1 1575 122 DNA METHYLATION PATTERNS OF GENES RELATED TO IMMUNE RESPONSE IN THE DIFFERENT CLINICAL FORMS OF ORAL LICHEN PLANUS. BACKGROUND: THE ORAL LICHEN PLANUS IS A CHRONIC INFLAMMATORY DISEASE. ALTHOUGH ITS AETIOLOGY IS NOT WELL UNDERSTOOD, THE ROLE OF T LYMPHOCYTES IN ITS INFLAMMATORY EVENTS IS RECOGNISED. IDENTIFYING THE EPIGENETIC MECHANISMS INVOLVED IN THE PATHOGENESIS OF THIS IMMUNE-MEDIATED CONDITION IS FUNDAMENTAL FOR UNDERSTANDING THE INFLAMMATORY REACTION THAT OCCURS IN THE DISEASE. THE PURPOSE OF THIS WORK WAS TO EVALUATE THE METHYLATION PATTERN OF 21 IMMUNE RESPONSE-RELATED GENES IN THE DIFFERENT CLINICAL FORMS OF ORAL LICHEN PLANUS. METHODS: A CROSS-SECTIONAL STUDY WAS PERFORMED TO ANALYSE THE DNA METHYLATION PATTERNS IN THREE DISTINCT GROUPS OF ORAL LICHEN PLANUS: (I) RETICULAR/PLAQUE LESIONS; (II) EROSIVE LESIONS; (III) NORMAL ORAL MUCOSA (CONTROL GROUP). AFTER DNA EXTRACTION FROM BIOPSIES, THE SAMPLES WERE SUBMITTED TO DIGESTIONS BY METHYLATION-SENSITIVE AND METHYLATION-DEPENDENT ENZYMES AND DOUBLE DIGESTION. THE RELATIVE PERCENTAGE OF METHYLATED DNA FOR EACH GENE WAS PROVIDED USING REAL-TIME POLYMERASE CHAIN REACTION ARRAYS. RESULTS: HYPERMETHYLATION OF THE STAT5A GENE WAS OBSERVED ONLY IN THE CONTROL GROUP (59.0%). A HIGHER HYPERMETHYLATION OF THE ELANE GENE WAS FOUND IN RETICULAR/PLAQUE LESIONS (72.1%) COMPARED TO THE EROSIVE LESIONS (50.0%). CONCLUSION: OUR RESULTS SHOW VARIATIONS IN THE METHYLATION PROFILE OF IMMUNE RESPONSE-RELATED GENES, ACCORDING TO THE CLINICAL TYPE OF ORAL LICHEN PLANUS AFTER COMPARING WITH THE NORMAL ORAL MUCOSA. FURTHER STUDIES ARE NECESSARY TO VALIDATE THESE FINDINGS USING GENE EXPRESSION ANALYSIS. 2018 2 5382 32 RECURRENT CHROMOSOMAL AND EPIGENETIC ALTERATIONS IN ORAL SQUAMOUS CELL CARCINOMA AND ITS PUTATIVE PREMALIGNANT CONDITION ORAL LICHEN PLANUS. HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AFFECTS ABOUT 700.000 INDIVIDUALS PER YEAR WORLDWIDE WITH ORAL SQUAMOUS CELL CARCINOMA (OSCC) AS A MAJOR SUBCATEGORY. DESPITE A COMPREHENSIVE TREATMENT CONCEPT INCLUDING SURGERY, RADIATION, AND CHEMOTHERAPY THE 5-YEAR SURVIVAL RATE IS STILL ONLY ABOUT 50 PERCENT. CHRONIC INFLAMMATION IS ONE OF THE HALLMARKS OF CARCINOGENESIS. UNTIL NOW, LITTLE IS KNOWN ABOUT THE PREMALIGNANT STATUS OF ORAL LICHEN PLANUS (OLP) AND MOLECULAR ALTERATIONS IN OLP ARE STILL POORLY CHARACTERIZED. OUR STUDY AIMS TO DELINEATE DIFFERENTIAL DNA METHYLATION PATTERNS IN OLP, OSCC, AND NORMAL ORAL MUCOSA. BY APPLYING A BEAD CHIP APPROACH, WE IDENTIFIED ALTERED CHROMOSOMAL PATTERNS CHARACTERISTIC FOR OSCC WHILE FINDING NO RECURRENT ALTERATIONS IN OLP. IN CONTRAST, WE IDENTIFIED NUMEROUS ALTERATIONS IN THE DNA METHYLATION PATTERN IN OLP, AS COMPARED TO NORMAL CONTROLS, THAT WERE ALSO PRESENT IN OSCC. OUR DATA SUPPORT THE HYPOTHESIS THAT OLP IS A PRECURSOR LESION OF OSCC SHARING MULTIPLE EPIGENETIC ALTERATIONS WITH OSCC. 2019 3 6759 23 WNT SIGNALLING PATHWAY IN ORAL LESIONS. WINGLESS-INTEGRATED/BETA-CATENIN (WNT/?-CATENIN) SIGNALLING PATHWAY IS ONE OF THE PRINCIPAL INTERCELLULAR SIGNALLING PATHWAYS IN HUMANS. IT PLAYS AN INTRINSIC ROLE IN THE CELLULAR PROLIFERATION, DIFFERENTIATION AND REGENERATION ALONG WITH MANY OTHER CELLULAR FUNCTIONS. EPIGENETIC DEOXYRIBONUCLEIC ACID METHYLATIONS AND SILENCING OF WNT SIGNALLING PATHWAY GENES HAVE A SIGNIFICANT ROLE IN MALIGNANT TRANSFORMATION OF ORAL LESIONS SUCH AS ORAL SUBMUCOUS FIBROSIS, ORAL LEUKOPLAKIA, ORAL LICHEN PLANUS AND ERYTHROPLAKIA. THE INCREASE IN WNT INHIBITORY PROTEINS ALONG WITH INFLAMMATORY FACTORS CAUSE BONE LOSS IN PERIAPICAL LESIONS, SUCH AS CHRONIC APICAL PERIODONTITIS. THIS REVIEW DISCUSSES THE MOLECULAR GENETICS OF POTENTIALLY MALIGNANT ORAL LESIONS, SHEDS LIGHT ON OUR UNDERSTANDING OF WNT/?-CATENIN SIGNALLING IN BONE LOSS PERTAINING TO PERIAPICAL LESIONS, AND ALTERATION OF THIS PATHWAY FOR THERAPEUTIC BENEFITS. 2019 4 2042 35 EPIGENETIC CHARACTERISTICS IN INFLAMMATORY CANDIDATE GENES IN AGGRESSIVE PERIODONTITIS. BACKGROUND: PERIODONTITIS IS A CHRONIC INFLAMMATORY DISEASE TRIGGERED BY THE HOST IMMUNE RESPONSE. EPIGENETIC MODIFICATIONS ALSO AFFECT THE IMMUNE RESPONSE. WE ASSESSED CPG METHYLATION IN 22 INFLAMMATORY CANDIDATE GENES (ATF2, CCL25, CXCL14, CXCL3, CXCL5, CXCL6, FADD, GATA3, IL10RA, IL12A, IL12B, IL13, IL13RA1, IL15, IL17C, IL17RA, IL4R, IL6R, IL6ST, IL7, INHA, AND TYK2) WITH RESPECT TO THE OCCURRENCE OF AGGRESSIVE PERIODONTITIS (AGP). PATIENTS AND METHODS: IN THIS STUDY 15 AGP PATIENTS (53.3% MALES, 41.4+/-10.5 YEARS) AND 10 CONTROLS (40.0% MALES, 36.9+/-17.5 YEARS) WERE INCLUDED. THE METHYLATION PATTERNS OF GINGIVAL BIOPSIES WERE QUANTIFIED USING EPITECT(R) METHYL SIGNATURE PCR ARRAY HUMAN INFLAMMATORY RESPONSE. RESULTS: IN GINGIVAL BIOPSIES TAKEN FROM PATIENTS WITH AGP, CPG METHYLATION OF CCL25 (1.73% VS. 2.59%, P=0.015) AND IL17C (6.89% VS. 19.27%, P=0.002) WAS SIGNIFICANTLY REDUCED AS COMPARED WITH PERIODONTALLY HEALTHY TISSUES. DISCUSSION: WE SHOWED FOR THE FIRST TIME A DIFFERENTIAL METHYLATION PATTERN FOR CCL25 AND IL17C IN PERIODONTITIS. CCL25 PLAYS AN IMPORTANT ROLE IN T-CELL DEVELOPMENT, WHEREAS IL17C REGULATES INNATE EPITHELIAL IMMUNE RESPONSES. THE DECREASE IN CPG METHYLATION IS PRESUMABLY ACCOMPANIED BY AN INCREASE IN GENE EXPRESSION. THIS COULD LEAD TO A GREATER AVAILABILITY OF CCL25 AND INTERLEUKIN 17C AND SUPPORT PERIODONTAL LOSS OF ATTACHMENT. 2016 5 1422 42 DIFFERENTIAL CPG DNA METHYLATION OF PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES IN IGG4-RELATED DISEASE. OBJECTIVES: IMMUNOGLOBULIN-G4-RELATED DISEASE (IGG4-RD) IS A DISTINCT SYSTEMIC AUTOIMMUNE-MEDIATED DISEASE MANIFESTING AS CHRONIC INFLAMMATION AND TISSUE FIBROSIS. SINCE THE ROLE OF DNA METHYLATION IN THE PATHOGENESIS OF IGG4-RD IS STILL UNCLEAR, WE CONDUCT THIS STUDY TO INVESTIGATE EPIGENETIC MODIFICATIONS IN IGG4-RD. METHODS: A GENOME-WIDE DNA METHYLATION STUDY WAS CONDUCTED WITH B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS AND MATCHED CONTROLS BY USING THE ILLUMINA HUMANMETHYLATION 850K BEADCHIP. WE FURTHER PERFORMED PYROSEQUENCING AND IMMUNOHISTOCHEMISTRY ASSAYS TO VALIDATE THE METHYLATION STATUS OF SOME TARGETS OF INTEREST. RESULTS: WE IDENTIFIED DIFFERENTIALLY METHYLATED CPG SITES INCLUDING 44 HYPOMETHYLATED AND 166 HYPERMETHYLATED DIFFERENTIALLY METHYLATED PROBES (DMPS) IN B CELLS AND 260 HYPOMETHYLATED AND 112 HYPERMETHYLATED DMPS IN CD4(+) T CELLS FROM 10 IGG4-RD PATIENTS COMPARED WITH 10 HEALTHY CONTROLS. WE ALSO IDENTIFIED 36945 HYPOMETHYLATED AND 78380 HYPERMETHYLATED DMPS IN SALIVARY GLAND TISSUES OF 4 IGG4-RD PATIENTS COMPARED WITH 4 CONTROLS. DPM2 (CG21181453), IQCK (CG10266221), AND ABCC13 (CG05699681, CG04985582) WERE HYPERMETHYLATED AND MBP (CG18455083) WAS HYPOMETHYLATED IN B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS. WE ALSO OBSERVED THE HYPOMETHYLATED HLA-DQB2 IN CD4(+) T CELLS FROM IGG4-RD PATIENTS. KYOTO ENCYCLOPEDIA OF GENES AND GENOMES (KEGG) PATHWAY ANALYSIS OF DMPS IN SALIVARY GLAND TISSUES OF IGG4-RD PATIENTS REVEALED ENRICHMENT OF PATHWAYS INVOLVED IN THE REGULATION OF IMMUNE CELL RESPONSES AND FIBROSIS. CONCLUSION: THIS IS THE FIRST DNA METHYLATION STUDY IN PERIPHERAL B CELLS, CD4(+) T CELLS, AND SALIVARY GLAND TISSUES FROM IGG4-RD PATIENTS. OUR FINDINGS HIGHLIGHTED THE ROLE OF EPIGENETIC MODIFICATION OF DNA METHYLATION AND IDENTIFIED SEVERAL GENES AND PATHWAYS POSSIBLY INVOLVED IN IGG4-RD PATHOGENESIS. 2023 6 2649 21 EPIGENOMIC, GENOMIC, AND TRANSCRIPTOMIC LANDSCAPE OF SCHWANNOMATOSIS. SCHWANNOMATOSIS (SWNTS) IS A GENETIC CANCER PREDISPOSITION SYNDROME THAT MANIFESTS AS MULTIPLE AND OFTEN PAINFUL NEURONAL TUMORS CALLED SCHWANNOMAS (SWNS). WHILE GERMLINE MUTATIONS IN SMARCB1 OR LZTR1, PLUS SOMATIC MUTATIONS IN NF2 AND LOSS OF HETEROZYGOSITY IN CHROMOSOME 22Q HAVE BEEN IDENTIFIED IN A SUBSET OF PATIENTS, LITTLE IS KNOWN ABOUT THE EPIGENOMIC AND GENOMIC ALTERATIONS THAT DRIVE SWNTS-RELATED SWNS (SWNTS-SWNS) IN A MAJORITY OF THE CASES. WE PERFORMED MULTIPLATFORM GENOMIC ANALYSIS AND ESTABLISHED THE MOLECULAR SIGNATURE OF SWNTS-SWNS. WE SHOW THAT SWNTS-SWNS HARBOR DISTINCT GENOMIC FEATURES RELATIVE TO THE HISTOLOGICALLY IDENTICAL NON-SYNDROMIC SPORADIC SWNS (NS-SWNS). WE DEMONSTRATE THE EXISTENCE OF FOUR DISTINCT DNA METHYLATION SUBGROUPS OF SWNTS-SWNS THAT ARE ASSOCIATED WITH SPECIFIC TRANSCRIPTIONAL PROGRAMS AND TUMOR LOCATION. WE SHOW SEVERAL NOVEL RECURRENT NON-22Q DELETIONS AND STRUCTURAL REARRANGEMENTS. WE DETECTED THE SH3PXD2A-HTRA1 GENE FUSION IN SWNTS-SWNS, WITH PREDOMINANCE IN LZTR1-MUTANT TUMORS. IN ADDITION, WE IDENTIFIED SPECIFIC GENETIC, EPIGENETIC, AND ACTIONABLE TRANSCRIPTIONAL PROGRAMS ASSOCIATED WITH PAINFUL SWNTS-SWNS INCLUDING PIGF, VEGF, MEK, AND MTOR PATHWAYS, WHICH MAY BE HARNESSED FOR MANAGEMENT OF THIS SYNDROME. 2021 7 3520 26 IGLV3-21R110 IDENTIFIES AN AGGRESSIVE BIOLOGICAL SUBTYPE OF CHRONIC LYMPHOCYTIC LEUKEMIA WITH INTERMEDIATE EPIGENETICS. B-CELL RECEPTOR (BCR) SIGNALING IS CRUCIAL FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) BIOLOGY. IGLV3-21-EXPRESSING B CELLS MAY ACQUIRE A SINGLE POINT MUTATION (R110) THAT TRIGGERS AUTONOMOUS BCR SIGNALING, CONFERRING AGGRESSIVE BEHAVIOR. EPIGENETIC STUDIES HAVE DEFINED 3 CLL SUBTYPES BASED ON METHYLATION SIGNATURES REMINISCENT OF NAIVE-LIKE (N-CLL), INTERMEDIATE (I-CLL), AND MEMORY-LIKE (M-CLL) B CELLS WITH DIFFERENT BIOLOGICAL FEATURES. I-CLL CARRIES A BORDERLINE IGHV MUTATIONAL LOAD AND SIGNIFICANTLY HIGHER USE OF IGHV3-21/IGLV3-21. TO DETERMINE THE CLINICAL AND BIOLOGICAL FEATURES OF IGLV3-21R110 CLL AND ITS RELATIONSHIP TO THESE EPIGENETIC SUBTYPES, WE CHARACTERIZED THE IMMUNOGLOBULIN GENE OF 584 CLL CASES USING WHOLE-GENOME/EXOME AND RNA SEQUENCING. IGLV3-21R110 WAS DETECTED IN 6.5% OF CASES: 30 (38%) OF 79 I-CLLS, 5 (1.7%) OF 291 M-CLLS, AND 1 (0.5%) OF 189 N-CLLS. ALL STEREOTYPE SUBSET 2 CASES CARRIED IGLV3-21R110, WHEREAS 62% OF IGLV3-21R110 I-CLL CASES HAD NONSTEREOTYPED BCR IMMUNOGLOBULINS. IGLV3-21R110 I-CLL HAD A SIGNIFICANTLY HIGHER NUMBER OF SF3B1 AND ATM MUTATIONS AND TOTAL NUMBER OF DRIVER ALTERATIONS. HOWEVER, THE R110 MUTATION WAS THE SOLE ALTERATION IN 1 I-CLL AND WAS ACCOMPANIED ONLY BY DEL(13Q) IN 3. ALTHOUGH IGHV MUTATIONAL STATUS VARIED, IGLV3-21R110 I-CLL TRANSCRIPTOMICALLY RESEMBLED N-CLL/UNMUTATED IGHV CLL WITH A SPECIFIC SIGNATURE INCLUDING WNT5A/B OVEREXPRESSION. IN CONTRAST, I-CLL LACKING IGLV3-21R110 MIRRORED M-CLL/MUTATED IGHV. PATIENTS WITH IGLV3-21R110 I-CLL HAD A SHORT TIME TO FIRST TREATMENT AND OVERALL SURVIVAL SIMILAR TO THOSE OF N-CLL/UNMUTATED IGHV PATIENTS, WHEREAS PATIENTS WITH NON-IGLV3-21R110 I-CLL HAD A GOOD PROGNOSIS SIMILAR TO THAT OF PATIENTS WITH M-CLL/MUTATED IGHV. IGLV3-21R110 DEFINES A CLL SUBGROUP WITH SPECIFIC BIOLOGICAL FEATURES AND AN UNFAVORABLE PROGNOSIS INDEPENDENT OF IGHV MUTATIONAL STATUS AND EPIGENETIC SUBTYPE. 2021 8 1171 21 CONTRIBUTION OF MATURE HEPATOCYTES TO BILIARY REGENERATION IN RATS WITH ACUTE AND CHRONIC BILIARY INJURY. WHETHER HEPATOCYTES CAN CONVERT INTO BILIARY EPITHELIAL CELLS (BECS) DURING BILIARY INJURY IS MUCH DEBATED. TO TEST THIS CONCEPT, WE TRACED THE FATE OF GENETICALLY LABELED [DIPEPTIDYL PEPTIDASE IV (DPPIV)-POSITIVE] HEPATOCYTES IN HEPATOCYTE TRANSPLANTATION MODEL FOLLOWING ACUTE HEPATO-BILIARY INJURY INDUCED BY 4,4'-METHYLENE-DIANILINE (DAPM) AND D-GALACTOSAMINE (DAPM+D-GAL) AND IN DPPIV-CHIMERIC LIVER MODEL SUBJECTED TO ACUTE (DAPM+D-GAL) OR CHRONIC BILIARY INJURY CAUSED BY DAPM AND BILE DUCT LIGATION (DAPM+BDL). IN BOTH MODELS BEFORE BILIARY INJURY, BECS ARE UNIFORMLY DPPIV-DEFICIENT AND PROLIFERATION OF DPPIV-DEFICIENT HEPATOCYTES IS RESTRICTED BY RETRORSINE. WE FOUND THAT MATURE HEPATOCYTES UNDERWENT A STEPWISE CONVERSION INTO BECS AFTER BILIARY INJURY. IN THE HEPATOCYTE TRANSPLANTATION MODEL, DPPIV-POSITIVE HEPATOCYTES ENTRAPPED PERIPORTALLY PROLIFERATED, AND FORMED TWO-LAYERED PLATES ALONG PORTAL VEINS. WITHIN THE TWO-LAYERED PLATES, THE HEPATOCYTES GRADUALLY LOST THEIR HEPATOCYTIC IDENTITY, PROCEEDED THROUGH AN INTERMEDIATE STATE, ACQUIRED A BILIARY PHENOTYPE, AND SUBSEQUENTLY FORMED BILE DUCTS ALONG THE HILUM-TO-PERIPHERY AXIS. IN DPPIV-CHIMERIC LIVER MODEL, PERIPORTAL HEPATOCYTES EXPRESSING HEPATOCYTE NUCLEAR FACTOR-1BETA (HNF-1BETA) WERE EXCLUSIVELY DPPIV-POSITIVE AND WERE IN CONTINUITY TO DPPIV-POSITIVES BILE DUCTS. INHIBITION OF HEPATOCYTE PROLIFERATION BY ADDITIONAL DOSES OF RETRORSINE IN DPPIV-CHIMERIC LIVERS PREVENTED THE APPEARANCE OF DPPIV-POSITIVE BECS AFTER BILIARY INJURY. MOREOVER, ENRICHED DPPIV-POSITIVE BEC/HEPATIC OVAL CELL TRANSPLANTATION PRODUCED DPPIV-POSITIVE BECS OR BILE DUCTS IN UNEXPECTEDLY LOW FREQUENCY AND IN MID-LOBULAR REGIONS. THESE RESULTS TOGETHER SUGGEST THAT MATURE HEPATOCYTES BUT NOT CONTAMINATING BECS/HEPATIC OVAL CELLS ARE THE SOURCES OF PERIPORTAL DPPIV-POSITIVE BECS. WE CONCLUDE THAT MATURE HEPATOCYTES CONTRIBUTE TO BILIARY REGENERATION IN THE ENVIRONMENT OF ACUTE AND CHRONIC BILIARY INJURY THROUGH A DUCTAL PLATE CONFIGURATION WITHOUT THE NEED OF EXOGENOUSLY GENETIC OR EPIGENETIC MANIPULATION. 2015 9 5674 31 SHARED GENETIC AND EPIGENETIC MECHANISMS BETWEEN CHRONIC PERIODONTITIS AND ORAL SQUAMOUS CELL CARCINOMA. OBJECTIVES: TO ANALYZE BIOINFORMATIC DATASETS FOR DETECTING GENETIC AND EPIGENETIC MECHANISMS SHARED BY CHRONIC PERIODONTITIS (CP) AND ORAL SQUAMOUS CELL CARCINOMA (OSCC). MATERIALS AND METHODS: DATASETS FROM GEO AND TCGA DATABASES REPORTING MRNAS, MIRNAS OR METHYLATION EXPRESSION IN HUMAN CP AND OSCC TISSUES WERE ANALYZED. DIFFERENTIAL EXPRESSION, FUNCTIONAL ENRICHMENT AND PROTEIN-PROTEIN INTERACTION (PPI) NETWORK ANALYSES WERE PERFORMED. DIFFERENTIALLY EXPRESSED MIRNAS (DEMIRNAS) AND GENES (DEG) IN CP AND OSCC WERE DETERMINED. DEMIRNA-TARGET AND DEMIRNA-DEG NETWORKS WERE CONSTRUCTED. DIRECTLY AND INDIRECTLY INTERACTING CROSS-TALK GENES WERE SCREENED, AND THEIR PREDICTION ACCURACY AND ASSOCIATION WITH OSCC PROGNOSIS WAS DETERMINED. RESULTS: 3 DE-MIRNAS (MIR-375, MIR-3609 AND MIR-3652) EXPRESSED IN BOTH CP AND OSCC CRITICALLY REGULATED MOST DEGS. AMONG 12 DIRECTLY INTERACTING CROSS-TALK GENES, NCAPH WAS SIGNIFICANTLY RELATED WITH THE PROGNOSIS OF OSCC. NR2F2 HAD HIGHEST DIFFERENTIAL EXPRESSION IN CP AND OSCC. AMONG 4 CROSS-TALK GENES (FN1, MPPED1, NDEL1, AND NR2F2) DIFFERENTIALLY EXPRESSED IN CP, 3 (FN1, MPPED1, NDEL1) WERE ALSO EXPRESSED IN OSCC. AMONG 12 INDIRECTLY INTERACTING CROSS-TALK GENES DIFFERENTIALLY EXPRESSED IN OSCC, 3 GENES (CDCA8, HIST1H3J, AND RAD51) WERE SIGNIFICANTLY RELATED TO ITS PROGNOSIS. SIGNIFICANT PATHWAYS INVOLVED IN CP AND OSCC INCLUDED: CHEMOKINE RECEPTORS, CLASS I PI3K SIGNALING EVENTS, EPITHELIAL-TO-MESENCHYMAL TRANSITION AND SIGNALING EVENTS BY VEGFR1 AND VEGFR2, EGF RECEPTOR (ERBB1). CONCLUSION: BIOINFORMATIC ANALYSIS OF AVAILABLE DATASETS IMPLICATED 1 DIRECTLY INTERACTING CROSS-TALK GENE (NCAPH), 4 INDIRECTLY INTERACTING CROSS-TALK GENES (NCAPH, NR2F2, FN1, AND MPPED1) AND 3 DE-MIRNAS (HSA-MIR-375, MIR-3609 AND MIR-3652) AS SHARED GENETIC AND EPIGENETIC EXPRESSION PATTERNS BETWEEN CP AND OSCC. 2018 10 850 33 CHILDREN WITH CHRONIC IMMUNE THROMBOCYTOPENIA EXHIBIT HIGH EXPRESSION OF HUMAN ENDOGENOUS RETROVIRUSES TRIM28 AND SETDB1. CHRONIC IMMUNE THROMBOCYTOPENIA (CITP) IS AN AUTOIMMUNE DISEASE WHOSE UNDERLYING BIOLOGIC MECHANISMS REMAIN ELUSIVE. HUMAN ENDOGENOUS RETROVIRUSES (HERVS) DERIVE FROM ANCESTRAL INFECTIONS AND CONSTITUTE ABOUT 8% OF OUR GENOME. A WEALTH OF CLINICAL AND EXPERIMENTAL STUDIES HIGHLIGHTS THEIR PIVOTAL PATHOGENETIC ROLE IN AUTOIMMUNE DISEASES. EPIGENETIC MECHANISMS, SUCH AS THOSE MODULATED BY TRIM28 AND SETDB1, ARE INVOLVED IN HERV ACTIVATION AND REGULATION OF IMMUNE RESPONSE. WE ASSESSED, THROUGH A POLYMERASE CHAIN REACTION REAL-TIME TAQMAN AMPLIFICATION ASSAY, THE TRANSCRIPTION LEVELS OF POL GENES OF HERV-H, HERV-K, AND HERV-W; ENV GENES OF SYNCYTIN (SYN)1, SYN2, AND HERV-W; AS WELL AS TRIM28 AND SETDB1 IN WHOLE BLOOD FROM 34 CHILDREN WITH CITP AND AGE-MATCHED HEALTHY CONTROLS (HC). THE TRANSCRIPTIONAL LEVELS OF ALL HERV SEQUENCES, WITH THE EXCEPTION OF HERV-W-ENV, WERE SIGNIFICANTLY ENHANCED IN CHILDREN WITH CITP AS COMPARED TO HC. PATIENTS ON ELTROMBOPAG TREATMENT EXHIBITED LOWER EXPRESSION OF SYN1, SYN2, AND HERV-W-ENV AS COMPARED TO UNTREATED PATIENTS. THE MRNA CONCENTRATIONS OF TRIM28 AND SETDB1 WERE SIGNIFICANTLY HIGHER AND WERE POSITIVELY CORRELATED WITH THOSE OF HERVS IN CITP PATIENTS. THE OVER-EXPRESSIONS OF HERVS AND TRIM28/SETDB1 AND THEIR POSITIVE CORRELATIONS IN PATIENTS WITH CITP ARE SUGGESTIVE CLUES OF THEIR CONTRIBUTION TO THE PATHOGENESIS OF THE DISEASE AND SUPPORT INNOVATIVE INTERVENTIONS TO INHIBIT HERV AND TRIM28/SETDB1 EXPRESSIONS IN PATIENTS UNRESPONSIVE TO STANDARD THERAPIES. 2023 11 564 35 BASAL CELL CARCINOMAS OF THE SCALP AFTER RADIOTHERAPY FOR TINEA CAPITIS IN CHILDHOOD: A GENETIC AND EPIGENETIC STUDY WITH COMPARISON WITH BASAL CELL CARCINOMAS EVOLVING IN CHRONICALLY SUN-EXPOSED AREAS. BACKGROUND: BASAL CELL CARCINOMA (BCC) HAS BEEN MOSTLY ASSOCIATED WITH SUN EXPOSURE, BUT IONIZING RADIATION IS ALSO A KNOWN RISK FACTOR. IT IS NOT CLEAR IF THE PATHOGENESIS OF BCC, NAMELY AT A GENOMIC AND EPIGENETIC LEVEL, DIFFERS ACCORDING TO THE UNDERLYING TRIGGERING FACTORS. OBJECTIVE: THE PRESENT STUDY AIMS TO COMPARE GENETIC AND EPIGENETIC CHANGES IN BCCS RELATED TO IONIZING RADIATION AND CHRONIC SUN EXPOSURE. METHODS: TUMOR SAMPLES FROM BCCS OF THE SCALP IN PATIENTS SUBMITTED TO RADIOTHERAPY TO TREAT TINEA CAPITIS IN CHILDHOOD AND BCCS FROM SUN-EXPOSED AREAS WERE ANALYSED THROUGH ARRAY COMPARATIVE GENOMIC HYBRIDIZATION (ARRAY-CGH) AND METHYLATION-SPECIFIC MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION (MS-MLPA) TO DETECT COPY NUMBER ALTERATIONS AND METHYLATION STATUS OF SPECIFIC GENES. RESULTS: GENOMIC CHARACTERIZATION OF TUMOR SAMPLES REVEALED SEVERAL COPY NUMBER GAINS AND LOSSES IN ALL CHROMOSOMES, WITH THE MOST FREQUENT GAINS OBSERVED AT 2P, 6P, 12P, 14Q, 15Q, 18Q, XP AND YP, AND THE MOST FREQUENT LOSSES OBSERVED AT 3Q, 14Q, 16P, 17Q, 22Q, XP, YP AND YQ. WE DEVELOPED A STATISTICAL MODEL, ENCOMPASSING GAINS IN 3P AND 16P AND LOSSES IN 14Q AND 20P, WITH POTENTIAL TO DISCRIMINATE BCC SAMPLES WITH SPORADIC AETIOLOGY FROM BCC SAMPLES THAT EVOLVE AFTER RADIOTHERAPY IN CHILDHOOD FOR THE TREATMENT OF TINEA CAPITIS, WHICH PRESENTED STATISTICAL SIGNIFICANCE (P = 0.003). FEW METHYLATED GENES WERE DETECTED THROUGH MS-MLPA, MOST FREQUENTLY RARB AND CD44. CONCLUSIONS: OUR STUDY REPRESENTS A STEP FORWARD IN THE UNDERSTANDING OF THE GENETIC MECHANISMS UNDERLYING THE PATHOGENESIS OF BCC AND SUGGESTS POTENTIAL DIFFERENCES ACCORDING TO THE UNDERLYING RIS K FACTORS. 2021 12 2127 36 EPIGENETIC INACTIVATION OF MIR-9 FAMILY MICRORNAS IN CHRONIC LYMPHOCYTIC LEUKEMIA--IMPLICATIONS ON CONSTITUTIVE ACTIVATION OF NFKAPPAB PATHWAY. BACKGROUND: THE MIR-9 FAMILY MICRORNAS HAVE BEEN IDENTIFIED AS A TUMOR SUPPRESSOR MIRNA IN CANCERS. WE POSTULATED THAT MIR-9-1, MIR-9-2 AND MIR-9-3 MIGHT BE INACTIVATED BY DNA HYPERMETHYLATION IN CHRONIC LYMPHOCYTIC LEUKEMIA (CLL). METHODS: METHYLATION OF MIR-9-1, MIR-9-2 AND MIR-9-3 WAS STUDIED IN EIGHT NORMAL CONTROLS INCLUDING NORMAL BONE MARROW, BUFFY COAT, AND CD19-SORTED PERIPHERAL BLOOD B-CELLS FROM HEALTHY INDIVIDUALS, SEVEN CLL CELL LINES, AND SEVENTY-EIGHT DIAGNOSTIC CLL SAMPLES BY METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION. RESULTS: THE PROMOTERS OF MIR-9-3 AND MIR-9-1 WERE BOTH UNMETHYLATED IN NORMAL CONTROLS, BUT METHYLATED IN FIVE (71.4%) AND ONE OF SEVEN CLL CELL LINES RESPECTIVELY. HOWEVER, MIR-9-2 PROMOTER WAS METHYLATED IN NORMAL CONTROLS INCLUDING CD19 + VE B-CELLS, HENCE SUGGESTIVE OF A TISSUE-SPECIFIC BUT NOT TUMOR-SPECIFIC METHYLATION, AND THUS NOT FURTHER STUDIED. DIFFERENT MSP STATUSES OF MIR-9-3, INCLUDING COMPLETE METHYLATION, PARTIAL METHYLATION, AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE METHYLATION ANALYSIS. 5-AZA-2'-DEOXYCYTIDINE TREATMENT RESULTED IN MIR-9-3 PROMOTER DEMETHYLATION AND RE-EXPRESSION OF PRI-MIR-9-3 IN I83-E95 AND WAC3CD5+ CELLS, WHICH WERE HOMOZYGOUSLY METHYLATED FOR MIR-9-3. MOREOVER, OVEREXPRESSION OF MIR-9 LED TO SUPPRESSED CELL PROLIFERATION AND ENHANCED APOPTOSIS TOGETHER WITH DOWNREGULATION OF NFKAPPAB1 IN I83-E95 CELLS, SUPPORTING A TUMOR SUPPRESSOR ROLE OF MIR-9-3 IN CLL. IN PRIMARY CLL SAMPLES, MIR-9-3 WAS DETECTED IN 17% AND MIR-9-1 METHYLATION IN NONE OF THE PATIENTS AT DIAGNOSIS. MOREOVER, MIR-9-3 METHYLATION WAS ASSOCIATED WITH ADVANCED RAI STAGE (>/= STAGE 2) (P = 0.04). CONCLUSIONS: OF THE MIR-9 FAMILY, MIR-9-3 IS A TUMOR SUPPRESSOR MIRNA RELATIVELY FREQUENTLY METHYLATED, AND HENCE SILENCED IN CLL; WHEREAS MIR-9-1 METHYLATION IS RARE IN CLL. THE ROLE OF MIR-9-3 METHYLATION IN THE CONSTITUTIVE ACTIVATION OF NFKAPPAB SIGNALING PATHWAY IN CLL WARRANTS FURTHER STUDY. 2013 13 4521 17 MULTI?LAYERED PREVENTION AND TREATMENT OF CHRONIC INFLAMMATION, ORGAN FIBROSIS AND CANCER ASSOCIATED WITH CANONICAL WNT/BETA?CATENIN SIGNALING ACTIVATION (REVIEW). BETA?CATENIN/CTNNB1 IS AN INTRACELLULAR SCAFFOLD PROTEIN THAT INTERACTS WITH ADHESION MOLECULES (E?CADHERIN/CDH1, N?CADHERIN/CDH2, VE?CADHERIN/CDH5 AND ALPHA?CATENINS), TRANSMEMBRANE?TYPE MUCINS (MUC1/CD227 AND MUC16/CA125), SIGNALING REGULATORS (APC, AXIN1, AXIN2 AND NHERF1/EBP50) AND EPIGENETIC OR TRANSCRIPTIONAL REGULATORS (BCL9, BCL9L, CREBBP/CBP, EP300/P300, FOXM1, MED12, SMARCA4/BRG1 AND TCF/LEF). GAIN?OF?FUNCTION CTTNB1 MUTATIONS ARE DETECTED IN BLADDER CANCER, COLORECTAL CANCER, GASTRIC CANCER, LIVER CANCER, LUNG CANCER, PANCREATIC CANCER, PROSTATE CANCER AND UTERINE CANCER, WHEREAS LOSS?OF?FUNCTION CTNNB1 MUTATIONS ARE ALSO DETECTED IN HUMAN CANCER. ABCB1, ALDH1A1, ASCL2, ATF3, AXIN2, BAMBI, CCND1, CD44, CLDN1, CTLA4, DKK1, EDN1, EOMES, FGF18, FGF20, FZD7, IL10, JAG1, LEF1, LGR5, MITF, MSX1, MYC, NEUROD1, NKD1, NODAL, NOTCH2, NOTUM, NRCAM, OPN, PAX3, PPARD, PTGS2, RNF43, SNAI1, SP5, TCF7, TERT, TNFRSF19, VEGFA AND ZNRF3 ARE REPRESENTATIVE BETA?CATENIN TARGET GENES. BETA?CATENIN SIGNALING IS INVOLVED IN MYOFIBROBLAST ACTIVATION AND SUBSEQUENT PULMONARY FIBROSIS, IN ADDITION TO OTHER TYPES OF FIBROSIS. BETA?CATENIN AND NF?KAPPAB SIGNALING ACTIVATION ARE INVOLVED IN FIELD CANCERIZATION IN THE STOMACH ASSOCIATED WITH HELICOBACTER PYLORI (H. PYLORI) INFECTION AND IN THE LIVER ASSOCIATED WITH HEPATITIS C VIRUS (HCV) INFECTION AND OTHER ETIOLOGIES. BETA?CATENIN?TARGETED THERAPEUTICS ARE FUNCTIONALLY CLASSIFIED INTO BETA?CATENIN INHIBITORS TARGETING UPSTREAM REGULATORS (AZ1366, ETC?159, G007?LK, GNF6231, IPAFRICEPT, NVP?TNKS656, ROSMANTUZUMAB, VANTICTUMAB, WNT?C59, WNT974 AND XAV939), BETA?CATENIN INHIBITORS TARGETING PROTEIN?PROTEIN INTERACTIONS (CGP049090, CWP232228, E7386, ICG?001, LF3 AND PRI?724), BETA?CATENIN INHIBITORS TARGETING EPIGENETIC REGULATORS (PKF118?310), BETA?CATENIN INHIBITORS TARGETING MEDIATOR COMPLEXES (CCT251545 AND CORTISTATIN A) AND BETA?CATENIN INHIBITORS TARGETING TRANSMEMBRANE?TYPE TRANSCRIPTIONAL OUTPUTS, INCLUDING CD44V6, FZD7 AND LGR5. ERADICATING H. PYLORI AND HCV IS THE OPTIMAL APPROACH FOR THE FIRST?LINE PREVENTION OF GASTRIC CANCER AND HEPATOCELLULAR CARCINOMA (HCC), RESPECTIVELY. HOWEVER, BETA?CATENIN INHIBITORS MAY BE APPLICABLE FOR THE PREVENTION OF ORGAN FIBROSIS, SECOND?LINE HCC PREVENTION AND TREATING BETA?CATENIN?DRIVEN CANCER. THE MULTI?LAYERED PREVENTION AND TREATMENT STRATEGY OF BETA?CATENIN?RELATED HUMAN DISEASES IS NECESSARY FOR THE PRACTICE OF PERSONALIZED MEDICINE AND IMPLEMENTATION OF PRECISION MEDICINE. 2018 14 1457 41 DISEASE PROGRESSION FROM CHRONIC HEPATITIS C TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA IS ASSOCIATED WITH INCREASING DNA PROMOTER METHYLATION. BACKGROUND: CHANGES IN DNA METHYLATION PATTERNS ARE BELIEVED TO BE EARLY EVENTS IN HEPATOCARCINOGENESIS. A BETTER UNDERSTANDING OF METHYLATION STATES AND HOW THEY CORRELATE WITH DISEASE PROGRESSION WILL AID IN FINDING POTENTIAL STRATEGIES FOR EARLY DETECTION OF HCC. THE AIM OF OUR STUDY WAS TO ANALYZE THE METHYLATION FREQUENCY OF TUMOR SUPPRESSOR GENES, P14, P15, AND P73, AND A MISMATCH REPAIR GENE (O6MGMT) IN HCV RELATED CHRONIC LIVER DISEASE AND HCC TO IDENTIFY CANDIDATE EPIGENETIC BIOMARKERS FOR HCC PREDICTION. MATERIALS AND METHODS: 516 EGYPTIAN PATIENTS WITH HCV-RELATED LIVER DISEASE WERE RECRUITED FROM KASR ALAINI MULTIDISCIPLINARY HCC CLINIC FROM APRIL 2010 TO JANUARY 2012. SUBJECTS WERE DIVIDED INTO 4 DIFFERENT CLINICALLY DEFINED GROUPS - HCC GROUP (N=208), LIVER CIRRHOSIS GROUP (N=108), CHRONIC HEPATITIS C GROUP (N=100), AND CONTROL GROUP (N=100) - TO ANALYZE THE METHYLATION STATUS OF THE TARGET GENES IN PATIENT PLASMA USING EPITECT METHYL QPCR ARRAY TECHNOLOGY. METHYLATION WAS CONSIDERED TO BE HYPERMETHYLATED IF >10% AND/OR INTERMEDIATELY METHYLATED IF >60%. RESULTS: IN OUR SERIES, A SIGNIFICANT DIFFERENCE IN THE HYPERMETHYLATION STATUS OF ALL STUDIED GENES WAS NOTED WITHIN THE DIFFERENT STAGES OF CHRONIC LIVER DISEASE AND ULTIMATELY HCC. HYPERMETHYLATION OF THE P14 GENE WAS DETECTED IN 100/208 (48.1%), 52/108 (48.1%), 16/100 (16%) AND 8/100 (8%) AMONG HCC, LIVER CIRRHOSIS, CHRONIC HEPATITIS AND CONTROL GROUPS, RESPECTIVELY, WITH A STATISTICALLY SIGNIFICANT DIFFERENCE BETWEEN THE STUDIED GROUPS (P-VALUE 0.008). WE ALSO DETECTED P15 HYPERMETHYLATION IN 92/208 (44.2%), 36/108 (33.3%), 20/100 (20%) AND 4/100 (4%) , RESPECTIVELY (P-VALUE 0.006). IN ADDITION, HYPERMETHYLATION OF P73 WAS DETECTED IN 136/208 (65.4%), 72/108 (66.7%), 32/100 (32%) AND 4/100 (4%) (P-VALUE <0.001). ALSO, WE DETECTED O6MGMT HYPERMETHYLATION IN 84/208 (40.4%), 60/108 (55.3%), 20/100 (20%) AND 4/100 (4%), RESPECTIVELY (P VALUE <0.001. CONCLUSIONS: THE EPIGENETIC CHANGES OBSERVED IN THIS STUDY INDICATE THAT HCC TUMORS EXHIBIT SPECIFIC DNA METHYLATION SIGNATURES WITH POTENTIAL CLINICAL APPLICATIONS IN DIAGNOSIS AND PROGNOSIS. IN ADDITION, METHYLATION FREQUENCY COULD BE USED TO MONITOR WHETHER A PATIENT WITH CHRONIC HEPATITIS C IS LIKELY TO PROGRESS TO LIVER CIRRHOSIS OR EVEN HCC. WE CAN CONCLUDE THAT METHYLATION PROCESSES ARE NOT JUST EARLY EVENTS IN HEPATOCARCINOGENESIS BUT ACCUMULATE WITH PROGRESSION TO CANCER. 2014 15 5289 37 PROSTANOID RECEPTOR GENES CONFER POOR PROGNOSIS IN HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA EPIGENETIC INACTIVATION. BACKGROUND: CHRONIC INFLAMMATION IS A RISK FACTOR FOR HEAD AND NECK SQUAMOUS CELL CARCINOMA (HNSCC) AND OTHER DISEASES. PROSTANOID RECEPTORS ARE CLEARLY INVOLVED IN THE DEVELOPMENT OF MANY TYPES OF CANCER. HOWEVER, THEIR ROLE IS NOT SIMPLE AND IS POORLY UNDERSTOOD IN HNSCC. METHODS: METHYLATION PROFILES OF PROSTANOID RECEPTOR FAMILY GENES WERE GENERATED FOR TUMOUR SAMPLES OBTAINED FROM 274 PATIENTS WITH HNSCC, INCLUDING 69 HYPOPHARYNX, 51 LARYNX, 79 ORAL CAVITY, AND 75 OROPHARYNX TUMOUR SAMPLES, BY QUANTITATIVE METHYLATION-SPECIFIC PCR. PROMOTER METHYLATION WAS THEN EVALUATED WITH RESPECT TO VARIOUS CLINICAL CHARACTERISTICS AND PATIENT SURVIVAL. RESULTS: THE MEAN NUMBER OF METHYLATED GENES PER SAMPLE WAS 2.05 +/- 2.59 (RANGE 0 TO 9). PROMOTERS OF PTGDR1, PTGDR2, PTGER1, PTGER2, PTGER3, PTGER4, PTGFR, PTGIR, AND TBXA2R WERE METHYLATED IN 43.8%, 18.2%, 25.5%, 17.5%, 41.2%, 8.0%, 19.3%, 20.4%, AND 11.3% OF THE SAMPLES, RESPECTIVELY. METHYLATION INDICES FOR PROSTANOID RECEPTOR FAMILY GENES TENDED TO BE HIGHER AS THE NUMBER OF TET METHYLATION EVENTS INCREASED. PATIENTS WITH 5-9 METHYLATED GENES HAD A SIGNIFICANTLY LOWER SURVIVAL RATE THAN THAT OF PATIENTS WITH 0-4 METHYLATED GENES (LOG-RANK TEST, P= 0.007). IN MULTIVARIATE ANALYSES, PTGDR1 METHYLATION WAS MOST HIGHLY CORRELATED WITH RECURRENCE IN PATIENTS WITH HYPOPHARYNGEAL CANCER (P = 0.014). A SIMILAR CORRELATION WAS OBSERVED FOR PTGER4 IN PATIENTS WITH LARYNGEAL CANCER (P = 0.046). METHYLATION OF THE PTGIR AND TBXA2R PROMOTERS WAS POSITIVELY CORRELATED WITH RECURRENCE IN OROPHARYNGEAL CANCER (P = 0.028 AND P = 0.006, RESPECTIVELY). MOREOVER, PATIENTS WITH 5-9 METHYLATED GENES WERE EXTREMELY LOWER OF 5HMC LEVELS (P = 0.035) AND WAS CORRELATED WITH INCREASING EXPRESSION OF DNMT3A AND DNMT3B (P < 0.05 AND P < 0.05, RESPECTIVELY). CONCLUSION: WE CHARACTERISED THE RELATIONSHIP BETWEEN THE METHYLATION STATUS OF PROSTANOID RECEPTOR GENES AND RECURRENCE IN HNSCC. THESE RESULTS PROVIDE NEW PERSPECTIVES FOR THE DEVELOPMENT OF MOLECULAR TARGETED TREATMENT APPROACHES. 2020 16 5004 27 PERIPHERAL B CELLS FROM PATIENTS WITH HEPATITIS C VIRUS-ASSOCIATED LYMPHOMA EXHIBIT CLONAL EXPANSION AND AN ANERGIC-LIKE TRANSCRIPTIONAL PROFILE. CHRONIC HCV INFECTION REMAINS A GLOBAL HEALTH CONCERN DUE TO ITS INVOLVEMENT IN HEPATIC AND EXTRAHEPATIC DISEASES, INCLUDING B CELL NON-HODGKIN LYMPHOMA (BNHL). CLINICAL AND EPIDEMIOLOGICAL EVIDENCE SUPPORT A CAUSAL ROLE FOR HCV IN BNHL DEVELOPMENT, ALTHOUGH MECHANISTIC INSIGHT IS LACKING. WE PERFORMED RNA-SEQUENCING ON PERIPHERAL B CELLS FROM PATIENTS WITH HCV ALONE, BNHL ALONE, AND HCV-ASSOCIATED BNHL TO IDENTIFY UNIQUE AND SHARED TRANSCRIPTIONAL PROFILES ASSOCIATED WITH TRANSFORMATION. IN PATIENTS WITH HCV-ASSOCIATED BNHL, WE OBSERVED THE ENRICHMENT OF AN ANERGIC-LIKE GENE SIGNATURE AND EVIDENCE OF CLONAL EXPANSION THAT WAS CORRELATED WITH THE EXPRESSION OF EPIGENETIC REGULATORY GENES. OUR DATA SUPPORT A ROLE FOR VIRAL-MEDIATED CLONAL EXPANSION OF ANERGIC-LIKE B CELLS IN HCV-ASSOCIATED BNHL DEVELOPMENT AND SUGGEST EPIGENETIC DYSREGULATION AS A POTENTIAL MECHANISM DRIVING EXPANSION. WE PROPOSE EPIGENETIC MECHANISMS MAY BE INVOLVED IN BOTH HCV-ASSOCIATED LYMPHOMA AND REGULATION OF B CELL ANERGY, REPRESENTING AN ATTRACTIVE TARGET FOR CLINICAL INTERVENTIONS. 2023 17 2134 29 EPIGENETIC INACTIVATION OF THE MIR129-2 IN HEMATOLOGICAL MALIGNANCIES. BACKGROUND: MIR129-2 HAS BEEN SHOWN TO BE A TUMOR SUPPRESSOR MICRORNA HYPERMETHYLATED IN EPITHELIAL CANCERS. PATIENTS AND METHODS: EPIGENETIC INACTIVATION OF MIR129-2 WAS STUDIED BY METHYLATION-SPECIFIC PCR (MSP) IN 13 CELL LINES (EIGHT MYELOMA AND FIVE LYMPHOMA), 15 NORMAL CONTROLS AND 344 PRIMARY SAMPLES INCLUDING ACUTE MYELOID LEUKEMIA (AML), ACUTE LYMPHOBLASTIC LEUKEMIA (ALL), CHRONIC MYELOID LEUKEMIA (CML), CHRONIC LYMPHOCYTIC LEUKEMIA (CLL), NON-HODGKIN'S LYMPHOMA (NHL), MULTIPLE MYELOMA (MM) AT DIAGNOSIS, MM AT RELAPSE/PROGRESSION, AND MONOCLONAL GAMMOPATHY OF UNDETERMINED SIGNIFICANCE (MGUS). EXPRESSION OF MIR129 AND ITS TARGET, SOX4, IN CELL LINES WAS MEASURED BEFORE AND AFTER HYPOMETHYLATING TREATMENT AND MIR129 OVEREXPRESSION. MIR129 EXPRESSION WAS CORRELATED WITH MIR129-2 METHYLATION STATUS IN PRIMARY LYMPHOMA SAMPLES. TUMOR SUPPRESSOR FUNCTION OF MIR129 WAS DEMONSTRATED BY MTT AND TRYPAN BLUE EXCLUSION ASSAY AFTER MIR129 OVEREXPRESSION. RESULTS: THE SENSITIVITY OF THE METHYLATED-MSP WAS ONE IN 10(3). DIFFERENT MSP STATUSES, INCLUDING COMPLETE METHYLATION, PARTIAL METHYLATION, AND COMPLETE UNMETHYLATION, WERE VERIFIED BY QUANTITATIVE BISULFITE PYROSEQUENCING. ALL FIVE LYMPHOMA AND SEVEN OF EIGHT MYELOMA CELL LINES SHOWED COMPLETE AND PARTIAL MIR129-2 METHYLATION. IN PRIMARY SAMPLES, MIR129-2 METHYLATION WAS ABSENT IN AML AND CML, BUT DETECTED IN 5% ALL, 45.9% CLL, 49.5% MM AT DIAGNOSIS, AND 59.1% NHL. IN CLL, MIR129-2 METHYLATION ADVERSELY IMPACTED ON SURVIVAL (P=0.004). IN MM, MIR129-2 METHYLATION INCREASED FROM 27.5% MGUS TO 49.5% MM AT DIAGNOSIS AND 41.5% AT RELAPSE/PROGRESSION (P=0.023). IN NHL, MIR129-2 METHYLATION WAS ASSOCIATED WITH MIR124-1 AND MIR203 METHYLATION (P<0.001), AND LOWER MIR129 EXPRESSION (P=0.009). HYPOMETHYLATION TREATMENT OF JEKO-1, HOMOZYGOUSLY METHYLATED FOR MIR129-2, LED TO MIR129-2 DEMETHYLATION AND MIR129 RE-EXPRESSION, WITH DOWNREGULATION OF SOX4 MRNA. MOREOVER, MIR129 OVEREXPRESSION IN BOTH MANTLE CELL LINES, JEKO-1 AND GRANTA-519, INHIBITED CELLULAR PROLIFERATION AND ENHANCED CELL DEATH, WITH CONCOMITANT SOX4 MRNA DOWNREGULATION. CONCLUSIONS: MIR129-2 IS A TUMOR SUPPRESSIVE MICRORNA FREQUENTLY METHYLATED IN LYMPHOID BUT NOT MYELOID MALIGNANCIES, LEADING TO REVERSIBLE MIR129-2 SILENCING. IN CLL, MIR129-2 METHYLATION WAS ASSOCIATED WITH AN INFERIOR SURVIVAL. IN MM, MIR129-2 METHYLATION MIGHT BE ACQUIRED DURING PROGRESSION FROM MGUS TO SYMPTOMATIC MM. IN NHL, MIR129-2 METHYLATION MIGHT COLLABORATE WITH MIR124-1 AND MIR203 METHYLATION IN LYMPHOMAGENESIS. 2013 18 3030 28 GENETICS OF OPISTHORCHIS VIVERRINI-RELATED CHOLANGIOCARCINOMA. PURPOSE OF REVIEW: WE REVIEW THE GENETIC, EPIGENETIC AND TRANSCRIPTIONAL LANDSCAPE OF LIVER FLUKE (OPISTHORCHIS VIVERRINI, OV)-RELATED CHOLANGIOCARCINOMA (CCA). ITS DISTINCT ALTERATIONS, AS COMPARED WITH NON-OV-RELATED CCA MAY HELP SHED LIGHT ON ITS UNDERLYING MOLECULAR MECHANISMS. RECENT FINDINGS: RECENT WHOLE-EXOME AND TARGETED SEQUENCING NOT ONLY CONFIRMED FREQUENT MUTATIONS IN KNOWN CCA-RELATED GENES INCLUDING TP53 (44%), KRAS (16.7%) AND SMAD4 (16.7%), BUT ALSO REVEALED MUTATIONS IN NOVEL CCA-RELATED GENES ASSOCIATED WITH CHROMATIN REMODELING [BAP1 (2.8%), ARID1A (17.6%), MLL3 (13%) AND IDH1/2 (2.8%)], WNT SIGNALING [RNF43 (9.3%) AND PEG3 (5.6%)] AND KRAS/G PROTEIN SIGNALING [GNAS (9.3%) AND ROBO2 (9.3%)]. INTERESTINGLY, THERE IS A SIGNIFICANT DIFFERENCE IN THE FREQUENCY OF MUTATED GENES BETWEEN OV-RELATED CCA AND NON-OV-RELATED CCA, SUCH AS P53 AND IDH1/2, REFLECTING THE IMPACT OF CAUSE ON PATHOGENESIS. ALTERED DNA METHYLATION AND TRANSCRIPTIONAL PROFILES ASSOCIATED WITH XENOBIOTIC METABOLISM AND PRO-INFLAMMATORY RESPONSES WERE ALSO FOUND IN OV-RELATED CCA. SUMMARY: LIVER FLUKE-INDUCED CHRONIC INFLAMMATION PLAYS A CRUCIAL ROLE IN CHOLANGIOCARCINOGENESIS, RESULTING IN DISTINCT SIGNATURES OF GENETIC, EPIGENETIC AND TRANSCRIPTIONAL ALTERATIONS. THESE ALTERATIONS, WHEN CONTRASTED WITH NON-OV-RELATED CCA, INDICATE A UNIQUE PATHOGENIC PROCESS IN OV-RELATED CCA AND MAY HAVE POTENTIAL CLINICAL IMPLICATIONS ON DIAGNOSTICS, THERAPEUTICS AND PREVENTION. 2015 19 829 24 CHARACTERIZATION OF P190-BCR-ABL CHRONIC MYELOID LEUKEMIA REVEALS SPECIFIC SIGNALING PATHWAYS AND THERAPEUTIC TARGETS. THE ONCOGENIC PROTEIN BCR-ABL HAS TWO MAJOR ISOFORMS, P190(BCR-ABL) AND P210(BCR-ABL). WHILE P210(BCR-ABL) IS THE HALLMARK OF CHRONIC MYELOID LEUKEMIA (CML), P190(BCR-ABL) OCCURS IN THE MAJORITY OF PHILADELPHIA-POSITIVE ACUTE LYMPHOBLASTIC LEUKEMIA (PH + ALL) PATIENTS. IN CML, P190(BCR-ABL) OCCURS IN A MINORITY OF PATIENTS ASSOCIATING WITH DISTINCT HEMATOLOGICAL FEATURES AND INFERIOR OUTCOMES, YET THE PATHOGENIC ROLE OF P190(BCR-ABL) AND POTENTIAL TARGETING THERAPIES ARE LARGELY UNCHARACTERIZED. WE EMPLOYED NEXT GENERATION SEQUENCING, PHOSPHO-PROTEOMIC PROFILING, AND DRUG SENSITIVITY TESTING TO CHARACTERIZE P190(BCR-ABL) IN CML AND HEMATOPOIETIC PROGENITOR CELL LINE MODELS (BA/F3 AND HPC-LSK). P190(BCR-ABL) CML PATIENTS DEMONSTRATED POOR RESPONSE TO IMATINIB AND FREQUENT MUTATIONS IN EPIGENETIC MODIFIERS GENES. IN CONTRAST WITH P210(BCR-ABL), P190(BCR-ABL) EXHIBITED SPECIFIC TRANSCRIPTIONAL UPREGULATION OF INTERFERON, INTERLEUKIN-1 RECEPTOR, AND P53 SIGNALING PATHWAYS, ASSOCIATED WITH HYPERPHOSPHORYLATION OF RELEVANT SIGNALING MOLECULES INCLUDING JAK1/STAT1 AND PAK1 IN ADDITION TO SRC HYPERPHOSPHORYLATION. COMPARABLE TO P190(BCR-ABL) CML PATIENTS, P190(BCR-ABL) CELL LINES DEMONSTRATED SIMILAR TRANSCRIPTIONAL AND PHOSPHO-SIGNALING SIGNATURES. WITH THE DRUG SENSITIVITY SCREENING WE IDENTIFIED TARGETED DRUGS WITH SPECIFIC ACTIVITY IN P190(BCR-ABL) CELL LINES INCLUDING IAP-, PAK1-, AND SRC INHIBITORS AND GLUCOCORTICOIDS. OUR RESULTS PROVIDE NOVEL INSIGHTS INTO THE MECHANISMS UNDERLYING THE DISTINCT FEATURES OF P190(BCR-ABL) CML AND PROMISING THERAPEUTIC TARGETS FOR THIS HIGH-RISK PATIENT GROUP. 2021 20 2974 39 GENETIC AND METHYLATION STATUS OF CDKN2A (P14(ARF)/P16(INK4A)) AND TP53 GENES IN RECURRENT RESPIRATORY PAPILLOMATOSIS. RECURRENT RESPIRATORY PAPILLOMATOSIS (RRP) IS A RARE AND CHRONIC DISEASE AFFECTING THE UPPER AIRWAY WITH PAPILLOMATOUS LESIONS CAUSED BY THE HUMAN PAPILLOMAVIRUS (HPV) INFECTION, ESPECIALLY HPV-6 AND/OR HPV-11 TYPES. LITTLE IS KNOWN ABOUT THE GENETIC AND EPIGENETIC DRIVERS IN RRP PATHOPHYSIOLOGY. FOR THIS PURPOSE, WE ANALYZED 27 PAPILLOMATOUS LESIONS FROM PATIENTS WITH RRP TO EVALUATE SOMATIC MUTATIONS AND METHYLATION STATUS IN CDKN2A (P14(ARF)/P16(INK4A)) AND TP53, WHICH ARE KEY TUMOR SUPPRESSOR GENES FOR THE CELL CYCLE CONTROL. SANGER SEQUENCING ANALYSIS REVEALED ONE SOMATIC MUTATION IN TP53 (C.733_734INSA) AND FOUR MUTATIONS IN CDKN2A (C.-30G > T, C.29_30INSA, C.69DELT, AND C.300C > A). THESE MUTATIONS WERE OBSERVED IN 10 PATIENTS, 6 OF WHICH CARRIED DOUBLE MUTATION. FURTHERMORE, 50% (5/10) OF THESE PATIENTS CARRYING SOMATIC MUTATIONS HAD RRP SEVERITY, REPRESENTING 62.5% (5/8) OF THE SEVERITY CASES IN THIS STUDY, ALBEIT NO SIGNIFICANT ASSOCIATION WAS FOUND BETWEEN SOMATIC MUTATIONS AND DISEASE SEVERITY. METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ASSAYS REVEALED P14(ARF) PROMOTER HYPERMETHYLATION IN 100% OF CASES, FOLLOWED BY TP53 (96.3%) AND P16(INK4A) (55.6%), SUGGESTING THE INFLUENCE OF HPV IN THE DNA METHYLATION MACHINERY. IN CONCLUSION, SOMATIC MUTATIONS WERE NOT COMMON EVENTS IDENTIFIED IN PATIENTS WITH RRP. HOWEVER, EPIGENETIC MODULATION BY HIGH METHYLATION RATES, PARTICULARLY FOR THE P14(ARF)/TP53 PATHWAY, SEEMS TO BE IN THE COURSE OF RRP DEVELOPMENT. 2022