFLAMMATION AND/OR PERSISTENT VIRAL INFECTION, SUCH AS CHRONIC HEPATITIS OR LIVER CIRRHOSIS RESULTING FROM INFECTION WITH HEPATITIS B OR C VIRUS. DNA METHYLATION ALTERATIONS CAN ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. OVEREXPRESSION OF DNA METHYLTRANSFERASE 1 IS NOT A SECONDARY RESULT OF INCREASED CELL PROLIFERATIVE ACTIVITY, BUT IS SIGNIFICANTLY CORRELATED WITH ACCUMULATION OF DNA HYPERMETHYLATION IN CPG ISLANDS OF TUMOR-RELATED GENES. ALTERATION OF DNA METHYLTRANSFERASE 3B SPLICING MAY RESULT IN CHROMOSOMAL INSTABILITY THROUGH DNA HYPOMETHYLATION IN PERICENTROMERIC SATELLITE REGIONS. GENOME-WIDE ANALYSIS OF DNA METHYLATION STATUS HAS REVEALED THAT THE DNA METHYLATION PROFILE AT THE PRECANCEROUS STAGE IS BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. DNA METHYLATION STATUS IS NOT SIMPLY ALTERED AT THE PRECANCEROUS STAGE; RATHER, DNA METHYLATION ALTERATIONS AT THE PRECANCEROUS STAGE MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. THEREFORE, GENOME-WIDE DNA METHYLATION PROFILING MAY PROVIDE OPTIMAL INDICATORS FOR CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION, AND THUS PROVIDE AN AVENUE FOR CANCER PREVENTION AND THERAPY ON AN INDIVIDUAL BASIS. 2010 10 2682 40 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC. 2011 11 2766 40 EXPRESSION, POLYMORPHISM AND METHYLATION PATTERN OF INTERLEUKIN-6 IN PERIODONTAL TISSUES. PERIODONTITIS IS CONSIDERED AN INFLAMMATORY DISORDER OF BACTERIAL ETIOLOGY THAT RESULTS IN PERIODONTAL TISSUE DESTRUCTION, AS A RESULT OF COMPLEX INTERACTIONS BETWEEN PERIODONTAL PATHOGENS, HOST AND IMMUNE RESPONSE. GENETIC AND EPIGENETIC MECHANISMS MAY MODULATE THE INDIVIDUAL RESPONSE SINCE IT IS ABLE TO INFLUENCE THE GENE EXPRESSION. THE AIM OF THIS STUDY WAS TO EVALUATE THE IMPACT OF -174 G/C POLYMORPHISM AND THE METHYLATION STATUS OF THE PROMOTER REGION OF IL-6 GENE ON THE EXPRESSION OF IL-6 IN GINGIVAL SAMPLES FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS. GINGIVAL BIOPSIES WERE COLLECTED FROM 21 PATIENTS WITH CHRONIC PERIODONTITIS AND 21 CONTROLS. HISTOLOGIC SECTIONS STAINED BY HEMATOXYLIN-EOSIN WERE USED FOR HISTOPATHOLOGICAL EVALUATION. THE IL-6 GENE EXPRESSION WAS ASSESSED BY QUANTITATIVE REAL-TIME PCR. THE POLYMORPHISM IL-6 -174 C/G WAS STUDIED BY POLYMERASE CHAIN REACTION (PCR) AMPLIFICATION AND RESTRICTION ENDONUCLEASE DIGESTION (HSPII). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION WAS USED TO VERIFY THE DNA METHYLATION PATTERN. THE NUMBER OF INFLAMMATORY CELLS IN TISSUE FRAGMENTS FROM INDIVIDUALS WITH CHRONIC PERIODONTITIS WAS HIGHER THAN IN THE CONTROL GROUP AND THE INFLAMMATORY INFILTRATE WAS PREDOMINANTLY MONONUCLEAR. THE EXPRESSION OF IL-6 WAS HIGHER IN THE GROUP WITH PERIODONTITIS. IN POLYMORPHISM ASSAY, NO STATISTICAL DIFFERENCE IN THE DISTRIBUTION OF GENOTYPES AND ALLELES IN BOTH GROUPS WERE OBSERVED. THE MOST OF SAMPLES WERE PARTIALLY METHYLATED. NO DIFFERENCE WAS OBSERVED IN METHYLATION PATTERN FROM TWO DIFFERENT REGIONS OF THE IL-6 GENE AMONG GROUPS. THE HIGH EXPRESSION OF IL-6 IS AN IMPORTANT FACTOR RELATED TO CHRONIC PERIODONTITIS, BUT WAS NOT ASSOCIATED WITH METHYLATION STATUS OR THE -174 (G/C) GENETIC POLYMORPHISM, SUGGESTING THAT OTHER MECHANISMS ARE INVOLVED IN THIS GENE TRANSCRIPTION REGULATION. 2013 12 5276 41 PROMOTER METHYLATION OF TUMOR-RELATED GENES IN GASTRIC CARCINOGENESIS. ABERRANT PROMOTER METHYLATION AND SUBSEQUENT SILENCING OF CANCER-RELATED GENES HAS BEEN RECOGNIZED AS AN IMPORTANT PATHWAY INVOLVED IN GASTRIC CARCINOGENESIS. IN FACT, SEVERAL FACTORS ARE BELIEVED TO CONTRIBUTE TO ITS INDUCTION IN GASTRIC EPITHELIA, INCLUDING AGING, DIET, CHRONIC INFLAMMATION AND INFECTION OF HELICOBACTER PYLORI (H. PYLORI) AND EPSTEIN-BARR VIRUS (EBV). HOWEVER, THE UNDERLING MECHANISMS ARE NOT COMPLETELY IDENTIFIED, DESPITE THE BELIEF THAT INCREASED EXPRESSION OR ACTIVITY OF DNA METHYLTRANSFERASES (DNMTS), OR DECREASED DEMETHYLATION ACTIVITY MAY CONTRIBUTE TO THE EXCESSIVE METHYLATION. A GREAT NUMBER OF GENES WITH PROMOTER METHYLATION HAVE BEEN OBSERVED IN GASTRIC CANCER (GC), AMONG WHICH P16INK4A (P16), MUT L HOMOLOGUE 1 (MLH1), EPITHELIAL-CADHERIN (E-CADHERIN), RUNT-RELATED TRANSCRIPTION FACTOR 3 (RUNX3), ADENOMATOUS POLYPOSIS COLI (APC), O(6)-METHYLGUANINE-DNA METHYLTRANSFERASE (MGMT), RAS ASSOCIATION DOMAIN FAMILY 1A (RASSF1A) AND DEATH-ASSOCIATED PROTEIN KINASE (DAPK) HAVE BEEN EXTENSIVELY STUDIED. UNLIKE THE DISTINCT METHYLATION CHARACTERIZATION IN SINGLE GENES, METHYLATION ANALYSIS OF MULTIPLE GENES MAY PROVIDE MORE INFORMATION IN RISK PREDICTION, EARLY DETECTION, PROGNOSIS ASSESSMENT AND CHEMOTHERAPY CHOICE FOR GC. SPECIFICALLY, PARTICULAR MONITORING AND SCREENING SHOULD BE PERFORMED ON THOSE OVER 45 YEARS OLD, WITH PRECANCEROUS GASTRIC DISEASE OR INFECTION OF H. PYLORI OR EBV. AS AN ALTERNATIVE TO TUMOR TISSUES, METHYLATION DETECTION IN PATIENT SERA OR GASTRIC WASHES MAY ALSO BE USED IN RISK PREDICTION AND EARLY DETECTION. HOWEVER, WHAT STILL POSES A GREAT CHALLENGE AS WELL AS A PUZZLE IS THE DETERMINATION OF THE VERY GENES THAT SHOULD BE USED IN METHYLATION ANALYSIS. BECAUSE EPIGENETIC ALTERATIONS ARE NORMALLY REVERSIBLE, DRUGS OR CHEMICAL COMPOUNDS WITH DEMETHYLATING ACTIVITY, SUCH AS 5-AZA-2'-DEOXYCYTIDINE (5-AZA-DC) COULD BE USED IN THE TREATMENT OF PATIENTS WITH MULTIPLE GENE METHYLATION. IN VIEW OF THE ADVERSE EFFECTS OF 5-AZA-DC, DNMT-TARGETED STRATEGY HAS BEEN PROPOSED AND MAY PROVE TO BE MORE EFFECTIVE THAN DEMETHYLATING AGENTS. 2012 13 4004 33 LOSS OF THE POLYCOMB MARK FROM BIVALENT PROMOTERS LEADS TO ACTIVATION OF CANCER-PROMOTING GENES IN COLORECTAL TUMORS. IN COLON TUMORS, THE TRANSCRIPTION OF MANY GENES BECOMES DEREGULATED BY POORLY DEFINED EPIGENETIC MECHANISMS THAT HAVE BEEN STUDIED MAINLY IN ESTABLISHED CELL LINES. IN THIS STUDY, WE USED FROZEN HUMAN COLON TISSUES TO ANALYZE PATTERNS OF HISTONE MODIFICATION AND DNA CYTOSINE METHYLATION IN CANCER AND MATCHED NORMAL MUCOSA SPECIMENS. DNA METHYLATION IS STRONGLY TARGETED TO BIVALENT H3K4ME3- AND H3K27ME3-ASSOCIATED PROMOTERS, WHICH LOSE BOTH HISTONE MARKS AND ACQUIRE DNA METHYLATION. HOWEVER, WE FOUND THAT LOSS OF THE POLYCOMB MARK H3K27ME3 FROM BIVALENT PROMOTERS WAS ACCOMPANIED OFTEN BY ACTIVATION OF GENES ASSOCIATED WITH CANCER PROGRESSION, INCLUDING NUMEROUS STEM CELL REGULATORS, ONCOGENES, AND PROLIFERATION-ASSOCIATED GENES. INDEED, WE FOUND MANY OF THESE SAME GENES WERE ALSO ACTIVATED IN PATIENTS WITH ULCERATIVE COLITIS WHERE CHRONIC INFLAMMATION PREDISPOSES THEM TO COLON CANCER. BASED ON OUR FINDINGS, WE PROPOSE THAT A LOSS OF POLYCOMB REPRESSION AT BIVALENT GENES COMBINED WITH AN ENSUING SELECTION FOR TUMOR-DRIVING EVENTS PLAYS A MAJOR ROLE IN CANCER PROGRESSION. 2014 14 925 37 CHRONIC INFLAMMATION INDUCES A NOVEL EPIGENETIC PROGRAM THAT IS CONSERVED IN INTESTINAL ADENOMAS AND IN COLORECTAL CANCER. CHRONIC INFLAMMATION REPRESENTS A MAJOR RISK FACTOR FOR TUMOR FORMATION, BUT THE UNDERLYING MECHANISMS HAVE REMAINED LARGELY UNKNOWN. EPIGENETIC MECHANISMS CAN RECORD THE EFFECTS OF ENVIRONMENTAL CHALLENGES ON THE GENOME LEVEL AND COULD THEREFORE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF INFLAMMATION-ASSOCIATED TUMORS. USING SINGLE-BASE METHYLATION MAPS AND TRANSCRIPTOME ANALYSES OF A COLITIS-INDUCED MOUSE COLON CANCER MODEL, WE IDENTIFIED A NOVEL EPIGENETIC PROGRAM THAT IS CHARACTERIZED BY HYPERMETHYLATION OF DNA METHYLATION VALLEYS THAT ARE CHARACTERIZED BY LOW CPG DENSITY AND ACTIVE CHROMATIN MARKS. THIS PROGRAM IS CONSERVED AND FUNCTIONAL IN MOUSE INTESTINAL ADENOMAS AND RESULTS IN SILENCING OF ACTIVE INTESTINAL GENES THAT ARE INVOLVED IN GASTROINTESTINAL HOMEOSTASIS AND INJURY RESPONSE. FURTHER ANALYSES REVEAL THAT THE PROGRAM REPRESENTS A PROMINENT FEATURE OF HUMAN COLORECTAL CANCER AND CAN BE USED TO CORRECTLY CLASSIFY COLORECTAL CANCER SAMPLES WITH HIGH ACCURACY. TOGETHER, OUR RESULTS SHOW THAT INFLAMMATORY SIGNALS ESTABLISH A NOVEL EPIGENETIC PROGRAM THAT SILENCES A SPECIFIC SET OF GENES THAT CONTRIBUTE TO INFLAMMATION-INDUCED CELLULAR TRANSFORMATION. 2015 15 2747 45 EXPRESSION ANALYSIS OF THE EPIGENETIC METHYLTRANSFERASES AND METHYL-CPG BINDING PROTEIN FAMILIES IN THE NORMAL B-CELL AND B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN CARCINOGENESIS HAS BEEN A SOURCE OF CONTROVERSY FOR SOME TIME. THERE IS LITTLE DOUBT THAT CHANGES IN GENOMIC HYPERMETHYLATION CONTRIBUTE TO THE SILENCING OF TUMOR SUPPRESSOR GENES. FURTHERMORE, RECENT STUDIES HAVE ALSO IDENTIFIED THE SIGNIFICANCE OF GENOMIC HYPOMETHYLATION ASSOCIATED WITH CHROMOSOMAL INSTABILITY AND TUMORIGENESIS. ONE OF THE MOST PERPLEXING QUESTIONS REGARDING EPIGENETIC MODIFICATIONS AND LEUKEMOGENESIS IS THE RELATIONSHIP WITH DNA METHYLTRANSFERASES (DNMT'S). THE PRIMARY FUNCTION OF THE DNMT ENZYMES IS TO METHYLATE GENOMIC DNA, WHEREAS THE METHYL-CPG BINDING DOMAIN PROTEINS (MBD) INTERPRET THIS METHYLATION SIGNAL AND REGULATE GENE EXPRESSION AND CHROMATIN BEHAVIOR. IN THIS STUDY WE ANALYSE THESE GENE FAMILIES BY QUANTITATIVE REAL-TIME PCR TO INVESTIGATE WHETHER EXPRESSION LEVELS AND THE B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) PHENOTYPE ARE ASSOCIATED. FURTHERMORE, GIVEN THE EPIGENETIC CROSSTALK BETWEEN GENOME STABILITY AND THE HISTONE CHROMATIN CODE WE HAVE ANALYSED EUKARYOTIC HISTONE METHYLTRANSFERASE (EU-HMTASEI). SURPRISINGLY, WE DID NOT OBSERVE SIGNIFICANT CHANGES IN DNMT1 EXPRESSION IN B-CLL CASES WHEN COMPARED TO NORMAL LYMPHOCYTES, REGARDLESS OF WHETHER WE NORMALISE AGAINST GAPDH OR PCNA AS REFERENCE STANDARDS. INDEED, EXPRESSION OF THE MAINTENANCE AND DE NOVO METHYLASES WERE INDEPENDENTLY REGULATED. OF PARTICULAR NOTE WAS THE SIGNIFICANT DOWN REGULATION OF DNMT3B. FURTHERMORE, WE OBSERVED A POSITIVE CORRELATION BETWEEN HMTASEI EXPRESSION LEVELS AND STAGE OF LEUKEMIA SUGGESTING THAT CHANGES IN THE METHYLATION PATTERNS IN B-CLL MAY REPRESENT DEREGULATION OF THE EPIGENETIC REPERTOIRE THAT ALSO INCLUDE THE METHYLATION DEPENDENT BINDING PROTEINS, MBD2 AND MECP2. WE ENVISAGE CHANGES IN THE EPIGENETIC PROGRAM ARE MULTIFACTORIAL IN NATURE AND POSTULATE THAT THE PREVALENT GENOMIC METHYLASES JUST ONE COMPONENT OF A LARGER EPIGENETIC REPERTOIRE. 2004 16 3791 40 INTERLEUKIN 6 SUPPORTS THE MAINTENANCE OF P53 TUMOR SUPPRESSOR GENE PROMOTER METHYLATION. A STRONG ASSOCIATION EXISTS BETWEEN STATES OF CHRONIC INFLAMMATION AND CANCER, AND IT IS BELIEVED THAT MEDIATORS OF INFLAMMATION MAY BE RESPONSIBLE FOR THIS PHENOMENON. INTERLEUKIN 6 (IL-6) IS AN INFLAMMATORY CYTOKINE KNOWN TO PLAY A ROLE IN THE GROWTH AND SURVIVAL OF MANY TYPES OF TUMORS, YET THE MECHANISMS EMPLOYED BY THIS PLEOMORPHIC CYTOKINE TO ACCOMPLISH THIS FEAT ARE STILL POORLY UNDERSTOOD. ANOTHER IMPORTANT FACTOR IN TUMOR DEVELOPMENT SEEMS TO BE THE HYPERMETHYLATION OF CPG ISLANDS LOCATED WITHIN THE PROMOTER REGIONS OF TUMOR SUPPRESSOR GENES. THIS COMMON EPIGENETIC ALTERATION ENABLES TUMOR CELLS TO REDUCE OR INACTIVATE THE EXPRESSION OF IMPORTANT TUMOR SUPPRESSOR AND CELL CYCLE REGULATORY GENES. HERE WE SHOW THAT IN THE IL-6-RESPONSIVE HUMAN MULTIPLE MYELOMA CELL LINE KAS 6/1, THE PROMOTER REGION OF P53 IS EPIGENETICALLY MODIFIED BY METHYLTRANSFERASES, RESULTING IN DECREASED LEVELS OF EXPRESSION. FURTHERMORE, CELLS TREATED WITH IL-6 EXHIBIT AN INCREASE IN THE EXPRESSION OF THE DNA MAINTENANCE METHYLATION ENZYME, DNMT-1. THE DNA METHYLTRANSFERASE INHIBITOR ZEBULARINE REVERSES THE METHYLATION OF THE P53 PROMOTER, ALLOWING THE RESUMPTION OF ITS EXPRESSION. HOWEVER, WHEN ZEBULARINE IS WITHDRAWN FROM THE CELLS, THE REESTABLISHMENT OF THE ORIGINAL CPG ISLAND METHYLATION WITHIN THE P53 PROMOTER DOES NOT OCCUR IN THE ABSENCE OF IL-6, AND CELLS WHICH DO NOT RECEIVE IL-6 EVENTUALLY DIE, AS P53 EXPRESSION CONTINUES UNCHECKED BY REMETHYLATION. INTERESTINGLY, THIS LOSS OF VIABILITY SEEMS TO INVOLVE NOT THE WITHDRAWAL OF CYTOKINE, BUT THE INABILITY OF THE CELL TO RESILENCE THE PROMOTER. CONSISTENT WITH THIS MODEL, WHEN CELLS THAT EXPRESS IL-6 IN AN AUTOCRINE FASHION ARE SUBJECTED TO IDENTICAL TREATMENT, P53 EXPRESSION IS REDUCED SHORTLY AFTER WITHDRAWAL OF ZEBULARINE. THEREFORE, IT SEEMS IL-6 IS CAPABLE OF MAINTAINING PROMOTER METHYLATION THUS REPRESENTING ONE OF THE POSSIBLE MECHANISMS USED BY INFLAMMATORY MEDIATORS IN THE GROWTH AND SURVIVAL OF TUMORS. 2005 17 6661 44 UPREGULATION OF DNA METHYLTRANSFERASE-MEDIATED GENE SILENCING, ANCHORAGE-INDEPENDENT GROWTH, AND MIGRATION OF COLON CANCER CELLS BY INTERLEUKIN-6. INFLAMMATORY BOWEL DISEASE IS CHARACTERIZED BY CHRONIC INFLAMMATION WHICH PREDISPOSES TO COLORECTAL CANCER. THE MECHANISMS BY WHICH INFLAMMATION PROMOTES TUMORIGENESIS ARE NOT FULLY KNOWN. WE AIMED TO INVESTIGATE THE LINKS BETWEEN COLONIC INFLAMMATION AND TUMORIGENESIS VIA EPIGENETIC GENE SILENCING. COLON CANCER SPECIMENS WERE ASSESSED FOR THE EXPRESSION OF DNA METHYLTRANSFERASE-1 (DNMT-1) USING IMMUNOHISTOCHEMISTRY. COLORECTAL CARCINOMA CELL LINES WERE ASSESSED FOR DNMT1 EXPRESSION, METHYLCYTOSINE CONTENT, PROMOTER METHYLATION, GENE EXPRESSION, AND TUMORIGENESIS IN RESPONSE TO INTERLEUKIN (IL)-6. DNMT1 WAS EXPRESSED AT HIGHER LEVELS IN BOTH THE PERITUMORAL STROMA AND TUMOR IN INFLAMMATORY BOWEL DISEASE-ASSOCIATED CANCERS COMPARED WITH SPORADIC COLON CANCERS. IL-6 TREATMENT OF COLON CANCER CELLS RESULTED IN AN INCREASE IN DNMT1 EXPRESSION, INDEPENDENT OF DE NOVO GENE EXPRESSION. IL-6 INCREASED THE METHYLATION OF PROMOTER REGIONS OF GENES ASSOCIATED WITH TUMOR SUPPRESSION, ADHESION, AND APOPTOSIS RESISTANCE. EXPRESSION OF A SUBSET OF THESE GENES WAS DOWNREGULATED BY IL-6, AN EFFECT THAT WAS PREVENTED BY PREINCUBATION WITH 5-AZADEOXYCYTIDINE, A DNMT1 INHIBITOR. ANCHORAGE-INDEPENDENT GROWTH AND MIGRATION OF COLON CANCER CELLS WAS ALSO INCREASED BY IL-6 IN A 5-AZADEOXYCYTIDINE-SENSITIVE MANNER. OUR RESULTS INDICATE THAT DNMT-MEDIATED GENE SILENCING MAY PLAY A ROLE IN INFLAMMATION-ASSOCIATED COLON TUMORIGENESIS. 2010 18 3636 32 INCREASED DNA METHYLTRANSFERASE ACTIVITY AND DNA METHYLATION FOLLOWING EPIDERMAL GROWTH FACTOR STIMULATION IN OVARIAN CANCER CELLS. OVARIAN CANCER PROGRESSION IS CORRELATED WITH ACCUMULATION OF ABERRANT CPG ISLAND METHYLATION. IN OVARIAN CANCER, ASCITES FLUID CONTAINS NUMEROUS EPIDERMAL-GROWTH-FACTOR-RECEPTOR (EGFR) ACTIVATORS, WHICH COULD RESULT IN A TUMOR MICROENVIRONMENT OF CONSTANT EGFR ACTIVATION. SIGNALING PATHWAYS DOWNSTREAM OF EGFR, SUCH AS RAS, REGULATE DNA METHYLATION. WE HYPOTHESIZED THAT CHRONIC EGFR ACTIVATION COULD ALTER DNA METHYLATION. WE FOUND THAT EGFR ACTIVATION INCREASED DNA METHYLTRANSFERASE (DNMT) ACTIVITY ACUTELY, AS WELL AS AFTER LONG-TERM EGF TREATMENT OR EXPRESSION OF A MUTATIONALLY ACTIVATED EGFR. FURTHERMORE, THIS INCREASE IN DNMT ACTIVITY WAS DEPENDENT ON EGFR CATALYTIC ACTIVITY AND RESULTED IN INCREASED GLOBAL DNA METHYLATION. ADDITIONALLY, TREATMENT WITH THE DNMT INHIBITOR/HYPOMETHYLATING AGENT 5-AZA-2'-DEOXYCYTIDINE (AZA) INHIBITED THE EGF INDUCED INCREASE OF BOTH DNMT ACTIVITY AND GLOBAL METHYLATION. THESE DATA SUPPORT A ROLE FOR EGFR IN THE PROCESS OF ACCUMULATED DNA METHYLATION DURING OVARIAN CANCER PROGRESSION AND SUGGEST THAT EPIGENETIC THERAPY MAY BE BENEFICIAL FOR THE TREATMENT OF OVARIAN CANCER. 2012 19 2494 31 EPIGENETICS AND CHRONIC LYMPHOCYTIC LEUKEMIA. THE DNA METHYLATION LEVEL IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS GENERALLY LOWER THAN HEALTHY INDIVIDUALS. ALTHOUGH DNA METHYLATION IS GLOBALLY DECREASED, REGIONAL HYPERMETHYLATION OF GENE PROMOTERS LEADS TO GENE SILENCING. MANY OF THESE GENES HAVE TUMOR SUPPRESSOR PHENOTYPES. UNLIKE MUTATIONS OR DELETIONS, HYPERMETHYLATION IS POTENTIALLY REVERSIBLE AFTER INHIBITION WITH DNA METHYLATION MODULATORS. MYELODYSPLASTIC SYNDROME HAS BEEN A MODEL DISEASE IN WHICH TREATMENT OF PATIENTS RESULTS IN DEMETHYLATION OF SPECIFIC GENES. THE STORY IN PATIENTS WITH CHRONIC LYMPHOCYTIC LEUKEMIA IS SLOWLY UNRAVELING AS EPIGENETIC MODIFICATIONS LIKELY ALSO PLAY AN IMPORTANT ROLE. ONGOING CLINICAL TRIALS CORRELATING CLINICAL RESPONSE TO GENE EXPRESSION AFTER TREATMENT WITH DNA METHYLATION INHIBITORS WILL ULTIMATELY ALLOW US TO BETTER RISK STRATIFY AND PREDICT THE SUBGROUP OF PATIENTS WHO WILL BENEFIT FROM TREATMENT WITH THIS CLASS OF DRUGS. 2006 20 3822 26 INVESTIGATING EPIGENETIC EFFECTS OF ACTIVATION-INDUCED DEAMINASE IN CHRONIC LYMPHOCYTIC LEUKEMIA. ACTIVATION INDUCED DEAMINASE (AID) HAS TWO DISTINCT AND WELL DEFINED ROLES, BOTH RELYING ON ITS DEOXYCYTIDINE (DC) DEAMINATING FUNCTION: ONE AS A DNA MUTATOR AND ANOTHER IN DNA DEMETHYLATION. IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), AID WAS PREVIOUSLY SHOWN TO BE AN INDEPENDENT NEGATIVE PROGNOSTIC FACTOR. WHILE THERE IS SUBSTANTIAL IMPACT ON DNA MUTATIONS, EFFECTS OF AID ON GENE EXPRESSION BY PROMOTER DEMETHYLATION OF DISEASE RELATED TARGET GENES IN LEUKEMIA HAS NOT BEEN ADDRESSED. TO SHED LIGHT ON THIS QUESTION, WE AIMED AT DETERMINING GENOME WIDE METHYLATION CHANGES AS WELL AS GENE EXPRESSION CHANGES IN RESPONSE TO AID EXPRESSION IN CLL. ALTHOUGH WE FOUND MINOR DIFFERENCES IN INDIVIDUAL METHYLATION VARIABLE POSITIONS FOLLOWING AID EXPRESSION, WE COULD NOT FIND RECURRENT METHYLATION CHANGES OF SPECIFIC TARGET SITES OR CHANGES IN GLOBAL METHYLATION. 2018