1  4227 96 METHYLATION OF FREE-FLOATING DEOXYRIBONUCLEIC ACID FRAGMENTS IN THE BRONCHOALVEOLAR LAVAGE FLUID OF DOGS WITH CHRONIC BRONCHITIS EXPOSED TO ENVIRONMENTAL TOBACCO SMOKE. BACKGROUND: THE ETIOLOGY OF CANINE CHRONIC BRONCHITIS (CB) IS NOT COMPLETELY UNDERSTOOD, ALTHOUGH EXPOSURE TO ENVIRONMENTAL TOBACCO SMOKE (ETS) AFFECTS THE AIRWAY INFLAMMATORY RESPONSES IN SOME DOGS WITH CB. THE MECHANISM BY WHICH THIS OCCURS IS UNKNOWN. FINDINGS: WE INVESTIGATED THE CONCENTRATIONS AND METHYLATION RATES OF FREE-FLOATING DNA FRAGMENTS IN BRONCHOALVEOLAR LAVAGE FLUID (BALF) FROM DOGS WITH CHRONIC BRONCHITIS. BASED ON SERUM COTININE LEVELS, DOGS WITH CB WERE DIVIDED INTO 2 GROUPS: DOGS THAT EITHER HAD OR HAD NOT BEEN EXPOSED TO ETS. OUR RESULTS DEMONSTRATED THAT THE TOTAL NUCLEATED CELL AND MACROPHAGE NUMBERS INCREASED IN BALF OF ETS-EXPOSED DOGS WITH CB. THERE WERE NO SIGNIFICANT DIFFERENCES IN DNA CONCENTRATIONS AND METHYLATION RATES IN BALF BETWEEN THE 2 GROUPS. HOWEVER, 3 OUT OF 8 DOGS EXPOSED TO ETS HAD HIGH DNA METHYLATION RATES IN THEIR BALF SAMPLES. CONCLUSION: OUR RESULTS SUGGEST THAT ETS EXPOSURE LEADS TO EPIGENETIC MODIFICATIONS OF CELLULAR COMPONENTS IN BALF IN DOGS DIAGNOSED WITH CB.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
2   740 29 CANCER/TESTIS ANTIGENS: EXPRESSION, REGULATION, TUMOR INVASION, AND USE IN IMMUNOTHERAPY OF CANCERS. CANCER/TESTIS ANTIGENS (CTAS) ARE NAMED BASED ON THEIR EXPRESSION PATTERN THAT IS RESTRICTED IN A NUMBER OF NORMAL AND ABNORMAL TISSUES. TUMOR CELLS FREQUENTLY EXPRESS ANTIGENS WHOSE EXPRESSION IS TYPICALLY RESTRICTED TO GERM CELLS. THEIR UNIQUE EXPRESSION PATTERN IS GUARANTEED BY PRECISE EPIGENETIC REGULATORY MECHANISMS. BECAUSE OF THEIR TUMOR-LIMITED, HIGH IMMUNOGENICITY, AND BIASED EXPRESSION, DISCOVERY OF THESE MOLECULES PROVIDES UNPRECEDENTED OPPORTUNITIES FOR FURTHER RESEARCH AND CLINICAL DEVELOPMENT IN THE FIELD OF CANCER DIAGNOSIS AND IMMUNOTHERAPY. EVOLVING EVIDENCE REVEALS THAT A NUMBER OF CTAS STIMULATE EPITHELIAL MESENCHYMAL TRANSITION (EMT) AND GENERATION OF CANCER STEM-LIKE CELLS, INTENSIFYING METASTASIS, INVASION, AND TUMORIGENESIS. BASED ON THESE FEATURES, CTAS ATTRACT ATTENTION TO BE CONSIDERED AS IDEAL TARGETS FOR DEVELOPING SEVERAL CLINICAL TRIALS, MANY OF THEM CONCENTRATING ON CTA VACCINE THERAPY. ACCORDING TO RECENT PRACTICAL CLINICAL INTEREST, MORE CHARACTERIZATIONS OF CTA REGULATION ARE IDENTIFIED. CTA EXPRESSION HAS BEEN DEMONSTRATED IN A VARIETY OF HUMAN CANCER TISSUES, AND SOME OF THEM HAVE BEEN FOUND TO ELICIT HUMORAL AND/OR CELLULAR IMMUNE RESPONSES IN CANCER PATIENTS. CTAS ARE BRILLIANT TARGETS FOR ANTICANCER DRUG DISCOVERY, TARGETED TUMOR THERAPY, AND DIAGNOSTIC BIOMARKERS, FURTHERMORE, VALUED GENES IN THE STUDY OF IMMUNOTHERAPY, PROMOTING TUMORIGENESIS, AND MALIGNANT PROGRESSION. THIS REVIEW OUTLINES AND CATEGORIZES OUR CURRENT UNDERSTANDING OF THE COMPLEX AND BIASED PROCESS OF CTAS MRNA AND PROTEIN EXPRESSION IN CANCER, AND SUPPLIES THE MOST RECENT INFORMATION ON THEIR REGULATION AND FUNCTION. BESIDES, A CONCISE SYNOPSIS OF THE MAJOR CLINICAL TRIALS INVOLVING CTAS, AS THERAPEUTIC AVENUES, IS DISCUSSED. ABBREVIATIONS: AIRE: AUTOIMMUNE REGULATOR; CAMP: CYCLIC ADENOSINE 3',5'-CYCLIC MONOPHOSPHATE; CEA: CARCINOEMBRYONIC ANTIGEN; CML: CHRONIC MYELOID LEUKEMIA; CREB: CYCLICAMP RESPONSE ELEMENT BINDING; CSCS: CANCER STEM CELLS; CTAS: CANCER/TESTIS ANTIGENS; CTL: CYTOTOXIC T LYMPHOCYTE; DCS: DENDRITIC CELLS; EMT: EPITHELIAL-MESENCHYMAL TRANSITION; ERK: EXTRACELLULAR SIGNAL-REGULATED KINASE; ESCC: ESOPHAGEAL SQUAMOUS CELL CARCINOMA; ETS: E26 TRANSFORMATION-SPECIFIC; HIS: HISTIDINE; HLA: HUMAN LEUKOCYTE ANTIGEN; HNSCC: HEAD AND NECK SQUAMOUS CELL CARCINOMA; IFN-GAMMA: INTERFERON-GAMMA; IHC: IMMUNOHISTOCHEMISTRY; IL-7: INTERLEUKIN7; MHC: MAJOR HISTOCOMPATIBILITY COMPLEX; MMP2: MATRIX METALLOPROTEINASE 2; MTECS: MEDULLARY THYMUS EPITHELIAL CELLS; MUC1: MUCIN 1; NSCLC: NON-SMALL CELL LUNG CANCER; PRAME: PREFERENTIALLY EXPRESSED ANTIGEN IN MELANOMA; RDA: REPRESENTATIONAL DIFFERENCE ANALYSIS; SEREX: SEROLOGICAL ANALYSIS OF CDNA EXPRESSION; SSX: SYNOVIAL SARCOMA X CHROMOSOME; TAAS: TUMOR-ASSOCIATED ANTIGENS; TCR: T-CELL RECEPTOR; TCGA: THE CANCER GENOME ATLAS; TGF-BETA: TRANSFORMING GROWTH FACTOR-BETA.	2016	

3  5984 25 TET2, DNMT3A, IDH1, AND JAK2 MUTATION IN MYELOPROLIFERATIVE NEOPLASMS IN SOUTHERN IRAN. BACKGROUND: FIVE EPIGENETIC REGULATOR MUTATIONS ARE CONSIDERED IN MYELOPROLIFERATIVE NEOPLASMS (MPN) THAT HAVE PROGNOSTIC AND THERAPEUTIC VALUES. OBJECTIVE: WE AIMED TO EVALUATE THESE MUTATIONS IN MPNS AMONG THE IRANIAN POPULATION. METHODS: WE SELECTED 5 MUTATIONS IN 4 EPIGENETIC REGULATORY GENES [TET2, DNMT3A, IDH1 (RS147001633&RS121913499), AND JAK2)] AND EVALUATED 130 PATIENTS WITH MPNS INCLUDING 78 PHILADELPHIA CHROMOSOME NEGATIVE (49 ETS, 20 PVS, AND 9 PMFS) AND 52 PHILADELPHIA CHROMOSOME-POSITIVE PATIENTS AS WELL AS 51 HEALTHY CONTROLS. RESULTS: EIGHT PATIENTS (6.5%) CARRIED THE DNMT3A MUTATION, 35 (27%) WERE POSITIVE FOR TET2 MUTATION AND 64 (49.3%) HAD THE JAK2V617F MUTATION. IN THE HEALTHY CONTROLS, 16 (31.4%) CASES HAD THE TET2 MUTATION (15 HETEROZYGOTE + 1 HOMOZYGOTE) AND ONE HAD HETEROZYGOTE JAK2 MUTATION. THERE WAS NO STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN PATIENT GROUPS FOR ANY OF THESE MUTATIONS, EXCEPT FOR JAK2. THE JAK2 MUTATION RATE WAS 18 (90%), 25 (51%), 7 (77.8%), 14 (26.9%) IN POLYCYTHEMIA VERA, ESSENTIAL THROMBOCYTHEMIA, PRIMARY MYELOFIBROSIS, AND CHRONIC MYELOCYTIC LEUKEMIA, RESPECTIVELY. PATIENTS AGED 60 AND OLDER WERE MORE LIKELY TO CARRY THE TET2 MUTATION (23% VS. 39% IN YOUNGER AND OLDER THAN 60 YEARS OLD INDIVIDUALS, P=0.025). IDH1 WAS NOT DETECTED AT ALL AND PV HAD THE HIGHEST TET2 MUTATION 7(35%). TWO PMF PATIENTS HAD A HISTORY OF BONE MARROW TRANSPLANTATION THAT WERE NEGATIVE FOR IDH1AND DNMT3A AND ONE WAS POSITIVE FOR TET2 MUTATION. CONCLUSION: IN THE NORMAL IRANIAN POPULATION, THE HETEROZYGOTE FORM OF TET2 MUTATION IS SIGNIFICANT, ESPECIALLY IN THE ELDERLY. NO ASSOCIATION WAS FOUND BETWEEN JAK2 AND TET2 MUTATIONS. BOTH OF THEM ARE MORE PREVALENT IN THE AGE GROUP OF 60 YEARS AND OLDER. DNMT3A MUTATION HAS A LOW PREVALENCE AND OCCURS IN BOTH POSITIVE AND NEGATIVE MPNS.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
4  6474 30 TOBACCO HEATING SYSTEM 2.2 HAS A LIMITED IMPACT ON DNA METHYLATION OF CANDIDATE ENHANCERS IN MOUSE LUNG COMPARED WITH CIGARETTE SMOKE. CIGARETTE SMOKE (CS) EXPOSURE HAS BEEN SHOWN TO CORRELATE WITH CHANGES IN DNA METHYLATION LEVELS, HOWEVER, THE IMPACT OF CS ON DNA METHYLATION AT GENOME-WIDE SCALE IS MISSING. HERE, WE USED WHOLE-GENOME BISULFITE SEQUENCING TO ASSESS THE EFFECTS OF CS EXTRACT AND AEROSOL FROM THE TOBACCO HEATING SYSTEM (THS) 2.2, A CANDIDATE MODIFIED RISK TOBACCO PRODUCT, ON DNA METHYLATION IN LUNG AND LIVER TISSUES FROM APOLIPOPROTEIN E-DEFICIENT MICE DURING AN EIGHT-MONTH PERIOD OF EXPOSURE. WE FOUND THAT IN LUNG TISSUE, CS MAINLY INDUCED HYPERMETHYLATION OF CANDIDATE ENHANCERS AT LATE TIME POINTS, WHILE PROMOTERS WERE LESS AFFECTED. THIS EFFECT WAS STRONGLY REDUCED UPON CESSATION OR SWITCHING TO THS 2.2. BY CONTRAST, CHRONIC EXPOSURE TO THS 2.2 HAD A LIMITED EFFECT ON DNA METHYLATION AT BOTH PROMOTERS AND ENHANCERS. WE ALSO IDENTIFIED MEMBERS OF THE ETS AND FOX FAMILIES OF TRANSCRIPTION FACTORS AS POTENTIAL PLAYERS IN THE EPIGENETIC RESPONSE TO CS EXPOSURE IN LUNG TISSUE. IN CONTRAST TO THE LUNG, DNA METHYLATION IN THE LIVER WAS LARGELY INSENSITIVE TO ALL INVESTIGATED EXPOSURES. IN SUMMARY, OUR INVESTIGATIONS INDICATE THAT CS-RELATED DNA METHYLATION ALTERATIONS ARE TISSUE-SPECIFIC, OCCUR MAINLY AT ENHANCERS AND ARE STRONGLY REDUCED UPON SMOKING CESSATION OR SWITCHING TO THS2.2.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5  2355 26 EPIGENETIC REGULATION OF PRAME GENE IN CHRONIC MYELOID LEUKEMIA. TUMOR ASSOCIATED ANTIGENS (TAA) PROVIDE ATTRACTIVE TARGETS FOR CANCER-SPECIFIC IMMUNOTHERAPY. PRAME IS A TAA GENE UP-REGULATED IN ADVANCED PHASES OF CHRONIC MYELOID LEUKEMIA (CML). TO DATE, MOLECULAR MECHANISMS FOR THE EXPRESSION OF PRAME HAVE NEVER BEEN STUDIED. WE FOUND THAT SOME PH'-POSITIVE CELL LINES DID NOT EXPRESS PRAME. THE EXPRESSION OF PRAME WAS RESTORED IN THESE CELL LINES BY TREATMENT WITH 5'-AZA-2'-DEOXYCYTIDINE, SUGGESTING THAT THE EXPRESSION OF PRAME IS MAINLY SUPPRESSED BY HYPERMETHYLATION. BISULFITE SEQUENCING ANALYSIS OF THE CPG SITES OF THE PRAME EXON 2 IN THESE CANCER CELL LINES REVEALED A CLOSE RELATIONSHIP BETWEEN THE METHYLATION STATUS OF THE PRAME GENE AND ITS EXPRESSION. A METHYLATION-SPECIFIC PCR ANALYSIS DEMONSTRATED THAT HYPOMETHYLATION OF PRAME WAS SIGNIFICANTLY MORE FREQUENT IN CML BLAST CRISIS (70%) THAN IN CHRONIC PHASE (36%) (P=0.01) AND WAS CORRELATED WITH HIGH EXPRESSION LEVELS OF PRAME TRANSCRIPTS (P<0.0001). THESE RESULTS SUGGEST THAT HYPOMETHYLATION OF PRAME UP-REGULATES ITS EXPRESSION IN CML AND MIGHT PLAY A SIGNIFICANT ROLE IN THE PROGRESSION OF THE DISEASE.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
6   150 26 ABERRANT HYPOMETHYLATION OF THE CANCER-TESTIS ANTIGEN PRAME CORRELATES WITH PRAME EXPRESSION IN ACUTE MYELOID LEUKEMIA. PRAME IS A TUMOR-ASSOCIATED ANTIGEN, WHICH BELONGS TO THE FAMILY OF CANCER-TESTIS ANTIGENS (CTA). THE EXPRESSION OF CTA IS MAINLY RESTRICTED TO THE TESTIS AND VARIOUS TUMORS. IN CONTRAST TO OTHER CTA, PRAME EXPRESSION IS ALSO FREQUENTLY DETECTED IN ACUTE AND CHRONIC LEUKEMIAS. DUE TO THIS EXPRESSION PATTERN, PRAME HAS ATTRACTED GREAT INTEREST AS A PROGNOSTIC TUMOR MARKER THAT CAN BE USED FOR THE DETECTION OF MINIMAL RESIDUAL DISEASE AND AS A POTENTIAL TARGET FOR IMMUNOTHERAPY. IN ACUTE MYELOID LEUKEMIA (AML), PRAME EXPRESSION HAS BEEN OBSERVED IN 30-64% OF CASES. TO EVALUATE WHETHER EPIGENETIC MECHANISMS CONTRIBUTE TO PRAME ACTIVATION IN AML, WE STUDIED DNA METHYLATION OF 15 CPG DINUCLEOTIDES WITHIN A CPG-RICH REGION LOCATED IN THE INTRON 1 OF THE PRAME GENE. DNA METHYLATION WAS DETERMINED BY SEQUENCE ANALYSIS OF CLONED PCR PRODUCTS GENERATED FROM BISULFITE-TREATED GENOMIC DNA. METHYLATION PATTERNS WERE CORRELATED WITH PRAME MRNA LEVELS AS DETERMINED BY MICROARRAY ANALYSIS AND REAL-TIME PCR. WE FOUND ALMOST COMPLETE METHYLATION IN MONONUCLEAR BLOOD CELLS FROM TWO HEALTHY DONORS AND IN BONE MARROW CELLS OF FOUR PRAME-NEGATIVE AML PATIENTS. IN CONTRAST, THE DEGREE OF PRAME METHYLATION WAS CLEARLY REDUCED IN FOUR PRAME-POSITIVE AML BONE MARROW SAMPLES. IN PARTICULAR, THESE SAMPLES WERE CHARACTERIZED BY THE PRESENCE OF CLONES, WHICH WERE COMPLETELY DEVOID OF METHYLATION. THE SIGNIFICANT INVERSE CORRELATION BETWEEN THE DEGREE OF METHYLATION AND PRAME EXPRESSION SUGGESTS A CAUSAL ROLE OF DNA METHYLATION IN PRAME REGULATION. SUCH A ROLE IS FURTHER SUPPORTED BY THE OBSERVATION THAT TREATMENT OF PRAME-NEGATIVE CELL LINES U-937 AND THP-1 WITH THE DEMETHYLATING AGENT 5'-AZA-2'DC RESULTED IN A DOSE-RELATED UPREGULATION OF PRAME EXPRESSION.	2008	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
7  2765 25 EXPRESSION, EPIGENETIC REGULATION, AND HUMORAL IMMUNOGENICITY OF CANCER-TESTIS ANTIGENS IN CHRONIC MYELOID LEUKEMIA. OBJECTIVE: CANCER-TESTIS (CT) ANTIGENS REPRESENT ATTRACTIVE TARGETS FOR TUMOR IMMUNOTHERAPY BASED ON THEIR TUMOR-RESTRICTED EXPRESSION AND IMMUNOGENICITY. HOWEVER, A BROAD PICTURE OF THE EXPRESSION OF CT ANTIGENS AND ASSOCIATED HUMORAL IMMUNE RESPONSES IN CHRONIC MYELOID LEUKEMIA (CML) IS STILL MISSING. METHODS: WE SCREENED CML CELL LINES AND BONE MARROW (BM) SAMPLES FROM HEALTHY DONORS BY RT-PCR FOR THE EXPRESSION OF 31 CT ANTIGENS BEFORE AND AFTER TREATMENT WITH EPIGENETIC AGENTS. EXPRESSION OF TUMOR-RESTRICTED ANTIGENS WAS FURTHER EXAMINED IN 60 CML PATIENTS AND HUMORAL IMMUNE RESPONSES AGAINST 15 CT ANTIGENS WERE SCREENED BY ELISA. RESULTS: IN UNTREATED CELL LINES WE DETECTED THE EXPRESSION OF 17 CT ANTIGENS THAT WERE ABSENT FROM NORMAL BM. EXPRESSION OF MOST ANTIGENS INCREASED FOLLOWING DEMETHYLATING TREATMENT WITH 5'-AZA-2'-DEOXYCYTIDINE. IN THESE SAMPLES, ONLY PRAME WAS REPEATEDLY DETECTED AND EXPRESSION CORRELATED WITH SEVERAL CLINICOPATHOLOGICAL PARAMETERS AND DECREASED OVERALL SURVIVAL. WE FURTHER SHOW THAT A LOWER FREQUENCY OF PRAME-POSITIVE SAMPLES DURING IMATINIB TREATMENT WAS NOT CAUSED BY GENE-SPECIFIC DOWNREGULATION. ANALYZING THE PATIENTS' ANTIBODY RESPONSES WE FOUND THAT THE VAST MAJORITY OF PATIENTS LACKED SPONTANEOUS IMMUNITY AGAINST CT ANTIGENS INCLUDING PRAME. CONCLUSIONS: CT ANTIGEN EXPRESSION CAN BE INCREASED BY THE APPLICATION OF EPIGENETIC AGENTS AND THE EXPRESSION OF PRAME CORRELATES WITH CLINICOPATHOLOGICAL PARAMETERS AND OVERALL SURVIVAL IN PATIENTS WITH CML, BUT DOES NOT LEAD TO HUMORAL IMMUNE RESPONSES. PRAME-SPECIFIC IMMUNOTHERAPY MIGHT REPRESENT A PROMISING APPROACH FOR THE ERADICATION OF RESIDUAL THERAPY-RESISTANT LEUKEMIC CELLS DUE TO ITS FREQUENT EXPRESSION AND STABILITY UNDER IMATINIB TREATMENT.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
8  3422 28 HUMAN MONOCYTE-TO-MACROPHAGE DIFFERENTIATION INVOLVES HIGHLY LOCALIZED GAIN AND LOSS OF DNA METHYLATION AT TRANSCRIPTION FACTOR BINDING SITES. BACKGROUND: MACROPHAGES AND THEIR PRECURSORS MONOCYTES PLAY A KEY ROLE IN INFLAMMATION AND CHRONIC INFLAMMATORY DISORDERS. MONOCYTE-TO-MACROPHAGE DIFFERENTIATION AND ACTIVATION PROGRAMS ARE ACCOMPANIED BY SIGNIFICANT EPIGENETIC REMODELING WHERE DNA METHYLATION ASSOCIATES WITH CELL IDENTITY. HERE WE SHOW THAT DNA METHYLATION CHANGES CHARACTERISTIC FOR MONOCYTE-TO-MACROPHAGE DIFFERENTIATION OCCUR AT TRANSCRIPTION FACTOR BINDING SITES, AND, IN CONTRAST TO WHAT WAS PREVIOUSLY DESCRIBED, ARE GENERALLY HIGHLY LOCALIZED AND ENCOMPASS BOTH LOSSES AND GAINS OF DNA METHYLATION. RESULTS: WE COMPARED GENOME-WIDE DNA METHYLATION ACROSS 440,292 CPG SITES BETWEEN HUMAN MONOCYTES, NAIVE MACROPHAGES AND MACROPHAGES FURTHER ACTIVATED TOWARD A PRO-INFLAMMATORY STATE (USING LPS/IFNGAMMA), AN ANTI-INFLAMMATORY STATE (IL-4) OR FOAM CELLS (OXLDL AND ACLDL). MOREOVER, WE INTEGRATED THESE DATA WITH PUBLIC WHOLE-GENOME SEQUENCING DATA ON MONOCYTES AND MACROPHAGES TO DEMARCATE DIFFERENTIALLY METHYLATED REGIONS. OUR ANALYSIS SHOWED THAT DIFFERENTIAL DNA METHYLATION WAS MOST PRONOUNCED DURING MONOCYTE-TO-MACROPHAGE DIFFERENTIATION, WAS TYPICALLY RESTRICTED TO SINGLE CPGS OR VERY SHORT REGIONS, AND CO-LOCALIZED WITH LINEAGE-SPECIFIC ENHANCERS IRRESPECTIVE OF WHETHER IT CONCERNS GAIN OR LOSS OF METHYLATION. FURTHERMORE, DIFFERENTIALLY METHYLATED CPGS WERE LOCATED AT SITES CHARACTERIZED BY INCREASED BINDING OF TRANSCRIPTION FACTORS KNOWN TO BE INVOLVED IN MONOCYTE-TO-MACROPHAGE DIFFERENTIATION INCLUDING C/EBP AND ETS FOR GAIN AND AP-1 FOR LOSS OF METHYLATION. CONCLUSION: OUR STUDY HIGHLIGHTS THE INVOLVEMENT OF SUBTLE, YET HIGHLY LOCALIZED REMODELING OF DNA METHYLATION AT REGULATORY REGIONS IN CELL DIFFERENTIATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
9  6068 29 THE DIET AS A CAUSE OF HUMAN PROSTATE CANCER. ASYMPTOMATIC PROSTATE INFLAMMATION AND PROSTATE CANCER HAVE REACHED EPIDEMIC PROPORTIONS AMONG MEN IN THE DEVELOPED WORLD. ANIMAL MODEL STUDIES IMPLICATE DIETARY CARCINOGENS, SUCH AS THE HETEROCYCLIC AMINES FROM OVER-COOKED MEATS AND SEX STEROID HORMONES, PARTICULARLY ESTROGENS, AS CANDIDATE ETIOLOGIES FOR PROSTATE CANCER. EACH ACTS BY CAUSING EPITHELIAL CELL DAMAGE, TRIGGERING AN INFLAMMATORY RESPONSE THAT CAN EVOLVE INTO A CHRONIC OR RECURRENT CONDITION. THIS MILIEU APPEARS TO SPAWN PROLIFERATIVE INFLAMMATORY ATROPHY (PIA) LESIONS, A TYPE OF FOCAL ATROPHY THAT REPRESENTS THE EARLIEST OF PROSTATE CANCER PRECURSOR LESIONS. RARE PIA LESIONS CONTAIN CELLS WHICH EXHIBIT HIGH C-MYC EXPRESSION, SHORTENED TELOMERE SEGMENTS, AND EPIGENETIC SILENCING OF GENES SUCH AS GSTP1, ENCODING THE PI-CLASS GLUTATHIONE S-TRANSFERASE, ALL CHARACTERISTIC OF PROSTATIC INTRAEPITHELIAL NEOPLASIA (PIN) AND PROSTATE CANCER. SUBSEQUENT GENETIC CHANGES, SUCH AS THE GENE TRANSLOCATIONS/DELETIONS THAT GENERATE FUSION TRANSCRIPTS BETWEEN ANDROGEN-REGULATED GENES (SUCH AS TMPRSS2) AND GENES ENCODING ETS FAMILY TRANSCRIPTION FACTORS (SUCH AS ERG1), ARISE IN PIN LESIONS AND MAY PROMOTE INVASIVENESS CHARACTERISTIC OF PROSTATIC ADENOCARCINOMA CELLS. LETHAL PROSTATE CANCERS CONTAIN MARKEDLY CORRUPTED GENOMES AND EPIGENOMES. EPIGENETIC SILENCING, WHICH SEEMS TO ARISE IN RESPONSE TO THE INFLAMED MICROENVIRONMENT GENERATED BY DIETARY CARCINOGENS AND/OR ESTROGENS AS PART OF AN EPIGENETIC "CATASTROPHE" AFFECTING HUNDREDS OF GENES, PERSISTS TO DRIVE CLONAL EVOLUTION THROUGH METASTATIC DISSEMINATION. THE CAUSE OF THE INITIAL EPIGENETIC "CATASTROPHE" HAS NOT BEEN DETERMINED BUT LIKELY INVOLVES DEFECTIVE CHROMATIN STRUCTURE MAINTENANCE BY OVER-EXUBERANT DNA METHYLATION OR HISTONE MODIFICATION. WITH DIETARY CARCINOGENS AND ESTROGENS DRIVING PRO-CARCINOGENIC INFLAMMATION IN THE DEVELOPED WORLD, IT IS TEMPTING TO SPECULATE THAT DIETARY COMPONENTS ASSOCIATED WITH DECREASED PROSTATE CANCER RISK, SUCH AS INTAKE OF FRUITS AND VEGETABLES, ESPECIALLY TOMATOES AND CRUCIFERS, MIGHT ACT TO ATTENUATE THE RAVAGES OF THE CHRONIC OR RECURRENT INFLAMMATORY PROCESSES. SPECIFICALLY, NUTRITIONAL AGENTS MIGHT PREVENT PIA LESIONS OR REDUCE THE PROPENSITY OF PIA LESIONS TO SUFFER "CATASTROPHIC" EPIGENOME CORRUPTION.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
10  5979 23 TET2 MUTATIONS ARE ASSOCIATED WITH SPECIFIC 5-METHYLCYTOSINE AND 5-HYDROXYMETHYLCYTOSINE PROFILES IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) HAS RECENTLY BEEN ASSOCIATED WITH A HIGH INCIDENCE OF DIVERSE MUTATIONS IN GENES SUCH AS TET2 OR EZH2 THAT ARE IMPLICATED IN EPIGENETIC MECHANISMS. WE HAVE PERFORMED GENOME-WIDE DNA METHYLATION ARRAYS AND MUTATIONAL ANALYSIS OF TET2, IDH1, IDH2, EZH2 AND JAK2 IN A GROUP OF 24 PATIENTS WITH CMML. 249 GENES WERE DIFFERENTIALLY METHYLATED BETWEEN CMML PATIENTS AND CONTROLS. USING INGENUITY PATHWAY ANALYSIS, WE IDENTIFIED ENRICHMENT IN A GENE NETWORK CENTERED AROUND PLC, JNK AND ERK SUGGESTING THAT THESE PATHWAYS, WHOSE DEREGULATION HAS BEEN RECENTLY DESCRIBED IN CMML, ARE AFFECTED BY EPIGENETIC MECHANISMS. MUTATIONS OF TET2, JAK2 AND EZH2 WERE FOUND IN 15 PATIENTS (65%), 4 PATIENTS (17%) AND 1 PATIENT (4%) RESPECTIVELY WHILE NO MUTATIONS IN THE IDH1 AND IDH2 GENES WERE IDENTIFIED. INTERESTINGLY, PATIENTS WITH WILD TYPE TET2 CLUSTERED SEPARATELY FROM PATIENTS WITH TET2 MUTATIONS, SHOWED A HIGHER DEGREE OF HYPERMETHYLATION AND WERE ASSOCIATED WITH HIGHER RISK KARYOTYPES. OUR RESULTS DEMONSTRATE THE PRESENCE OF ABERRANT DNA METHYLATION IN CMML AND IDENTIFIES TET2 MUTANT CMML AS A BIOLOGICALLY DISTINCT DISEASE SUBTYPE WITH A DIFFERENT EPIGENETIC PROFILE.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
11  4555 20 MUTATIONAL SPECTRUM ANALYSIS OF CHRONIC MYELOMONOCYTIC LEUKEMIA INCLUDES GENES ASSOCIATED WITH EPIGENETIC REGULATION: UTX, EZH2, AND DNMT3A. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A MYELODYSPLASTIC/MYELOPROLIFERATIVE NEOPLASM, IS CHARACTERIZED BY MONOCYTIC PROLIFERATION, DYSPLASIA, AND PROGRESSION TO ACUTE MYELOID LEUKEMIA. CMML HAS BEEN ASSOCIATED WITH SOMATIC MUTATIONS IN DIVERSE RECENTLY IDENTIFIED GENES. WE ANALYZED 72 WELL-CHARACTERIZED PATIENTS WITH CMML (N = 52) AND CMML-DERIVED ACUTE MYELOID LEUKEMIA (N = 20) FOR RECURRENT CHROMOSOMAL ABNORMALITIES WITH THE USE OF ROUTINE CYTOGENETICS AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAYS ALONG WITH COMPREHENSIVE MUTATIONAL SCREENING. CYTOGENETIC ABERRATIONS WERE PRESENT IN 46% OF CASES, WHEREAS SINGLE NUCLEOTIDE POLYMORPHISM ARRAY INCREASED THE DIAGNOSTIC YIELD TO 60%. AT LEAST 1 MUTATION WAS FOUND IN 86% OF ALL CASES; NOVEL UTX, DNMT3A, AND EZH2 MUTATIONS WERE FOUND IN 8%, 10%, AND 5.5% OF PATIENTS, RESPECTIVELY. TET2 MUTATIONS WERE PRESENT IN 49%, ASXL1 IN 43%, CBL IN 14%, IDH1/2 IN 4%, KRAS IN 7%, NRAS IN 4%, AND JAK2 V617F IN 1% OF PATIENTS. VARIOUS MUTANT GENOTYPE COMBINATIONS WERE OBSERVED, INDICATING MOLECULAR HETEROGENEITY IN CMML. OUR RESULTS SUGGEST THAT MOLECULAR DEFECTS AFFECTING DISTINCT PATHWAYS CAN LEAD TO SIMILAR CLINICAL PHENOTYPES.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
12  2421 20 EPIGENETIC SIGNATURE OF PD-1+ TCF1+ CD8 T CELLS THAT ACT AS RESOURCE CELLS DURING CHRONIC VIRAL INFECTION AND RESPOND TO PD-1 BLOCKADE. WE HAVE RECENTLY DEFINED A NOVEL POPULATION OF PD-1 (PROGRAMMED CELL DEATH 1)+ TCF1 (T CELL FACTOR 1)+ VIRUS-SPECIFIC CD8 T CELLS THAT FUNCTION AS RESOURCE CELLS DURING CHRONIC LCMV INFECTION AND PROVIDE THE PROLIFERATIVE BURST SEEN AFTER PD-1 BLOCKADE. SUCH CD8 T CELLS HAVE BEEN FOUND IN OTHER CHRONIC INFECTIONS AND ALSO IN CANCER IN MICE AND HUMANS. THESE CD8 T CELLS EXHIBIT STEM-LIKE PROPERTIES UNDERGOING SELF-RENEWAL AND ALSO DIFFERENTIATING INTO THE TERMINALLY EXHAUSTED CD8 T CELLS. HERE WE COMPARED THE EPIGENETIC SIGNATURE OF STEM-LIKE CD8 T CELLS WITH EXHAUSTED CD8 T CELLS. ATAC-SEQ ANALYSIS SHOWED THAT STEM-LIKE CD8 T CELLS HAD A UNIQUE SIGNATURE IMPLICATING ACTIVITY OF HMG (TCF) AND RHD (NF-KAPPAB) TRANSCRIPTION FACTOR FAMILY MEMBERS IN CONTRAST TO HIGHER ACCESSIBILITY TO ETS AND RUNX MOTIFS IN EXHAUSTED CD8 T CELLS. IN ADDITION, REGULATORY REGIONS OF THE TRANSCRIPTION FACTORS TCF7 AND ID3 WERE MORE ACCESSIBLE IN STEM-LIKE CELLS WHEREAS PRDM1 AND ID2 WERE MORE ACCESSIBLE IN EXHAUSTED CD8 T CELLS. WE ALSO COMPARED THE EPIGENETIC SIGNATURES OF THE 2 CD8 T CELL SUBSETS FROM CHRONICALLY INFECTED MICE WITH EFFECTOR AND MEMORY CD8 T CELLS GENERATED AFTER AN ACUTE LCMV INFECTION. BOTH CD8 T CELL SUBSETS GENERATED DURING CHRONIC INFECTION WERE STRIKINGLY DIFFERENT FROM CD8 T CELL SUBSETS FROM ACUTE INFECTION. INTERESTINGLY, THE STEM-LIKE CD8 T CELL SUBSET FROM CHRONIC INFECTION, DESPITE SHARING KEY FUNCTIONAL PROPERTIES WITH MEMORY CD8 T CELLS, HAD A VERY DISTINCT EPIGENETIC PROGRAM. THESE RESULTS SHOW THAT THE CHRONIC STEM-LIKE CD8 T CELL PROGRAM REPRESENTS A SPECIFIC ADAPTATION OF THE T CELL RESPONSE TO PERSISTENT ANTIGENIC STIMULATION.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
13  5435 29 RELATIVE ROLE OF METHYLATOR AND TUMOR SUPPRESSOR PATHWAYS IN ULCERATIVE COLITIS-ASSOCIATED COLON CANCER. BACKGROUND: CHRONIC ULCERATIVE COLITIS (UC) IS ASSOCIATED WITH AN INCREASED COLORECTAL CANCER RISK WHICH MAY BE SECONDARY TO REPETITIVE MUCOSAL INJURY. BOTH EPIGENETIC METHYLATION AND THE CLASSIC ADENOMA-TO-CARCINOMA SEQUENCE HAVE BEEN IMPLICATED IN THIS MALIGNANT TRANSFORMATION, BUT THE UNDERLYING MOLECULAR MECHANISMS REMAIN POORLY DEFINED. THIS STUDY COMPARES THE MOLECULAR CHARACTERISTICS OF COLITIS-ASSOCIATED AND COMMON COLORECTAL CANCERS. METHODS: NINETEEN PATIENTS WITH COLORECTAL ADENOCARCINOMAS ARISING WITHIN UC WERE MATCHED FOR AGE AND CANCER SITE WITH 54 PATIENTS WITH SPORADIC ADENOCARCINOMAS. TUMOR TISSUE WAS EXAMINED FOR BRAF MUTATIONS, CPG ISLAND METHYLATOR PHENOTYPE (CIMP), AND MLH1 PROMOTER METHYLATION. MUTATIONS OF KRAS AND P53 WERE ASSESSED BY SEQUENCING. RESULTS: PATIENT DEMOGRAPHICS WERE SIMILAR FOR THE TWO GROUPS. CIMP WAS OBSERVED IN 22% OF SPORADIC COLORECTAL CANCERS AND IN 5% OF UC CANCERS (P = 0.162). RATES OF BRAF MUTATION (4% VS 5%, P = 1.0), MLH1 METHYLATION (9% VERSUS 5%, P = 0.682), AND KRAS MUTATIONS (24% VERSUS 32%, P = 0.552) WERE SIMILAR BETWEEN THE GROUPS. HOWEVER, COLITIS-ASSOCIATED COLORECTAL CANCERS WERE MORE LIKELY TO HAVE A P53 MUTATION COMPARED TO SPORADIC ADENOCARCINOMAS (95% VERSUS 53%, P = 0.001). THE DOMINANT MUTATION FOR COLITIS-ASSOCIATED CANCERS WAS A MUTATION IN CODON 4, REPRESENTING HALF OF THE MUTATIONS. FURTHERMORE, COLITIS-ASSOCIATED CANCERS HAD A HIGHER RATE OF MUTATION IN CODON 8 (48% VERSUS 6%, P < 0.001) THAN SPORADIC COUNTERPARTS. CONCLUSIONS: UNLIKE OTHER INFLAMMATORY GASTROINTESTINAL CANCERS, COLITIS-ASSOCIATED COLORECTAL CANCERS DO NOT PREFERENTIALLY ARISE VIA A METHYLATOR PATHWAY WHEN COMPARED TO SPORADIC COLORECTAL CANCERS. CHROMOSOMAL INSTABILITY REMAINS AN IMPORTANT ETIOLOGY, BUT WITH A UNIQUE P53 FREQUENCY AND MUTATION PATTERN.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
14  6415 21 THE STUDY OF P16 AND P15 GENE METHYLATION IN HEAD AND NECK SQUAMOUS CELL CARCINOMA AND THEIR QUANTITATIVE EVALUATION IN PLASMA BY REAL-TIME PCR. EPIGENETIC SILENCING OF THE P16 AND P15 GENES BY PROMOTER METHYLATION ARE COMMONLY OBSERVED IN HUMAN EPITHELIAL MALIGNANCIES, INCLUDING HEAD AND NECK SQUAMOUS CELL CARCINOMAS (HNSCC). IN THIS STUDY, A METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION (MSP) WAS USED TO EVALUATE THE METHYLATION STATUS OF THE P16 AND P15 GENES IN 73 HNSCC SURGICAL SPECIMENS. P16 AND P15 GENE METHYLATION WAS ALSO EXAMINED IN 29 PAIRED METASTATIC LYMPH NODES AND 29 PAIRED HISTOLOGICALLY, NORMAL RESECTION MARGIN MUCOSAE. THE QUANTITY OF CELL-FREE METHYLATED P16 AND P15 DNA IN THE PLASMA SAMPLES OF 20 HNSCC PATIENTS AND 24 HEALTHY CONTROLS WAS ALSO EXAMINED USING A FLUORESCENCE-BASED REAL-TIME PCR ASSAY. THE FREQUENCIES OF P16 AND P15 METHYLATION IN THE PRIMARY TUMOUR WERE 49% AND 60%, RESPECTIVELY. CONCORDANT METHYLATION OF P16 AND P15 IN TUMOUR SAMPLES AND METASTATIC LYMPH NODES WAS FOUND IN 59 AND 38% OF CASES, RESPECTIVELY. A SIGNIFICANTLY HIGHER PREVALENCE OF P15 METHYLATION WAS FOUND IN HISTOLOGICALLY-NORMAL SURGICAL MARGIN EPITHELIA OF HNSCC PATIENTS WITH CHRONIC SMOKING AND DRINKING HABITS COMPARED WITH NON-SMOKERS AND NON-DRINKERS. IN ADDITION, METHYLATED P16 AND P15 DNA LEVELS WERE SIGNIFICANTLY HIGHER IN THE PLASMA OF HNSCC PATIENTS (MEAN 56 COPIES/ML PLASMA AND 65 COPIES/ML PLASMA, RESPECTIVELY) COMPARED WITH NORMAL CONTROLS (MEAN 6 COPIES/ML PLASMA AND 16 COPIES/ML PLASMA, RESPECTIVELY). IN CONCLUSION, PROMOTER METHYLATION OF THE P16 AND P15 GENES IS INVOLVED IN THE PATHOGENESIS OF HNSCC AND MAY BE RELATED TO CHRONIC SMOKING AND DRINKING. THE DIFFERENTIAL LEVELS OF METHYLATED P16 AND P15 DNA IN PLASMA MIGHT BE POTENTIAL USEFUL MARKERS IN SCREENING HIGH-RISK POPULATIONS FOR EARLY HNSCC AND MONITORING THEIR TREATMENT RESPONSE.	2003	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
15  3560 21 IMPACT OF CLINICAL, CYTOGENETIC, AND MOLECULAR PROFILES ON LONG-TERM SURVIVAL AFTER TRANSPLANTATION IN PATIENTS WITH CHRONIC MYELOMONOCYTIC LEUKEMIA. CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A HETEROGENEOUS GROUP OF CLONAL HEMATOPOIETIC MALIGNANCIES WITH VARIABLE CLINICAL AND MOLECULAR FEATURES. WE ANALYZED LONG-TERM RESULTS OF ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION IN PATIENTS WITH CMML AND DETERMINED CLINICAL AND MOLECULAR RISK FACTORS ASSOCIATED WITH OUTCOMES. DATA FROM 129 PATIENTS, AGED 7-74 (MEDIAN 55) YEARS, AT VARIOUS STAGES OF THE DISEASE AND TRANSPLANTED FROM RELATED OR UNRELATED DONORS WERE ANALYZED. USING A PANEL OF 75 GENES SOMATIC MUTATIONS PRESENT BEFORE HEMATOPOIETIC CELL TRANSPLANTATION WERE IDENTIFIED IN 52 PATIENTS. THE PROGRESSION-FREE SURVIVAL RATE AT 10 YEARS WAS 29%. THE MAJOR CAUSE OF DEATH WAS RELAPSE (32%), WHICH WAS SIGNIFICANTLY ASSOCIATED WITH ADVERSE CYTOGENETICS (HAZARD RATIO, 3.77; P=0.0002), CMML PROGNOSTIC SCORING SYSTEM (HAZARD RATIO, 14.3, P=0.01), AND MD ANDERSON PROGNOSTIC SCORES (HAZARD RATIO, 9.4; P=0.005). MORTALITY WAS ASSOCIATED WITH HIGH-RISK CYTOGENETICS (HAZARD RATIO, 1.88; P=0.01) AND HIGH HEMATOPOIETIC CELL TRANSPLANTATION COMORBIDITY INDEX (SCORE >/=4: HAZARD RATIO, 1.99; P=0.01). HIGH OVERALL MUTATION BURDEN (>/=10 MUTATIONS: HAZARD RATIO, 3.4; P=0.02), AND >/=4 MUTATED EPIGENETIC REGULATORY GENES (HAZARD RATIO 5.4; P=0.003) WERE LINKED TO RELAPSE. UNSUPERVISED CLUSTERING OF THE CORRELATION MATRIX REVEALED DISTINCT HIGH-RISK GROUPS WITH UNIQUE ASSOCIATIONS OF MUTATIONS AND CLINICAL FEATURES. CMML WITH A HIGH MUTATION BURDEN APPEARED TO BE DISTINCT FROM HIGH-RISK GROUPS DEFINED BY COMPLEX CYTOGENETICS. NEW TRANSPLANT STRATEGIES MUST BE DEVELOPED TO TARGET SPECIFIC DISEASE SUBGROUPS, STRATIFIED BY MOLECULAR PROFILING AND CLINICAL RISK FACTORS.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
16  5245 25 PROGNOSTIC RELEVANCE OF INTEGRATED GENETIC PROFILING IN ADULT T-CELL LEUKEMIA/LYMPHOMA. ADULT T-CELL LEUKEMIA/LYMPHOMA (ATL) IS A HETEROGENEOUS GROUP OF PERIPHERAL T-CELL MALIGNANCIES CHARACTERIZED BY HUMAN T-CELL LEUKEMIA VIRUS TYPE-1 INFECTION, WHOSE GENETIC PROFILE HAS RECENTLY BEEN FULLY INVESTIGATED. HOWEVER, IT IS STILL POORLY UNDERSTOOD HOW THESE ALTERATIONS AFFECT CLINICAL FEATURES AND PROGNOSIS. WE INVESTIGATED THE EFFECTS OF GENETIC ALTERATIONS COMMONLY FOUND IN ATL ON DISEASE PHENOTYPES AND CLINICAL OUTCOMES, BASED ON GENOTYPING DATA OBTAINED FROM 414 AND 463 ATL PATIENTS USING TARGETED-CAPTURE SEQUENCING AND SINGLE NUCLEOTIDE POLYMORPHISM ARRAY KARYOTYPING, RESPECTIVELY. AGGRESSIVE (ACUTE/LYMPHOMA) SUBTYPES WERE ASSOCIATED WITH AN INCREASED BURDEN OF GENETIC AND EPIGENETIC ALTERATIONS, HIGHER FREQUENCIES OF TP53 AND IRF4 MUTATIONS, AND MANY COPY NUMBER ALTERATIONS (CNAS), INCLUDING PD-L1 AMPLIFICATIONS AND CDKN2A DELETIONS, COMPARED WITH INDOLENT (CHRONIC/SMOLDERING) SUBTYPES. BY CONTRAST, STAT3 MUTATIONS WERE MORE CHARACTERISTIC OF INDOLENT ATL. HIGHER NUMBERS OF SOMATIC MUTATIONS AND CNAS SIGNIFICANTLY CORRELATED WITH WORSE SURVIVAL. IN A MULTIVARIATE ANALYSIS INCORPORATING BOTH CLINICAL FACTORS AND GENETIC ALTERATIONS, THE JAPAN CLINICAL ONCOLOGY GROUP PROGNOSTIC INDEX HIGH-RISK, OLDER AGE, PRKCB MUTATIONS, AND PD-L1 AMPLIFICATIONS WERE INDEPENDENT POOR PROGNOSTIC FACTORS IN AGGRESSIVE ATL. IN INDOLENT ATL, IRF4 MUTATIONS, PD-L1 AMPLIFICATIONS, AND CDKN2A DELETIONS WERE SIGNIFICANTLY ASSOCIATED WITH SHORTER SURVIVAL, ALTHOUGH THE CHRONIC SUBTYPE WITH UNFAVORABLE CLINICAL FACTORS WAS ONLY MARGINALLY SIGNIFICANT. THUS, SOMATIC ALTERATIONS CHARACTERIZING AGGRESSIVE DISEASES PREDICT WORSE PROGNOSIS IN INDOLENT ATL, AMONG WHICH PD-L1 AMPLIFICATIONS ARE A STRONG GENETIC PREDICTOR IN BOTH AGGRESSIVE AND INDOLENT ATL. ATL SUBTYPES ARE FURTHER CLASSIFIED INTO MOLECULARLY DISTINCT SUBSETS WITH DIFFERENT PROGNOSIS. GENETIC PROFILING MIGHT CONTRIBUTE TO IMPROVED PROGNOSTICATION AND MANAGEMENT OF ATL PATIENTS.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17   417 21 ANATOMIC SITE-SPECIFIC PATTERNS OF GENE COPY NUMBER GAINS IN SKIN, MUCOSAL, AND UVEAL MELANOMAS DETECTED BY FLUORESCENCE IN SITU HYBRIDIZATION. TO ASSESS THE DIFFERENCES BETWEEN MELANOMAS OF DIFFERENT LOCATION AND DIFFERENT ETIOLOGY, 372 MALIGNANT MELANOMAS WERE BROUGHT IN A TISSUE MICROARRAY FORMAT. THE COLLECTION INCLUDED 23 ACRAL AND 118 NON-ACRAL SKIN MELANOMAS, 9 MUCOSAL MELANOMAS, 100 UVEAL MELANOMAS, AND 122 MELANOMA METASTASES. FLUORESCENCE IN SITU HYBRIDIZATION (FISH) WAS USED TO ASSESS COPY NUMBER CHANGES OF THE CYCLIN D1 (CCND1), MDM2, C-MYC (MYC), AND HER2 GENES. FISH ANALYSIS REVEALED DISTINCT DIFFERENCES BETWEEN MELANOMAS FROM DIFFERENT LOCATIONS. CCND1 AMPLIFICATIONS WERE DETECTED IN SKIN MELANOMAS FROM SITES WITH CHRONIC SUN EXPOSURE (6 OF 32 CASES), ACRAL MELANOMAS (4 OF 17 CASES), AND MUCOSAL MELANOMAS (ONE OF TEN CASES) BUT NOT IN UVEAL MELANOMAS. HIGH-LEVEL MDM2 AMPLIFICATIONS WERE EXCLUSIVELY PRESENT IN ACRAL MELANOMAS (2 OF 19 CASES). MYC COPY NUMBER GAINS WERE DETECTED IN 32 OF 71 UVEAL MELANOMAS, FIVE OF EIGHT MUCOSAL MELANOMAS, AND 6 OF 67 MELANOMAS FROM SITES WITH INTERMITTENT SUN EXPOSURE BUT NOT IN ACRAL MELANOMAS NOR MELANOMAS FROM SITES WITH CHRONIC SUN EXPOSURE. ALTERATIONS OF THE MYC GENE WERE ASSOCIATED WITH ADVANCED TUMOR STAGE. THERE WERE NO HIGH-LEVEL HER2 AMPLIFICATIONS. SITE-SPECIFIC GENETIC AND EPIGENETIC FEATURES MAY IMPACT THE RESPONSE OF MELANOMAS TO VARIOUS ANTI-CANCER DRUGS AND SHOULD BE CONSIDERED IN FUTURE STUDIES ON THE MOLECULAR PATHOGENESIS OF MALIGNANT MELANOMAS.	2006	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
18   536 19 ASXL1 MUTATIONS PREDICT INFERIOR MOLECULAR RESPONSE TO NILOTINIB TREATMENT IN CHRONIC MYELOID LEUKEMIA. GENE MUTATIONS INDEPENDENT OF BCR::ABL1 HAVE BEEN IDENTIFIED IN NEWLY DIAGNOSED PATIENTS WITH CHRONIC MYELOID LEUKEMIA (CML) IN CHRONIC PHASE, WHEREBY MUTATIONS IN EPIGENETIC MODIFIER GENES WERE MOST COMMON. THESE FINDINGS PROMPTED THE SYSTEMATIC ANALYSIS OF PREVALENCE, DYNAMICS, AND PROGNOSTIC SIGNIFICANCE OF SUCH MUTATIONS, IN A CLINICALLY WELL-CHARACTERIZED PATIENT POPULATION OF 222 CML PATIENTS FROM THE TIGER STUDY (CML-V) BY TARGETED NEXT-GENERATION SEQUENCING COVERING 54 MYELOID LEUKEMIA-ASSOCIATED GENES. IN TOTAL, 53/222 CML PATIENTS (24%) CARRIED 60 MUTATIONS AT DIAGNOSIS WITH ASXL1 BEING MOST COMMONLY AFFECTED (N = 20). TO STUDY MUTATION DYNAMICS, LONGITUDINAL DEEP SEQUENCING ANALYSIS OF SERIAL SAMPLES WAS PERFORMED IN 100 PATIENTS AFTER 12, 24, AND 36 MONTHS OF THERAPY. TYPICAL PATTERNS OF CLONAL EVOLUTION INCLUDED ERADICATION, PERSISTENCE, AND EMERGENCE OF MUTATED CLONES. PATIENTS CARRYING AN ASXL1 MUTATION AT DIAGNOSIS SHOWED A LESS FAVORABLE MOLECULAR RESPONSE TO NILOTINIB TREATMENT, AS A MAJOR MOLECULAR RESPONSE (MMR) WAS ACHIEVED LESS FREQUENTLY AT MONTH 12, 18, AND 24 COMPARED TO ALL OTHER PATIENTS. PATIENTS WITH ASXL1 MUTATIONS WERE ALSO YOUNGER AND MORE FREQUENTLY FOUND IN THE HIGH RISK CATEGORY, SUGGESTING A CENTRAL ROLE OF CLONAL EVOLUTION ASSOCIATED WITH ASXL1 MUTATIONS IN CML PATHOGENESIS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
19  2848 24 FREQUENT SOMATIC MUTATIONS IN EPIGENETIC REGULATORS IN NEWLY DIAGNOSED CHRONIC MYELOID LEUKEMIA. ALTHOUGH TYROSINE KINASE INHIBITORS (TKIS) HAVE SIGNIFICANTLY IMPROVED THE PROGNOSIS OF CHRONIC MYELOID LEUKEMIA (CML), THE ABILITY OF TKIS TO ERADICATE CML REMAINS UNCERTAIN AND PATIENTS MUST CONTINUE TKI THERAPY FOR INDEFINITE PERIODS. IN THIS STUDY, WE PERFORMED WHOLE-EXOME SEQUENCING TO IDENTIFY SOMATIC MUTATIONS IN 24 PATIENTS WITH NEWLY DIAGNOSED CHRONIC PHASE CML WHO WERE REGISTERED IN THE JALSG CML212 STUDY. WE IDENTIFIED 191 SOMATIC MUTATIONS OTHER THAN THE BCR-ABL1 FUSION GENE (MEDIAN 8, RANGE 1-17). AGE, HEMOGLOBIN CONCENTRATION AND WHITE BLOOD CELL COUNTS WERE CORRELATED WITH THE NUMBER OF MUTATIONS. PATIENTS WITH MUTATIONS ?6 SHOWED HIGHER RATE OF ACHIEVING MAJOR MOLECULAR RESPONSE THAN THOSE<6 (P=0.0381). MUTATIONS IN EPIGENETIC REGULATOR, ASXL1, TET2, TET3, KDM1A AND MSH6 WERE FOUND IN 25% OF PATIENTS. TET2 OR TET3, AKT1 AND RUNX1 WERE MUTATED IN ONE PATIENT EACH. ASXL1 WAS MUTATED WITHIN EXON 12 IN THREE CASES. MUTATED GENES WERE SIGNIFICANTLY ENRICHED WITH CELL SIGNALING AND CELL DIVISION PATHWAYS. FURTHERMORE, DNA COPY NUMBER ANALYSIS SHOWED THAT 2 OF 24 PATIENTS HAD UNIPARENTAL DISOMY OF CHROMOSOME 1P OR 3Q, WHICH DISAPPEARED MAJOR MOLECULAR RESPONSE WAS ACHIEVED. THESE MUTATIONS MAY PLAY SIGNIFICANT ROLES IN CML PATHOGENESIS IN ADDITION TO THE STRONG DRIVER MUTATION BCR-ABL1.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
20   144 22 ABERRANT DNA METHYLATION PROFILE OF CHRONIC AND TRANSFORMED CLASSIC PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS. MOST DNA METHYLATION STUDIES IN CLASSIC PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS HAVE BEEN PERFORMED ON A GENE-BY-GENE BASIS. THEREFORE, A MORE COMPREHENSIVE METHYLATION PROFILING IS NEEDED TO STUDY THE IMPLICATIONS OF THIS EPIGENETIC MARKER IN MYELOPROLIFERATIVE NEOPLASMS. HERE, WE HAVE ANALYZED 71 CHRONIC (24 POLYCYTHEMIA VERA, 23 ESSENTIAL THROMBOCYTHEMIA AND 24 PRIMARY MYELOFIBROSIS) AND 13 TRANSFORMED MYELOPROLIFERATIVE NEOPLASMS USING GENOME-WIDE DNA METHYLATION ARRAYS. THE THREE TYPES OF CHRONIC PHILADELPHIA-NEGATIVE MYELOPROLIFERATIVE NEOPLASMS SHOWED A SIMILAR ABERRANT DNA METHYLATION PATTERN WHEN COMPARED TO CONTROL SAMPLES. DIFFERENTIALLY METHYLATED REGIONS WERE ENRICHED IN A GENE NETWORK CENTERED ON THE NF-KAPPAB PATHWAY, INDICATING THAT THEY MAY BE INVOLVED IN THE PATHOGENESIS OF THESE DISEASES. IN THE CASE OF TRANSFORMED MYELOPROLIFERATIVE NEOPLASMS, WE DETECTED AN INCREASED NUMBER OF DIFFERENTIALLY METHYLATED REGIONS WITH RESPECT TO CHRONIC MYELOPROLIFERATIVE NEOPLASMS. INTERESTINGLY, THESE GENES WERE ENRICHED IN A LIST OF DIFFERENTIALLY METHYLATED REGIONS IN PRIMARY ACUTE MYELOID LEUKEMIA AND IN A GENE NETWORK CENTERED AROUND THE IFN PATHWAY. OUR RESULTS SUGGEST THAT ALTERATIONS IN THE DNA METHYLATION LANDSCAPE PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS AND LEUKEMIC TRANSFORMATION OF MYELOPROLIFERATIVE NEOPLASMS. THE THERAPEUTIC MODULATION OF EPIGENETICALLY-DEREGULATED PATHWAYS MAY ALLOW US TO DESIGN TARGETED THERAPIES FOR THESE PATIENTS.	2013