1 4052 114 MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR (DNET) CHARACTERIZED BY GENOME-WIDE METHYLATION ANALYSIS. DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMORS (DNET) ARE CONSIDERED TO BE RARE, BENIGN, AND ASSOCIATED WITH CHRONIC EPILEPSY. WE PRESENT THE CASE OF A 28-YEAR-OLD MAN WITH A HISTORY OF EPILEPSY SINCE AGE 12. SURGERY OF AN OCCIPITAL CORTICAL LESION IN 2009 REVEALED A DNET. FIVE YEARS LATER, A RECURRENT TUMOR AT THE EDGE OF THE RESECTION CAVITY WAS REMOVED, AND THE TISSUE UNDERWENT AN INTENSIVE DIAGNOSTIC WORKUP. THE FIRST TUMOR WAS UNEQUIVOCALLY CHARACTERIZED AS A DNET, BUT NEUROPATHOLOGICAL DIAGNOSTICS OF THE RECURRENT TUMOR REVEALED A GLIOBLASTOMA. AFTER 6 MONTHS, ANOTHER RECURRENT TUMOR WAS DETECTED NEXT TO THE LOCATION OF THE ORIGINAL TUMOR, AND THIS WAS ALSO RESECTED. AN ILLUMINA 450 K BEADCHIP METHYLATION ARRAY WAS PERFORMED TO CHARACTERIZE ALL OF THE TUMORS. THE METHYLATION PROFILE OF THESE TUMORS SIGNIFICANTLY DIFFERED FROM OTHER GLIOBLASTOMA AND EPILEPSY-ASSOCIATED TUMOR PROFILES AND REVEALED A DNET-LIKE METHYLATION PROFILE. THUS, MOLECULAR CHARACTERIZATION OF THESE RECURRENT TUMORS SUGGESTS MALIGNANT TRANSFORMATION OF A PREVIOUSLY BENIGN DNET. WE FOUND INCREASED COPY NUMBER CHANGES IN THE RECURRENT DNET TUMORS AFTER MALIGNANT TRANSFORMATION. MODERN HIGH-THROUGHPUT ANALYSIS ADDS ESSENTIAL MOLECULAR INFORMATION IN ADDITION TO STANDARD HISTOPATHOLOGY FOR PROPER IDENTIFICATION OF RARE BRAIN TUMORS THAT PRESENT WITH AN UNUSUAL CLINICAL COURSE. 2016 2 6813 47 [EPILEPSY-ASSOCIATED TUMORS OF THE CENTRAL NERVOUS SYSTEM: EPILEPSY SURGERY AND ONCOLOGICAL ASPECTS]. BACKGROUND: AMONG THE TUMORS ASSOCIATED WITH CHRONIC EPILEPSY, DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR AND GANGLIOGLIOMA ARE THE MOST COMMON BESIDES ANGIOCENTRIC GLIOMA, PLEOMORPHIC XANTHOASTROCYTOMA AND PILOCYTIC ASTROCYTOMA. THESE TUMORS ARE USUALLY CONSIDERED AS BEING BENIGN. OBJECTIVE: TO DETERMINE THE BEST CONSERVATIVE AND SURGICAL TREATMENT OF TUMORS ASSOCIATED WITH EPILEPSY. MATERIAL AND METHODS: THIS ARTICLE PRESENTS CASE REPORTS OF MALIGNANT TRANSFORMATION OF A DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR AND OF A TUMOR INITIALLY DIAGNOSED AS A GANGLIOGLIOMA BASED ON MAGNETIC RESONANCE IMAGING (MRI) CRITERIA. DESCRIPTION OF REFERENCES IN THE LITERATURE ON EPILEPSY SURGERY AND THE NEURO-ONCOLOGY OF EPILEPSY-ASSOCIATED TUMORS. RESULTS: IN THE CASE OF THE INITIALLY HISTOPATHOLOGICALLY DIAGNOSED DYSEMBRYOPLASTIC NEUROEPITHELIAL TUMOR, A MALIGNANT TRANSFORMATION OCCURRED 5 YEARS AFTER INCOMPLETE RESECTION. THE DIFFERENTIATION FROM A GLIOBLASTOMA WAS POSSIBLE THROUGH THE ANALYSIS OF THE METHYLATION PROFILE. IN ANOTHER CASE A TUMOR ASSUMED TO BE A GANGLIOGLIOMA SHOWED AN INCREASE IN SIZE AFTER 6 YEARS. INITIAL HISTOPATHOLOGICAL RESULTS REVEALED A GLIOBLASTOMA. THE ANALYSIS OF THE METHYLATION PROFILE SUGGESTED THE DIAGNOSIS OF AN ANAPLASTIC PLEOMORPHIC XANTHOASTROCYTOMA AND AS A DIFFERENTIAL DIAGNOSIS AN ANAPLASTIC GANGLIOGLIOMA. TUMOR PROGRESS CORRELATED WITH THE WORSENING OF SEIZURES. CONCLUSION: RECENT STUDIES HAVE SHOWN THAT IN THE TREATMENT OF PREDOMINANTLY BENIGN EPILEPSY-ASSOCIATED TUMORS NEURO-ONCOLOGICAL ASPECTS SHOULD ALSO BE TAKEN INTO ACCOUNT IN ADDITION TO THE EPILEPTOLOGICAL CONSIDERATIONS. IN THE CASE OF MALIGNANT TRANSFORMATION EPIGENETIC SCREENING (METHYLATION PROFILES) CAN HELP TO CLASSIFY THE TUMOR ENTITY MORE PRECISELY. 2016 3 59 35 A GENOME-WIDE SCREEN IDENTIFIES FREQUENTLY METHYLATED GENES IN HAEMATOLOGICAL AND EPITHELIAL CANCERS. BACKGROUND: GENETIC AS WELL AS EPIGENETIC ALTERATIONS ARE A HALLMARK OF BOTH EPITHELIAL AND HAEMATOLOGICAL MALIGNANCIES. HIGH THROUGHPUT SCREENS ARE REQUIRED TO IDENTIFY EPIGENETIC MARKERS THAT CAN BE USEFUL FOR DIAGNOSTIC AND PROGNOSTIC PURPOSES ACROSS MALIGNANCIES. RESULTS: HERE WE REPORT FOR THE FIRST TIME THE USE OF THE MIRA ASSAY (METHYLATED CPG ISLAND RECOVERY ASSAY) IN COMBINATION WITH GENOME-WIDE CPG ISLAND ARRAYS TO IDENTIFY EPIGENETIC MOLECULAR MARKERS IN CHILDHOOD ACUTE LYMPHOBLASTIC LEUKEMIA (ALL) ON A GENOME-WIDE SCALE. WE IDENTIFIED 30 GENES DEMONSTRATING METHYLATION FREQUENCIES OF > OR =25% IN CHILDHOOD ALL, NINE GENES SHOWED SIGNIFICANTLY DIFFERENT METHYLATION FREQUENCIES IN B VS T-ALL. FOR MAJORITY OF THE GENES EXPRESSION COULD BE RESTORED IN METHYLATED LEUKEMIA LINES AFTER TREATMENT WITH 5-AZADC. FORTY-FOUR PERCENT OF THE GENES REPRESENT TARGETS OF THE POLYCOMB COMPLEX. IN CHRONIC MYELOID LEUKEMIA (CML) TWO OF THE GENES, (TFAP2A AND EBF2), DEMONSTRATED INCREASED METHYLATION IN BLAST CRISIS COMPARED TO CHRONIC PHASE (P < 0.05). FURTHERMORE HYPERMETHYLATION OF AN AUTOPHAGY RELATED GENE ATG16L2 WAS ASSOCIATED WITH POORER PROGNOSIS IN TERMS OF MOLECULAR RESPONSE TO IMATINIB TREATMENT. LASTLY WE DEMONSTRATED THAT TEN OF THESE GENES WERE ALSO FREQUENTLY METHYLATED IN COMMON EPITHELIAL CANCERS. CONCLUSION: IN SUMMARY WE HAVE IDENTIFIED A LARGE NUMBER OF GENES SHOWING FREQUENT METHYLATION IN CHILDHOOD ALL, METHYLATION STATUS OF TWO OF THESE GENES IS ASSOCIATED WITH ADVANCED DISEASE IN CML AND METHYLATION STATUS OF ANOTHER GENE IS ASSOCIATED WITH PROGNOSIS. IN ADDITION A SUBSET OF THESE GENES MAY ACT AS EPIGENETIC MARKERS ACROSS HEMATOLOGICAL MALIGNANCIES AS WELL AS COMMON EPITHELIAL CANCERS. 2010 4 1561 29 DNA METHYLATION OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH DIFFERENTIAL RESPONSE TO CHEMOTHERAPY. ACQUIRED RESISTANCE TO CHEMOTHERAPY IS AN IMPORTANT CLINICAL PROBLEM AND CAN ALSO OCCUR WITHOUT DETECTABLE CYTOGENETIC ABERRATIONS OR GENE MUTATIONS. CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) IS MOLECULARLY WELL CHARACTERIZED AND HAS BEEN ELEMENTAL FOR ESTABLISHING CENTRAL PARADIGMS IN ONCOLOGY. THIS PROMPTED US TO CHECK WHETHER SPECIFIC EPIGENETIC CHANGES AT THE LEVEL OF DNA METHYLATION MIGHT UNDERLIE DEVELOPMENT OF TREATMENT RESISTANCE. WE USED ILLUMINA INFINIUM HUMANMETHYLATION450 BEADCHIPS TO OBTAIN DNA METHYLATION PROFILES OF 71 CLL PATIENTS WITH DIFFERENTIAL RESPONSES. THIRTY-SIX PATIENTS WERE CATEGORIZED AS RELAPSED/REFRACTORY AFTER TREATMENT WITH FLUDARABINE OR BENDAMUSTINE AND 21 OF THEM HAD GENETIC ABERRATIONS OF TP53. THE OTHER 35 PATIENTS WERE UNTREATED AT THE TIME OF SAMPLING AND 15 OF THEM HAD GENETIC ABERRATION OF TP53. ALTHOUGH WE COULD NOT CORRELATE CHEMORESISTANCE WITH EPIGENETIC CHANGES, THE PATIENTS WERE COMPREHENSIVELY CHARACTERIZED REGARDING RELEVANT PROGNOSTIC AND MOLECULAR MARKERS (E.G. IGHV MUTATION STATUS, CHROMOSOME ABERRATIONS, TP53 MUTATION STATUS, CLINICAL PARAMETERS), WHICH MAKES OUR DATASET A UNIQUE AND VALUABLE RESOURCE THAT CAN BE USED BY RESEARCHERS TO TEST ALTERNATIVE HYPOTHESES. 2020 5 3503 22 IDENTIFICATION OF POTENTIAL DIFFERENTIALLY METHYLATED GENE-RELATED BIOMARKERS IN ENDOMETRIOSIS. AIM: TO IDENTIFY EPIGENETIC ALTERATIONS OF DIFFERENTIALLY EXPRESSED GENES AND SCREEN OUT TARGETED THERAPEUTIC DRUGS IN ENDOMETRIOSIS. METHODS: BASED ON THE GENE EXPRESSION OMNIBUS DATABASE AND A SERIES OF BIOLOGICAL INFORMATION ANALYSIS TOOLS, SUPPLEMENTED BY VALIDATION OF CLINICAL SAMPLES, ABERRANT DNA METHYLATION-DRIVEN GENES AND THEIR FUNCTIONS WERE EXPLORED, AS WELL AS POSSIBLE TARGETED DRUGS. RESULTS: THIS STUDY SCREENED OUT A RANGE OF DNA METHYLATION-DRIVEN GENES THAT WERE ASSOCIATED WITH POWERFUL PROPERTIES AND CORRESPONDING PATHWAYS. AMONG THEM, BDNF AND CCL2 WERE KEY GENES IN THE DEVELOPMENT OF ENDOMETRIOSIS. FOUR CHEMICAL AGENTS HAVE BEEN FLAGGED AS POTENTIAL TREATMENTS FOR ENDOMETRIOSIS. CONCLUSION: THESE CANDIDATE GENES AND SMALL-MOLECULE AGENTS MAY BE FURTHER EXPLORED AS POTENTIAL TARGETS AND DRUGS FOR ENDOMETRIOSIS DIAGNOSIS AND THERAPY, RESPECTIVELY. 2022 6 1345 24 DETECTION OF DIFFERENTIALLY METHYLATED REGIONS USING BAYES FACTOR FOR ORDINAL GROUP RESPONSES. 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 DNA SEQUENCE. THERE HAVE BEEN SIGNIFICANT ADVANCES IN DEVELOPING STATISTICAL METHODS TO DETECT DIFFERENTIALLY METHYLATED REGIONS (DMRS) ASSOCIATED WITH BINARY DISEASE STATUS. MOST OF THESE METHODS ARE BEING DEVELOPED FOR DETECTING DIFFERENTIAL METHYLATION RATES BETWEEN CASES AND CONTROLS. WE CONSIDER MULTIPLE SEVERITY LEVELS OF DISEASE, AND DEVELOP A BAYESIAN STATISTICAL METHOD TO DETECT THE REGION WITH INCREASING (OR DECREASING) METHYLATION RATES AS THE DISEASE SEVERITY INCREASES. PATIENTS ARE CLASSIFIED INTO MORE THAN TWO GROUPS, BASED ON THE DISEASE SEVERITY (E.G., STAGES OF CANCER), AND DMRS ARE DETECTED BY USING MOVING WINDOWS ALONG THE GENOME. WITHIN EACH WINDOW, THE BAYES FACTOR IS CALCULATED TO TEST THE HYPOTHESIS OF MONOTONIC INCREASE IN METHYLATION RATES CORRESPONDING TO SEVERITY OF THE DISEASE VERSUS NO DIFFERENCE. A MIXED-EFFECT MODEL IS USED TO INCORPORATE THE CORRELATION OF METHYLATION RATES OF NEARBY CPG SITES IN THE REGION. RESULTS FROM EXTENSIVE SIMULATION INDICATE THAT OUR PROPOSED METHOD IS STATISTICALLY VALID AND REASONABLY POWERFUL. WE DEMONSTRATE OUR APPROACH ON A BISULFITE SEQUENCING DATASET FROM A CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) STUDY. 2019 7 2920 32 GENE-SET ANALYSIS IS SEVERELY BIASED WHEN APPLIED TO GENOME-WIDE METHYLATION DATA. MOTIVATION: DNA METHYLATION IS AN EPIGENETIC MARK THAT CAN STABLY REPRESS GENE EXPRESSION. BECAUSE OF ITS BIOLOGICAL AND CLINICAL SIGNIFICANCE, SEVERAL METHODS HAVE BEEN DEVELOPED TO COMPARE GENOME-WIDE PATTERNS OF METHYLATION BETWEEN GROUPS OF SAMPLES. THE APPLICATION OF GENE SET ANALYSIS TO IDENTIFY RELEVANT GROUPS OF GENES THAT ARE ENRICHED FOR DIFFERENTIALLY METHYLATED GENES IS OFTEN A MAJOR COMPONENT OF THE ANALYSIS OF THESE DATA. THIS CAN BE USED, FOR EXAMPLE, TO IDENTIFY PROCESSES OR PATHWAYS THAT ARE PERTURBED IN DISEASE DEVELOPMENT. WE SHOW THAT GENE-SET ANALYSIS, AS IT IS TYPICALLY APPLIED TO GENOME-WIDE METHYLATION ASSAYS, IS SEVERELY BIASED AS A RESULT OF DIFFERENCES IN THE NUMBERS OF CPG SITES ASSOCIATED WITH DIFFERENT CLASSES OF GENES AND GENE PROMOTERS. RESULTS: WE DEMONSTRATE THIS BIAS USING PUBLISHED DATA FROM A STUDY OF DIFFERENTIAL CPG ISLAND METHYLATION IN LUNG CANCER AND A DATASET WE GENERATED TO STUDY METHYLATION CHANGES IN PATIENTS WITH LONG-STANDING ULCERATIVE COLITIS. WE SHOW THAT SEVERAL OF THE GENE SETS THAT SEEM ENRICHED WOULD ALSO BE IDENTIFIED WITH RANDOMIZED DATA. WE SUGGEST TWO EXISTING APPROACHES THAT CAN BE ADAPTED TO CORRECT THE BIAS. ACCOUNTING FOR THE BIAS IN THE LUNG CANCER AND ULCERATIVE COLITIS DATASETS PROVIDES NOVEL BIOLOGICAL INSIGHTS INTO THE ROLE OF METHYLATION IN CANCER DEVELOPMENT AND CHRONIC INFLAMMATION, RESPECTIVELY. OUR RESULTS HAVE SIGNIFICANT IMPLICATIONS FOR MANY PREVIOUS GENOME-WIDE METHYLATION STUDIES THAT HAVE DRAWN CONCLUSIONS ON THE BASIS OF SUCH STRONGLY BIASED ANALYSIS. CONTACT: CATHAL.SEOIGHE@NUIGALWAY.IE SUPPLEMENTARY INFORMATION: SUPPLEMENTARY DATA ARE AVAILABLE AT BIOINFORMATICS ONLINE. 2013 8 1307 27 DEFINING A METHYLATION SIGNATURE ASSOCIATED WITH OPERATIONAL TOLERANCE IN KIDNEY TRANSPLANT RECIPIENTS. OPERATIONAL TOLERANCE AFTER KIDNEY TRANSPLANTATION IS DEFINED AS STABLE GRAFT ACCEPTANCE WITHOUT THE NEED FOR IMMUNOSUPPRESSION THERAPY. HOWEVER, IT IS NOT CLEAR WHICH CELLULAR AND MOLECULAR PATHWAYS ARE DRIVING TOLERANCE IN THESE PATIENTS. WE PERFORMED GENOME-WIDE ANALYSIS OF DNA METHYLATION IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM KIDNEY TRANSPLANT RECIPIENTS WITH CHRONIC REJECTION AND OPERATIONAL TOLERANCE FROM THE GENETIC ANALYSIS OF MOLECULAR BIOMARKERS OF IMMUNOLOGICAL TOLERANCE (GAMBIT) STUDY. OUR RESULTS SHOWED THAT BOTH CLINICAL STAGES DIVERGE IN 2737 GENES, INDICATING THAT EACH ONE HAS A SPECIFIC METHYLATION SIGNATURE ASSOCIATED WITH TRANSPLANT OUTCOME. WE ALSO OBSERVED THAT TOLERANCE IS ASSOCIATED WITH DEMETHYLATION IN GENES INVOLVED IN IMMUNE FUNCTION, INCLUDING B AND T CELL ACTIVATION AND TH17 DIFFERENTIATION, WHILE IN CHRONIC REJECTION IT IS ASSOCIATED WITH INTRACELLULAR SIGNALING AND UBIQUITINATION PATHWAYS. USING CO-EXPRESSION NETWORK ANALYSIS, WE SELECTED 12 GENOMIC REGIONS THAT ARE SPECIFICALLY HYPOMETHYLATED OR HYPERMETHYLATED IN TOLERANT PATIENTS. ANALYSIS OF THESE GENES IN TRANSPLANTED PATIENTS WITH LOW DOSE OF STEROIDS SHOWED THAT THESE HAVE A SIMILAR METHYLATION SIGNATURE TO THAT OF TOLERANT RECIPIENTS. OVERALL, THESE RESULTS DEMONSTRATE THAT METHYLATION ANALYSIS CAN MIRROR THE IMMUNE STATUS ASSOCIATED WITH TRANSPLANT OUTCOME AND PROVIDES A STARTING POINT FOR UNDERSTANDING THE EPIGENETIC MECHANISMS ASSOCIATED WITH TOLERANCE. 2021 9 1582 27 DNA METHYLATION PROFILES IN PRECANCEROUS TISSUE AND CANCERS: CARCINOGENETIC RISK ESTIMATION AND PROGNOSTICATION BASED ON DNA METHYLATION STATUS. ALTERATIONS IN DNA METHYLATION, WHICH ARE ASSOCIATED WITH DNA METHYLTRANSFERASE ABNORMALITIES AND RESULT IN SILENCING OF TUMOR-RELATED GENES AND CHROMOSOMAL INSTABILITY, ARE INVOLVED EVEN IN PRECANCEROUS CHANGES IN VARIOUS ORGANS. DNA METHYLATION ALTERATIONS ALSO ACCOUNT FOR THE HISTOLOGICAL HETEROGENEITY AND CLINICOPATHOLOGICAL DIVERSITY OF HUMAN CANCERS. THEREFORE, WE HAVE ANALYZED DNA METHYLATION ON A GENOME-WIDE SCALE IN CLINICAL TISSUE SAMPLES. OUR APPROACH USING THE BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION METHOD HAS REVEALED THAT DNA METHYLATION ALTERATIONS CORRELATED WITH THE FUTURE DEVELOPMENT OF MORE MALIGNANT CANCERS ARE ALREADY ACCUMULATED AT THE PRECANCEROUS STAGE IN THE KIDNEY, LIVER AND URINARY TRACT. DNA METHYLATION PROFILES AT PRECANCEROUS STAGES ARE BASICALLY INHERITED BY THE CORRESPONDING CANCERS DEVELOPING IN INDIVIDUAL PATIENTS. SUCH DNA METHYLATION ALTERATIONS MAY CONFER VULNERABILITY TO FURTHER GENETIC AND EPIGENETIC ALTERATIONS, GENERATE MORE MALIGNANT CANCERS, AND THUS DETERMINE PATIENT OUTCOME. ON THE BASIS OF BACTERIAL ARTIFICIAL CHROMOSOME ARRAY-BASED METHYLATED CPG ISLAND AMPLIFICATION DATA, INDICATORS FOR CARCINOGENETIC RISK ESTIMATION HAVE BEEN ESTABLISHED USING LIVER TISSUE SPECIMENS FROM PATIENTS WITH HEPATITIS VIRUS INFECTION, CHRONIC HEPATITIS AND LIVER CIRRHOSIS OR HISTOLOGICALLY NORMAL UROTHELIA, AND FOR PROGNOSTICATION USING BIOPSY OR SURGICALLY RESECTED SPECIMENS FROM PATIENTS WITH RENAL CELL CARCINOMA, HEPATOCELLULAR CARCINOMA AND UROTHELIAL CARCINOMA. SUCH GENOME-WIDE DNA METHYLATION PROFILING HAS NOW FIRMLY ESTABLISHED THE CLINICAL RELEVANCE OF TRANSLATIONAL EPIGENETICS. 2010 10 1599 32 DNA METHYLATION SIGNATURE OF CHILDHOOD CHRONIC PHYSICAL AGGRESSION IN T CELLS OF BOTH MEN AND WOMEN. BACKGROUND: HIGH FREQUENCY OF PHYSICAL AGGRESSION IS THE CENTRAL FEATURE OF SEVERE CONDUCT DISORDER AND IS ASSOCIATED WITH A WIDE RANGE OF SOCIAL, MENTAL AND PHYSICAL HEALTH PROBLEMS. WE HAVE PREVIOUSLY TESTED THE HYPOTHESIS THAT DIFFERENTIAL DNA METHYLATION SIGNATURES IN PERIPHERAL T CELLS ARE ASSOCIATED WITH A CHRONIC AGGRESSION TRAJECTORY IN MALES. DESPITE THE FACT THAT SEX DIFFERENCES APPEAR TO PLAY A PIVOTAL ROLE IN DETERMINING THE DEVELOPMENT, MAGNITUDE AND FREQUENCY OF AGGRESSION, MOST OF PREVIOUS STUDIES FOCUSED ON MALES, SO LITTLE IS KNOWN ABOUT FEMALE CHRONIC PHYSICAL AGGRESSION. WE THEREFORE TESTED HERE WHETHER OR NOT THERE IS A SIGNATURE OF PHYSICAL AGGRESSION IN FEMALE DNA METHYLATION AND, IF THERE IS, HOW IT RELATES TO THE SIGNATURE OBSERVED IN MALES. METHODOLOGY/PRINCIPAL FINDINGS: METHYLATION PROFILES WERE CREATED USING THE METHOD OF METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) FOLLOWED BY MICROARRAY HYBRIDIZATION AND STATISTICAL AND BIOINFORMATIC ANALYSES ON T CELL DNA OBTAINED FROM ADULT WOMEN WHO WERE FOUND TO BE ON A CHRONIC PHYSICAL AGGRESSION TRAJECTORY (CPA) BETWEEN 6 AND 12 YEARS OF AGE COMPARED TO WOMEN WHO FOLLOWED A NORMAL PHYSICAL AGGRESSION TRAJECTORY. WE CONFIRMED THE EXISTENCE OF A WELL-DEFINED, GENOME-WIDE SIGNATURE OF DNA METHYLATION ASSOCIATED WITH CHRONIC PHYSICAL AGGRESSION IN THE PERIPHERAL T CELLS OF ADULT FEMALES THAT INCLUDES MANY OF THE GENES SIMILARLY ASSOCIATED WITH PHYSICAL AGGRESSION IN THE SAME CELL TYPES OF ADULT MALES. CONCLUSIONS: THIS STUDY IN A SMALL NUMBER OF WOMEN PRESENTS PRELIMINARY EVIDENCE FOR A GENOME-WIDE VARIATION IN PROMOTER DNA METHYLATION THAT ASSOCIATES WITH CPA IN WOMEN THAT WARRANT LARGER STUDIES FOR FURTHER VERIFICATION. A SIGNIFICANT PROPORTION OF THESE ASSOCIATIONS WERE PREVIOUSLY OBSERVED IN MEN WITH CPA SUPPORTING THE HYPOTHESIS THAT THE EPIGENETIC SIGNATURE OF EARLY LIFE AGGRESSION IN FEMALES IS COMPOSED OF A COMPONENT SPECIFIC TO FEMALES AND ANOTHER COMMON TO BOTH MALES AND FEMALES. 2014 11 2483 26 EPIGENETIC VARIATION AND HUMAN DISEASE. CYTOSINE GUANINE DINUCLEOTIDE (CPG) ISLAND METHYLATION IS A KNOWN MECHANISM OF EPIGENETIC INHERITANCE IN POSTMEIOTIC CELLS. THROUGH ASSOCIATED CHROMATIN CHANGES AND SILENCING, SUCH EPIGENETIC STATES CAN INFLUENCE CELLULAR PHYSIOLOGY AND AFFECT DISEASE RISK AND SEVERITY. OUR STUDIES OF CPG ISLAND METHYLATION IN NORMAL COLORECTAL MUCOSA REVEALED PROGRESSIVE AGE-RELATED INCREASES AT MULTIPLE GENE LOCI, SUGGESTING GENOME-WIDE MOLECULAR ALTERATIONS WITH POTENTIAL TO SILENCE GENE EXPRESSION. HOWEVER, THERE WAS CONSIDERABLE VARIATION IN THE DEGREE OF METHYLATION AMONG INDIVIDUALS OF COMPARABLE AGES. SUCH VARIATION COULD BE RELATED TO GENETIC FACTORS, LIFESTYLE, OR ENVIRONMENTAL EXPOSURES. STUDIES IN ULCERATIVE COLITIS AND HEPATOCELLULAR CIRRHOSIS AND NEOPLASIA REVEALED THAT CHRONIC INFLAMMATORY STATES ARE ACCOMPANIED BY MARKED INCREASES IN CPG ISLAND METHYLATION IN NORMAL-APPEARING TISSUES, CONFIRMING THE HYPOTHESIS THAT PROINFLAMMATORY EXPOSURES COULD ACCOUNT FOR PART OF THE EPIGENETIC VARIATION IN HUMAN POPULATIONS. PRELIMINARY DATA ALSO SUGGEST POTENTIAL INFLUENCES OF LIFESTYLE AND EXPOSURE FACTORS ON CPG ISLAND METHYLATION. IT IS SUGGESTED THAT EPIGENETIC VARIATION RELATED TO AGING, LIFESTYLE, EXPOSURES AND POSSIBLY GENETIC FACTORS, IS ONE OF THE MODULATORS OF ACQUIRED, AGE-RELATED HUMAN DISEASES, INCLUDING NEOPLASIA. 2002 12 3067 31 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 13 70 25 A METHOD TO DETECT DIFFERENTIALLY METHYLATED LOCI WITH NEXT-GENERATION SEQUENCING. EPIGENETIC CHANGES, ESPECIALLY DNA METHYLATION AT CPG LOCI HAVE IMPORTANT IMPLICATIONS IN CANCER AND OTHER COMPLEX DISEASES. WITH THE DEVELOPMENT OF NEXT-GENERATION SEQUENCING (NGS), IT IS FEASIBLE TO GENERATE DATA TO INTERROGATE THE DIFFERENCE IN METHYLATION STATUS FOR GENOME-WIDE LOCI USING CASE-CONTROL DESIGN. HOWEVER, A PROPER AND EFFICIENT STATISTICAL TEST IS LACKING. THERE ARE SEVERAL CHALLENGES. FIRST, UNLIKE METHYLATION EXPERIMENTS USING MICROARRAYS, WHERE THERE IS ONE MEASURE OF METHYLATION FOR ONE INDIVIDUAL AT A PARTICULAR CPG SITE, HERE WE HAVE THE COUNTS OF METHYLATION ALLELE AND UNMETHYLATION ALLELE FOR EACH INDIVIDUAL. SECOND, DUE TO THE NATURE OF SAMPLE PREPARATION, THE MEASURED METHYLATION REFLECTS THE METHYLATION STATUS OF A MIXTURE OF CELLS INVOLVED IN SAMPLE PREPARATION. THEREFORE, THE UNDERLYING DISTRIBUTION OF THE MEASURED METHYLATION LEVEL IS UNKNOWN, AND A ROBUST TEST IS MORE DESIRABLE THAN PARAMETRIC APPROACH. THIRD, CURRENTLY NGS MEASURES METHYLATION AT OVER 2 MILLION CPG SITES. ANY STATISTICAL TESTS HAVE TO BE COMPUTATIONALLY EFFICIENT IN ORDER TO BE APPLIED TO THE NGS DATA. TAKING THESE CHALLENGES INTO ACCOUNT, WE PROPOSE A TEST FOR DIFFERENTIAL METHYLATION BASED ON CLUSTERED DATA ANALYSIS BY MODELING THE METHYLATION COUNTS. WE PERFORMED SIMULATIONS TO SHOW THAT IT IS ROBUST UNDER SEVERAL DISTRIBUTIONS FOR THE MEASURED METHYLATION LEVELS. IT HAS GOOD POWER AND IS COMPUTATIONALLY EFFICIENT. FINALLY, WE APPLY THE TEST TO OUR NGS DATA ON CHRONIC LYMPHOCYTIC LEUKEMIA. THE RESULTS INDICATE THAT IT IS A PROMISING AND PRACTICAL TEST. 2013 14 2494 18 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 15 287 33 AGING AND CHRONIC SUN EXPOSURE CAUSE DISTINCT EPIGENETIC CHANGES IN HUMAN SKIN. EPIGENETIC CHANGES ARE WIDELY CONSIDERED TO PLAY AN IMPORTANT ROLE IN AGING, BUT EXPERIMENTAL EVIDENCE TO SUPPORT THIS HYPOTHESIS HAS BEEN SCARCE. WE HAVE USED ARRAY-BASED ANALYSIS TO DETERMINE GENOME-SCALE DNA METHYLATION PATTERNS FROM HUMAN SKIN SAMPLES AND TO INVESTIGATE THE EFFECTS OF AGING, CHRONIC SUN EXPOSURE, AND TISSUE VARIATION. OUR RESULTS REVEAL A HIGH DEGREE OF TISSUE SPECIFICITY IN THE METHYLATION PATTERNS AND ALSO SHOWED VERY LITTLE INTERINDIVIDUAL VARIATION WITHIN TISSUES. DATA STRATIFICATION BY AGE REVEALED THAT DNA FROM OLDER INDIVIDUALS WAS CHARACTERIZED BY A SPECIFIC HYPERMETHYLATION PATTERN AFFECTING LESS THAN 1% OF THE MARKERS ANALYZED. INTERESTINGLY, STRATIFICATION BY SUN EXPOSURE PRODUCED A FUNDAMENTALLY DIFFERENT PATTERN WITH A SIGNIFICANT TREND TOWARDS HYPOMETHYLATION. OUR RESULTS THUS IDENTIFY DEFINED AGE-RELATED DNA METHYLATION CHANGES AND SUGGEST THAT THESE ALTERATIONS MIGHT CONTRIBUTE TO THE PHENOTYPIC CHANGES ASSOCIATED WITH SKIN AGING. 2010 16 1577 23 DNA METHYLATION PROFILE IN CHRONIC MYELOMONOCYTIC LEUKEMIA ASSOCIATES WITH DISTINCT CLINICAL, BIOLOGICAL AND GENETIC FEATURES. CHROMOSOMAL ABNORMALITIES ARE DETECTED IN 20-30% OF PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) AND CORRELATE WITH PROGNOSIS. ON THE MUTATION LEVEL, DISRUPTIVE ALTERATIONS ARE PARTICULARLY FREQUENT IN CHROMATIN REGULATORY GENES. HOWEVER, LITTLE IS KNOWN ABOUT THE CONSEQUENTIAL ALTERATIONS IN THE EPIGENETIC MARKING OF THE GENOME. HERE, WE REPORT THE ANALYSIS OF GENOMIC DNA METHYLATION PATTERNS OF 64 CMML PATIENTS AND 10 HEALTHY CONTROLS, USING A DNA METHYLATION MICROARRAY FOCUSED ON PROMOTER REGIONS. DIFFERENTIAL METHYLATION ANALYSIS BETWEEN PATIENTS AND CONTROLS ALLOWED US TO IDENTIFY ABNORMALITIES IN DNA METHYLATION, INCLUDING HYPERMETHYLATION OF SPECIFIC GENES AND LARGE GENOME REGIONS WITH ABERRANT DNA METHYLATION. UNSUPERVISED HIERARCHICAL CLUSTER ANALYSIS IDENTIFIED TWO MAIN CLUSTERS THAT ASSOCIATED WITH THE CLINICAL, BIOLOGICAL, AND GENETIC FEATURES OF PATIENTS. GROUP 1 WAS ENRICHED IN PATIENTS WITH ADVERSE CLINICAL AND BIOLOGICAL CHARACTERISTICS AND POORER OVERALL AND PROGRESSION-FREE SURVIVAL. IN ADDITION, SIGNIFICANT DIFFERENCES IN DNA METHYLATION WERE OBSERVED BETWEEN PATIENTS WITH LOW RISK AND INTERMEDIATE/HIGH RISK KARYOTYPES AND BETWEEN TET2 MUTANT AND WILD TYPE PATIENTS. TAKEN TOGETHER, OUR RESULTS DEMONSTRATE THAT ALTERED DNA METHYLATION PATTERNS REFLECT THE CMML DISEASE STATE AND ALLOW TO IDENTIFY PATIENT GROUPS WITH DISTINCT CLINICAL FEATURES. 2018 17 3925 27 LIQUID BIOPSIES BASED ON DNA METHYLATION AS BIOMARKERS FOR THE DETECTION AND PROGNOSIS OF LUNG CANCER. LUNG CANCER (LC) IS THE MAIN CAUSE OF CANCER-RELATED MORTALITY. MOST LC PATIENTS ARE DIAGNOSED IN AN ADVANCED STAGE WHEN THE SYMPTOMS ARE OBVIOUS, AND THE PROGNOSIS IS QUITE POOR. ALTHOUGH LOW-DOSE COMPUTED TOMOGRAPHY (LDCT) IS A ROUTINE CLINICAL EXAMINATION FOR EARLY DETECTION OF LC, THE FALSE-POSITIVE RATE IS OVER 90%. AS ONE OF THE INTENSELY STUDIED EPIGENETIC MODIFICATIONS, DNA METHYLATION PLAYS A KEY ROLE IN VARIOUS DISEASES, INCLUDING CANCER AND OTHER DISEASES. HYPERMETHYLATION IN TUMOR SUPPRESSOR GENES OR HYPOMETHYLATION IN ONCOGENES IS AN IMPORTANT EVENT IN TUMORIGENESIS. REMARKABLY, DNA METHYLATION USUALLY OCCURS IN THE VERY EARLY STAGE OF MALIGNANT TUMORS. THUS, DNA METHYLATION ANALYSIS MAY PROVIDE SOME USEFUL INFORMATION ABOUT THE EARLY DETECTION OF LC. IN RECENT YEARS, LIQUID BIOPSY HAS DEVELOPED RAPIDLY. LIQUID BIOPSY CAN DETECT AND MONITOR BOTH PRIMARY AND METASTATIC MALIGNANT TUMORS AND CAN REFLECT TUMOR HETEROGENEITY. MOREOVER, IT IS A MINIMALLY INVASIVE PROCEDURE, AND IT CAUSES LESS PAIN FOR PATIENTS. THIS REVIEW SUMMARIZED VARIOUS LIQUID BIOPSIES BASED ON DNA METHYLATION FOR LC. AT FIRST, WE BRIEFLY DISCUSSED SOME EMERGING TECHNOLOGIES FOR DNA METHYLATION ANALYSIS. SUBSEQUENTLY, WE OUTLINED CELL-FREE DNA (CFDNA), SPUTUM, BRONCHOALVEOLAR LAVAGE FLUID, BRONCHIAL ASPIRATES, AND BRONCHIAL WASHINGS DNA METHYLATION-BASED LIQUID BIOPSY FOR THE EARLY DETECTION OF LC. FINALLY, THE PROGNOSTIC VALUE OF DNA METHYLATION IN CFDNA AND SPUTUM AND THE DIAGNOSTIC VALUE OF OTHER DNA METHYLATION-BASED LIQUID BIOPSIES FOR LC WERE ALSO ANALYZED. 2022 18 3652 29 INDIVIDUAL DNA METHYLATION PATTERN SHIFTS IN NANOPARTICLES-EXPOSED WORKERS ANALYZED IN FOUR CONSECUTIVE YEARS. A DNA METHYLATION PATTERN REPRESENTS AN ORIGINAL PLAN OF THE FUNCTION SETTINGS OF INDIVIDUAL CELLS AND TISSUES. THE BASIC STRATEGIES OF ITS DEVELOPMENT AND CHANGES DURING THE HUMAN LIFETIME ARE KNOWN, BUT THE DETAILS RELATED TO ITS MODIFICATION OVER THE YEARS ON AN INDIVIDUAL BASIS HAVE NOT YET BEEN STUDIED. MOREOVER, CURRENT EVIDENCE SHOWS THAT ENVIRONMENTAL EXPOSURE COULD GENERATE CHANGES IN DNA METHYLATION SETTINGS AND, SUBSEQUENTLY, THE FUNCTION OF GENES. IN THIS STUDY, WE ANALYZED THE EFFECT OF CHRONIC EXPOSURE TO NANOPARTICLES (NP) IN OCCUPATIONALLY EXPOSED WORKERS REPEATEDLY SAMPLED IN FOUR CONSECUTIVE YEARS (2016-2019). A DETAILED METHYLATION PATTERN ANALYSIS OF 14 PERSONS (10 EXPOSED AND 4 CONTROLS) WAS PERFORMED ON AN INDIVIDUAL BASIS. A MICROARRAY-BASED APPROACH USING CHIPS, ALLOWING THE ASSESSMENT OF MORE THAN 850 K CPG LOCI, WAS USED. INDIVIDUAL DNA METHYLATION PATTERNS WERE COMPARED BY PRINCIPAL COMPONENT ANALYSIS (PCA). THE RESULTS SHOW THE SHIFT IN DNA METHYLATION PATTERNS IN INDIVIDUAL YEARS IN ALL THE EXPOSED AND CONTROL SUBJECTS. THE OVERALL RANGE OF DIFFERENCES VARIED BETWEEN THE YEARS IN INDIVIDUAL PERSONS. THE DIFFERENCES BETWEEN THE FIRST AND LAST YEAR OF EXAMINATION (A THREE-YEAR TIME PERIOD) SEEM TO BE CONSISTENTLY GREATER IN THE NP-EXPOSED SUBJECTS IN COMPARISON WITH THE CONTROLS. THE SELECTED 14 MOST DIFFERENTLY METHYLATED CG LOCI WERE RELATIVELY STABLE IN THE CHRONICALLY EXPOSED SUBJECTS. IN SUMMARY, THE SPECIFIC TYPE OF LONG-TERM EXPOSURE CAN CONTRIBUTE TO THE FIXING OF RELEVANT EPIGENETIC CHANGES RELATED TO A SPECIFIC ENVIRONMENT AS, E.G., NP INHALATION. 2021 19 3686 20 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 20 606 30 BEYOND GENETICS--THE EMERGING ROLE OF EPIGENETIC CHANGES IN HEMATOPOIETIC MALIGNANCIES. THE TERM EPIGENETIC REFERS TO A HERITABLE CHANGE IN GENE EXPRESSION THAT IS MEDIATED BY MECHANISMS OTHER THAN ALTERATIONS IN THE PRIMARY NUCLEOTIDE SEQUENCE. DNA METHYLATION AT CYTOSINE BASES THAT ARE LOCATED 5' TO GUANOSINE WITHIN A CPG DINUCLEOTIDE IS THE MAIN EPIGENETIC MODIFICATION IN HUMANS. PATTERNS OF DNA METHYLATION ARE PROFOUNDLY DERANGED IN HUMAN CANCER AND COMPRISE GENOME-WIDE LOSSES AS WELL AS REGIONAL GAINS IN DNA METHYLATION. HYPERMETHYLATION OF CPG ISLANDS WITHIN GENE PROMOTER REGIONS IS ASSOCIATED WITH TRANSCRIPTIONAL INACTIVATION AND REPRESENTS, IN ADDITION TO GENETIC ABERRATIONS, AN IMPORTANT MECHANISM OF GENE SILENCING IN THE PATHOGENESIS OF HEMATOPOIETIC MALIGNANCIES. THIS EPIGENETIC PHENOMENON ACTS AS AN ALTERNATIVE TO MUTATIONS AND DELETIONS TO DISRUPT TUMOR SUPPRESSOR GENE FUNCTION. A LARGE NUMBER OF GENES INVOLVING FUNDAMENTAL CELLULAR PATHWAYS MAY BE AFFECTED IN VIRTUALLY ALL TYPES OF HUMAN CANCER BY ABERRANT CPG ISLAND METHYLATION IN ASSOCIATION WITH TRANSCRIPTIONAL SILENCING. ALTERED METHYLATION PATTERNS CAN BE USED AS BIOMARKERS FOR CANCER DETECTION, ASSESSMENT OF PROGNOSIS, AND PREDICTION OF RESPONSE TO ANTITUMOR TREATMENT. FURTHERMORE, CLINICAL TRIALS USING EPIGENETICALLY TARGETED THERAPIES HAVE YIELDED PROMISING RESULTS FOR ACUTE AND CHRONIC LEUKEMIAS AS WELL AS FOR MYELODYSPLASTIC SYNDROMES. THE EXPLORATION OF OUR GROWING KNOWLEDGE ABOUT EPIGENETIC ABERRATIONS MAY HELP DEVELOP NOVEL STRATEGIES FOR THE DIAGNOSIS AND TREATMENT OF HEMATOPOIETIC MALIGNANCIES IN THE FUTURE. 2004