1 5382 103 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
2 2637  30 EPIGENOME-WIDE STUDY IDENTIFIES EPIGENETIC OUTLIERS IN NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. NONGENETIC PREDISPOSITION TO COLORECTAL CANCER CONTINUES TO BE DIFFICULT TO MEASURE PRECISELY, HAMPERING EFFORTS IN TARGETED PREVENTION AND SCREENING. EPIGENETIC CHANGES IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER CAN SERVE AS A TOOL IN PREDICTING COLORECTAL CANCER OUTCOMES. WE IDENTIFIED EPIGENETIC CHANGES AFFECTING THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER. DNA METHYLATION PROFILING ON NORMAL COLON MUCOSA FROM 77 PATIENTS WITH COLORECTAL CANCER AND 68 CONTROLS IDENTIFIED A DISTINCT SUBGROUP OF NORMALLY-APPEARING MUCOSA WITH MARKEDLY DISRUPTED DNA METHYLATION AT A LARGE NUMBER OF CPGS, TERMED AS "OUTLIER METHYLATION PHENOTYPE" (OMP) AND ARE PRESENT IN 15 OF 77 PATIENTS WITH CANCER VERSUS 0 OF 68 CONTROLS (P < 0.001). SIMILAR FINDINGS WERE ALSO SEEN IN PUBLICLY AVAILABLE DATASETS. COMPARISON OF NORMAL COLON MUCOSA TRANSCRIPTION PROFILES OF PATIENTS WITH OMP CANCER WITH THOSE OF PATIENTS WITH NON-OMP CANCER INDICATES GENES WHOSE PROMOTERS ARE HYPERMETHYLATED IN THE OMP PATIENTS ARE ALSO TRANSCRIPTIONALLY DOWNREGULATED, AND THAT MANY OF THE GENES MOST AFFECTED ARE INVOLVED IN INTERACTIONS BETWEEN EPITHELIAL CELLS, THE MUCUS LAYER, AND THE MICROBIOME. ANALYSIS OF 16S RRNA PROFILES SUGGESTS THAT NORMAL COLON MUCOSA OF OMPS ARE ENRICHED IN BACTERIAL GENERA ASSOCIATED WITH COLORECTAL CANCER RISK, ADVANCED TUMOR STAGE, CHRONIC INTESTINAL INFLAMMATION, MALIGNANT TRANSFORMATION, NOSOCOMIAL INFECTIONS, AND KRAS MUTATIONS. IN CONCLUSION, OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. PROSPECTIVE STUDIES ARE NEEDED TO DETERMINE WHETHER OMP COULD SERVE AS A BIOMARKER FOR AN ELEVATED EPIGENETIC RISK FOR COLORECTAL CANCER DEVELOPMENT. PREVENTION RELEVANCE: OUR STUDY IDENTIFIES AN EPIGENETICALLY DISTINCT OMP GROUP IN THE NORMAL MUCOSA OF PATIENTS WITH COLORECTAL CANCER THAT IS CHARACTERIZED BY A DISRUPTED METHYLOME, ALTERED GENE EXPRESSION, AND MICROBIAL DYSBIOSIS. IDENTIFICATION OF OMPS IN HEALTHY CONTROLS AND PATIENTS WITH COLORECTAL CANCER WILL LEAD TO PREVENTION AND BETTER PROGNOSIS, RESPECTIVELY.	2022	

3 5673  29 SHARED EPIGENETIC ALTERATIONS BETWEEN ORAL CANCER AND PERIODONTITIS: A PRELIMINARY STUDY. INTRODUCTION: WE RECENTLY DEVELOPED A NON-INVASIVE SAMPLING PROCEDURE FOR ORAL SQUAMOUS CELL CARCINOMA (OSCC) DETECTION BASED ON DNA METHYLATION ANALYSIS OF A PANEL OF 13 GENES. ORAL CANCER, AS WELL AS ACUTE AND CHRONIC INFLAMMATORY DISEASES, MAY INFLUENCE THE METHYLATION LEVEL OF SEVERAL GENES IN THE ORAL CAVITY. IN THE PRESENT STUDY, WE EVALUATED THE PRESENCE OF PERIODONTAL DISEASE (PD) AND THE METHYLATION STATUS USING OUR 13-GENE PANEL. METHODS: ORAL BRUSHING SPECIMENS WERE COLLECTED FROM THREE DIFFERENT PATIENT GROUPS: 23 GINGIVAL OSCC PATIENTS, 15 PATIENTS AFFECTED BY PD, AND 15 HEALTHY VOLUNTEERS LACKING EVIDENCE OF PD. DNA METHYLATION ANALYSIS WAS PERFORMED AND EACH SAMPLE WAS DETERMINED TO BE POSITIVE OR NEGATIVE BASED ON A PREDEFINED CUT-OFF VALUE. RESULTS: POSITIVE RESULTS WERE FOUND FOR 23/23 OSCC PATIENTS, 3/15 PD PATIENTS, AND 0/15 SAMPLES FROM HEALTHY VOLUNTEERS. THE GP1BB AND MIR193 GENES IN THE PD GROUP EXHIBITED MEAN METHYLATION LEVELS SIMILAR TO OSCC PATIENTS. ZAP70 SHOWED DIFFERENT METHYLATION LEVELS AMONG THREE GROUPS. CONCLUSION: PRELIMINARY DATA IDENTIFIED SHARED EPIGENETIC ALTERATIONS BETWEEN PD AND OSCC PATIENTS IN TWO INFLAMMATORY GENES (GP1BB AND MIR193). THIS STUDY MAY HELP TO IDENTIFY POTENTIAL LINKS BETWEEN THE TWO DISEASES AND SERVE AS A STARTING POINT FOR THE FUTURE RESEARCH FOCUSED ON PATHOGENESIS.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
4 3125  22 GHSR DNA HYPERMETHYLATION IS A COMMON EPIGENETIC ALTERATION OF HIGH DIAGNOSTIC VALUE IN A BROAD SPECTRUM OF CANCERS. IDENTIFICATION OF A SINGLE MOLECULAR TRAIT THAT IS DETERMINANT OF COMMON MALIGNANCIES MAY SERVE AS A POWERFUL DIAGNOSTIC SUPPLEMENT TO CANCER TYPE-SPECIFIC MARKERS. HERE, WE REPORT A DNA METHYLATION MARK THAT IS CHARACTERISTIC OF SEVEN STUDIED MALIGNANCIES, NAMELY CANCERS OF LUNG, BREAST, PROSTATE, PANCREAS, COLORECTUM, GLIOBLASTOMA AND B CELL CHRONIC LYMPHOCYTIC LEUKAEMIA (CLL) (N = 137). THIS MARK WAS DEFINED BY SUBSTANTIAL HYPERMETHYLATION AT THE PROMOTER AND FIRST EXON OF GROWTH HORMONE SECRETAGOUGE RECEPTOR (GHSR) THROUGH BISULFITE PYROSEQUENCING. THE DEGREE OF ABERRANT METHYLATION WAS CAPABLE OF ACCURATE DISCRIMINATION BETWEEN CANCER AND CONTROL SAMPLES. THE HIGHEST SENSITIVITY AND SPECIFICITY OF CANCER DETECTION WAS ACHIEVED FOR CANCERS OF PANCREAS, LUNG, BREAST AND CLL YIELDING THE AREA UNDER THE CURVE (AUC) VALUES OF 1.0000, 0.9952, 0.9800 AND 0.9400, RESPECTIVELY. NARROWING TO A SINGLE CPG SITE WITHIN THE GENE'S PROMOTER OR FOUR CONSECUTIVE CPG UNITS OF THE HIGHEST METHYLATION LEVELS WITHIN THE FIRST EXON IMPROVED THE DETECTION POWER. GHSR HYPERMETHYLATION WAS DETECTED ALREADY AT THE EARLY STAGE TUMORS. THE ACCURATE PERFORMANCE OF THIS MARKER WAS FURTHER REPLICATED IN AN INDEPENDENT SET OF PANCREATIC CANCER AND CONTROL SAMPLES (N = 78). THESE FINDINGS SUPPORT THE CANDIDATURE OF GHSR METHYLATION AS A HIGHLY ACCURATE PAN-CANCER MARKER.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
5 3296  24 HIGH RESOLUTION INTEGRATIVE ANALYSIS REVEALS WIDESPREAD GENETIC AND EPIGENETIC CHANGES AFTER CHRONIC IN-VITRO ACID AND BILE EXPOSURE IN BARRETT'S EPITHELIUM CELLS. BARRETT'S EPITHELIUM (BE) IS A PREMALIGNANT CONDITION RESULTING FROM CHRONIC GASTROESOPHAGEAL REFLUX THAT MAY PROGRESS TO ESOPHAGEAL ADENOCARCINOMA (EAC). EARLY INTERVENTION HOLDS PROMISE IN PREVENTING BE PROGRESSION. HOWEVER, IDENTIFICATION OF HIGH-RISK BE PATIENTS REMAINS CHALLENGING DUE TO INADEQUATE BIOMARKERS FOR EARLY DIAGNOSIS. WE INVESTIGATED THE EFFECT OF PROLONGED CHRONIC ACID AND BILE EXPOSURE ON TRANSCRIPTOME, METHYLOME, AND MUTATOME OF CELLS IN AN IN-VITRO BE CARCINOGENESIS (BEC) MODEL. TWENTY WEEKS ACID AND BILE EXPOSED CELLS FROM THE BEC MODEL (BEC20W) WERE COMPARED WITH THEIR NAIVE PREDECESSORS HISEQ ILLUMINA BASED RNA SEQUENCING WAS PERFORMED ON RNA FROM BOTH THE CELLS FOR GENE EXPRESSION AND MUTATIONAL ANALYSIS. HELP TAGGING ASSAY WAS PERFORMED FOR DNA METHYLATION ANALYSIS. INGENUITY PATHWAY, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES WERE THEN PERFORMED ON DATASETS. WIDESPREAD ABERRANT GENETIC AND EPIGENETIC CHANGES WERE OBSERVED IN THE BEC20W CELLS. COMBINATORIAL ANALYSES REVEALED 433 FROM A TOTAL OF 863 DOWNREGULATED GENES HAD ACCOMPANYING HYPERMETHYLATION OF PROMOTERS. SIMULTANEOUSLY, 690 GENES FROM A TOTAL OF 1,492 WERE UPREGULATED WITH ACCOMPANYING PROMOTER HYPOMETHYLATION. IN ADDITION, 763 MUTATIONS WERE IDENTIFIED ON 637 GENES. INGENUITY PATHWAY ANALYSIS, GENE ONTOLOGY, AND KEGG PATHWAY ANALYSES ASSOCIATED THE GENETIC AND EPIGENETIC CHANGES IN BEC20W CELLS WITH CELLULAR AND BIOLOGICAL FUNCTIONS. INTEGRATION OF HIGH RESOLUTION COMPARATIVE ANALYSES OF NAIVE BAR-T AND BEC20W CELLS REVEALED STRIKING GENETIC AND EPIGENETIC CHANGES INDUCED BY CHRONIC ACID AND BILE EXPOSURE THAT MAY DISRUPT NORMAL CELLULAR FUNCTIONS AND PROMOTE CARCINOGENESIS. THIS NOVEL STUDY REVEALS SEVERAL POTENTIAL TARGETS FOR FUTURE BIOMARKERS AND THERAPEUTIC DEVELOPMENT.	2013	
                                                                                                                                                                                                                                                                                                                                                                       
6 6584  25 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
7  546  24 ATTENUATED EXPRESSION OF SLCO2A1 CAUSED BY DNA METHYLATION IN PEDIATRIC INFLAMMATORY BOWEL DISEASE. BACKGROUND: SLCO2A1 ENCODES A PROSTAGLANDIN (PG) TRANSPORTER, AND AUTOSOMAL RECESSIVE PATHOGENIC VARIANTS OF THIS GENE CAUSE CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1. IT IS UNCLEAR WHETHER A HETEROZYGOUS PATHOGENIC VARIANT OF SLCO2A1 HAS A ROLE IN THE PATHOGENESIS OF OTHER TYPES OF INFLAMMATORY BOWEL DISEASE (IBD). IN THIS STUDY, WE INVESTIGATED THE POSSIBLE INVOLVEMENT OF A LOCAL EPIGENETIC ALTERATION IN SLCO2A1 IN PATIENTS WITH A HETEROZYGOUS PATHOGENIC VARIANT. METHODS: WE CONDUCTED WHOLE-EXOME SEQUENCING OF SAMPLES FROM 2 SISTERS WITH SUSPECTED MONOGENIC IBD. IN ADDITION, WE PERFORMED BISULFITE SEQUENCING USING DNA EXTRACTED FROM THEIR SMALL AND LARGE INTESTINE SAMPLES TO EXPLORE EPIGENETIC ALTERATIONS. RESULTS: A HETEROZYGOUS SPLICING SITE VARIANT, SLCO2A1:C.940 + 1G > A, WAS DETECTED IN BOTH PATIENTS. TO EXPLORE THE POSSIBLE INVOLVEMENT OF EPIGENETIC ALTERATIONS, WE ANALYZED PROTEIN AND MESSENGER RNA EXPRESSION OF SLCO2A1, AND OBSERVED ATTENUATED SLCO2A1 EXPRESSION IN THE INFLAMED LESIONS OF THESE PATIENTS COMPARED WITH THAT IN THE CONTROL INDIVIDUALS. FURTHERMORE, BISULFITE SEQUENCING INDICATED DENSE METHYLATION IN THE PROMOTER REGION OF SLCO2A1 ONLY IN THE INFLAMED LESIONS OF BOTH PATIENTS. THE URINARY PG METABOLITE LEVELS IN THESE PATIENTS WERE COMPARABLE TO THOSE IN PATIENTS WITH CHRONIC ENTEROPATHY ASSOCIATED WITH SLCO2A1 AND HIGHER THAN THOSE IN THE CONTROL INDIVIDUALS. WE FOUND CONSIDERABLY HIGHER LEVELS OF THE METABOLITES IN PATIENT 1, WHO SHOWED MORE SEVERE SYMPTOMS THAN PATIENT 2. CONCLUSIONS: LOCAL DNA METHYLATION ATTENUATED SLCO2A1 EXPRESSION, WHICH MAY EVOKE LOCAL INFLAMMATION OF THE MUCOSA BY THE UNINCORPORATED PG. THESE FINDINGS MAY IMPROVE OUR UNDERSTANDING OF THE EPIGENETIC MECHANISMS UNDERLYING IBD DEVELOPMENT.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                              
8 6826  28 [GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PATIENTS WITH PRIMARY PROGRESSIVE MULTIPLE SCLEROSIS INDICATES INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE DISEASE IMMUNOPATHOGENESIS]. THE PATHOGENESIS OF MULTIPLE SCLEROSIS (MS), A CHRONIC DISEASE OF THE CNS, INCLUDES AUTOIMMUNE AND NEURODEGENERATIVE COMPONENTS. IN MOST CASES, PATIENTS DEVELOP RELAPSING-REMITTING MS (RRMS), WHILE 10-15% OF PATIENTS DEVELOP PRIMARY PROGRESSIVE MS (PPMS), WHICH DIFFERS FROM RRMS IN THE MECHANISMS OF THE PATHOLOGICAL PROCESS, SOME DEMOGRAPHIC, AND SOME CLINICAL CHARACTERISTICS. THESE DIFFERENCES MAY BE EXPLAINED BY THE EPIGENETIC REGULATION OF GENE EXPRESSION IN PPMS INCLUDING DNA METHYLATION AS ONE OF THE KEY EPIGENETIC PROCESSES. THE FEATURES OF DNA METHYLATION IN VARIOUS CELL POPULATIONS IN PPMS PATIENTS REMAIN UNDERSTUDIED. THE GOAL OF THIS STUDY IS TO IDENTIFY DIFFERENTIALLY METHYLATED CPG SITES (DMSS) OF THE GENOME OF CD4+ T LYMPHOCYTES, WHICH CHARACTERIZE PPMS. THE STUDY INCLUDED EIGHT TREATMENT-NAIVE PPMS PATIENTS AND EIGHT HEALTHY CONTROLS. GENOME-WIDE ANALYSIS OF DNA METHYLATION OF CD4+ T LYMPHOCYTES WAS PERFORMED USING HIGH-DENSITY DNA MICROARRAYS. WE HAVE IDENTIFIED 108 DMSS, WHICH DISTINGUISH PPMS PATIENTS FROM HEALTHY CONTROLS. IN PPMS PATIENTS 81% OF THE DMSS ARE HYPERMETHYLATED. MORE THAN A HALF OF THE IDENTIFIED DMSS ARE LOCATED IN KNOWN GENES IN CPG ISLANDS AND ADJACENT REGIONS, WHICH INDICATES A HIGH FUNCTIONAL SIGNIFICANCE OF THESE DMSS IN PPMS DEVELOPMENT. ANALYSIS OF THE OVERREPRESENTATION OF DMS-CONTAINING GENES IN THE MAIN BIOLOGICAL PROCESSES DEMONSTRATES THEIR INVOLVEMENT IN THE REGULATION OF CELL ADHESION TO THE EXTRACELLULAR MATRIX AND THE DEVELOPMENT OF THE IMMUNE RESPONSE, I.E., ANTIGEN PROCESSING AND PRESENTATION, AND DEVELOPMENT OF THE IMMUNE SYSTEM. GENOME-WIDE ANALYSIS OF DNA METHYLATION IN CD4+ T LYMPHOCYTES OF PPMS PATIENTS INDICATES THE INVOLVEMENT OF THIS EPIGENETIC PROCESS IN THE IMMUNOPATHOGENESIS OF THE DISEASE. THESE RESULTS MAY HELP BETTER UNDERSTAND THE PATHOGENESIS OF THIS SEVERE FORM OF MS.	2022	
                                                                                                                                                                                                                                                   
9 1545  29 DNA METHYLATION IN LIVER TUMORIGENESIS IN FISH FROM THE ENVIRONMENT. THE LINK BETWEEN ENVIRONMENT, ALTERATION IN DNA METHYLATION AND CANCER HAS BEEN WELL ESTABLISHED IN HUMANS; YET, IT IS UNDER-STUDIED IN UNSEQUENCED NON-MODEL ORGANISMS. THE OCCURRENCE OF LIVER TUMORS IN THE FLATFISH DAB COLLECTED AT CERTAIN UK SAMPLING SITES EXCEEDS 20%, YET THE CAUSATIVE AGENTS AND THE MOLECULAR MECHANISMS OF TUMOR FORMATION ARE NOT KNOWN, ESPECIALLY REGARDING THE BALANCE BETWEEN EPIGENETIC AND GENETIC FACTORS. METHYLATED DNA IMMUNOPRECIPITATION (MEDIP) COMBINED WITH DE NOVO HIGH-THROUGHPUT DNA SEQUENCING WERE USED TO INVESTIGATE DNA METHYLATION CHANGES IN DAB HEPATOCELLULAR ADENOMA TUMORS FOR THE FIRST TIME IN AN UNSEQUENCED SPECIES. NOVEL CUSTOM-MADE DAB GENE EXPRESSION ARRAYS WERE DESIGNED AND USED TO DETERMINE THE RELATIONSHIP BETWEEN DNA METHYLATION AND GENE EXPRESSION. IN ADDITION, THE CONFIRMATORY TECHNIQUES OF BISULFITE SEQUENCING PCR (BSP) AND RT-PCR WERE APPLIED. GENES INVOLVED IN PATHWAYS RELATED TO CANCER, INCLUDING APOPTOSIS, WNT/BETA-CATENIN SIGNALING AND GENOMIC AND NON-GENOMIC ESTROGEN RESPONSES, WERE ALTERED BOTH IN METHYLATION AND TRANSCRIPTION. GLOBAL METHYLATION WAS STATISTICALLY SIGNIFICANTLY 1.8-FOLD REDUCED IN HEPATOCELLULAR ADENOMA AND NON-CANCEROUS SURROUNDING TISSUES COMPARED WITH LIVER FROM NON-CANCER BEARING DAB. BASED ON THE IDENTIFIED CHANGES AND CHEMICAL EXPOSURE DATA, OUR STUDY SUPPORTS THE EPIGENETIC MODEL OF CANCER. WE HYPOTHESIZE THAT CHRONIC EXPOSURE TO A MIXTURE OF ENVIRONMENTAL CONTAMINANTS CONTRIBUTES TO A GLOBAL HYPOMETHYLATION FOLLOWED BY FURTHER EPIGENETIC AND GENOMIC CHANGES. THE FINDINGS SUGGEST A LINK BETWEEN ENVIRONMENT, EPIGENETICS AND CANCER IN FISH TUMORS IN THE WILD AND SHOW THE UTILITY OF THIS METHODOLOGY FOR STUDIES IN NON-MODEL ORGANISMS.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
10 1575  32 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11 2935  20 GENETIC ALTERATION ASSOCIATED WITH CHRONIC LYMPHOCYTIC LEUKEMIA. THE GENETICS OF B-CELL CHRONIC LYMPHOCYTIC LEUKEMIA (B-CLL) DIFFER CONSIDERABLY FROM MOST OTHER FORMS OF HEMATOLOGIC MALIGNANCY WHICH ARE USUALLY CHARACTERIZED BY CHROMOSOME TRANSLOCATIONS. B-CLL TYPICALLY CONTAINS CHROMOSOMAL DELETIONS AND CHROMOSOMES 13Q14 AND 11Q22-->Q23 ARE THE MOST COMMON. THESE TWO REGIONS APPEAR TO SHARE A COMMON ANCESTRAL ORIGIN (AUER ET AL., 2007B). OVERALL, CHROMOSOMAL ABNORMALITIES CAN BE FOUND IN THE MAJORITY OF PATIENTS WITH B-CLL WHEN USING SENSITIVE TECHNIQUES (DOHNERET AL., 2000) AND POSSIBLY REFLECTS AN UNDERLYING PREDISPOSITION, WITH A SMALL BUT SIGNIFICANT NUMBER OF FAMILIAL CASES. ALTHOUGH SINGLE AND CONSISTENT ABNORMALITIES ARE MOST COMMON, MULTIPLE REARRANGEMENTS CAN OCCUR, OFTEN WITH DISEASE PROGRESSION (FEGANETAL., 1995; DOHNER ET AL., 2000). REGIONS OF RECURRENT DELETION SUGGEST THE PRESENCE OF TUMOR SUPPRESSOR GENES IF FOLLOWING KNUDSON'S THEORETICAL 2-HIT MODEL. HOWEVER, DESPITE EXTENSIVE SEQUENCING ANALYSIS OVER THE LAST DECADE AND LACK OF PATHOGENIC MUTATIONS IDENTIFIED, THERE HAS BEEN A MOVE AWAY FROM THIS SUGGESTED HYPOTHESIS AND ALTERNATIVE MECHANISMS OF GENE INACTIVATION INVOLVING EPIGENETIC SILENCING OR HAPLOINSUFFICIENCY MAY BE CONSIDERED AS MORE LIKELY IN THIS DISEASE. THIS REVIEW FOCUSES ON THE COMMON GENETIC ABNORMALITIES IN B-CLL AND RELATES THEM TO SOME OF THE MORE RECENT HYPOTHESES ON INACTIVATION OF GENES WITHIN THESE REGIONS OF DELETION.	2007	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
12 5785  25 SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 RAT LIVER EPITHELIAL CELLS. SEVERAL STUDIES HAVE SHOWN THAT CULTURED RAT LIVER EPITHELIAL CELLS TRANSFORM SPONTANEOUSLY AFTER CHRONIC MAINTENANCE IN A CONFLUENT STATE IN VITRO. IN THE PRESENT STUDY, MULTIPLE INDEPENDENT LINEAGES OF LOW-PASSAGE WB-F344 RAT LIVER EPITHELIAL STEM-LIKE CELLS WERE INITIATED AND SUBJECTED IN PARALLEL TO SELECTION FOR SPONTANEOUS TRANSFORMATION TO DETERMINE WHETHER SPONTANEOUS ACQUISITION OF TUMORIGENICITY WAS THE RESULT OF EVENTS (GENETIC OR EPIGENETIC) THAT OCCURRED INDEPENDENTLY AND STOCHASTICALLY, OR REFLECTED THE EXPRESSION OF A PRE-EXISTING ALTERATION WITHIN THE PARENTAL WB-F344 CELL LINE. TEMPORAL ANALYSIS OF THE SPONTANEOUS ACQUISITION OF TUMORIGENICITY BY WB-F344 CELLS DEMONSTRATED LINEAGE-SPECIFIC DIFFERENCES IN THE TIME OF FIRST EXPRESSION OF THE TUMORIGENIC PHENOTYPE, FREQUENCIES AND LATENCIES OF TUMOR FORMATION, AND TUMOR DIFFERENTIATIONS. ALTHOUGH SPONTANEOUSLY TRANSFORMED WB-F344 CELLS PRODUCED DIVERSE TUMOR TYPES (INCLUDING HEPATOCELLULAR CARCINOMAS, CHOLANGIOCARCINOMAS, HEPATOBLASTOMAS, AND OSTEOGENIC SARCOMAS), INDIVIDUAL LINEAGES YIELDED TUMORS WITH CONSISTENT AND SPECIFIC PATTERNS OF DIFFERENTIATION. THESE RESULTS PROVIDE SUBSTANTIAL EVIDENCE THAT THE STOCHASTIC ACCUMULATION OF INDEPENDENT TRANSFORMING EVENTS DURING THE SELECTION REGIMEN IN VITRO WERE RESPONSIBLE FOR SPONTANEOUS NEOPLASTIC TRANSFORMATION OF WB-F344 CELLS. FURTHERMORE, CELL LINEAGE COMMITMENT TO A SPECIFIC DIFFERENTIATION PROGRAM WAS STABLE WITH TIME IN CULTURE AND WITH SITE OF TRANSPLANTATION. THIS IS THE FIRST REPORT OF A COHORT OF RELATED, BUT INDEPENDENT, RAT LIVER EPITHELIAL CELL LINES THAT COLLECTIVELY PRODUCE A SPECTRUM OF TUMOR TYPES BUT INDIVIDUALLY REPRODUCE A SPECIFIC TUMOR TYPE. THESE CELL LINES WILL PROVIDE VALUABLE REAGENTS FOR INVESTIGATION OF THE MOLECULAR MECHANISMS INVOLVED IN THE DIFFERENTIATION OF HEPATIC STEM-LIKE CELLS AND FOR EXAMINATION OF POTENTIAL CAUSAL RELATIONSHIPS IN SPONTANEOUSLY TRANSFORMED RAT LIVER EPITHELIAL CELL LINES BETWEEN MOLECULAR/CELLULAR ALTERATIONS AND THE ABILITY TO PRODUCE TUMORS IN SYNGENEIC ANIMALS.	1998	
                                                                                                                                                                         
13 6421  23 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES.	2018	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
14 4545  21 MUTANT P53 GAIN OF FUNCTION AND CHEMORESISTANCE: THE ROLE OF MUTANT P53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. PURPOSE: TO REVIEW MECHANISMS UNDERLYING MUTANT P53 (MUTP53) GAIN OF FUNCTION (GOF) AND MUTP53-INDUCED CHEMORESISTANCE, AND TO INVESTIGATE THE ROLE OF MUTP53 IN RESPONSE TO CLINICAL CHEMOTHERAPY. METHODS: WE SEARCHED THE PUBMED DATABASE FOR CLINICAL STUDIES FROM THE PAST DECADE, INCLUDING DATA EVALUATING THE IMPACT OF MUTP53 IN CLINICAL CHEMOTHERAPY RESPONSE. RESULTS: INTERACTIONS BETWEEN MUTP53 AND TRANSCRIPTIONAL FACTORS, PROTEINS OR DNA STRUCTURES, AS WELL AS EPIGENETIC REGULATION, CONTRIBUTE TO MUTP53 GOF. MAJOR MECHANISMS OF MUTP53-INDUCED CHEMORESISTANCE INCLUDE ENHANCED DRUG EFFLUX AND METABOLISM, PROMOTING SURVIVAL, INHIBITING APOPTOSIS, UPREGULATING DNA REPAIR, SUPPRESSING AUTOPHAGY, ELEVATING MICROENVIRONMENTAL RESISTANCE AND INDUCING A STEM-LIKE PHENOTYPE. CLINICALLY, MUTP53 PREDICTED RESISTANCE TO CHEMOTHERAPY IN DIFFUSE LARGE B-CELL LYMPHOMA, AND ESOPHAGEAL AND OROPHARYNGEAL CANCERS, BUT ITS IMPACT ON CHRONIC LYMPHOCYTIC LEUKEMIA WAS UNCLEAR. IN BLADDER CANCER, MUTP53 DID NOT PREDICT RESISTANCE, WHEREAS IN SOME BREAST AND OVARIAN CANCERS, IT WAS ASSOCIATED WITH SENSITIVITY TO CERTAIN CHEMOTHERAPEUTIC AGENTS. CONCLUSION: MUTP53 HAS AN INTRICATE ROLE IN THE RESPONSE TO CLINICAL CHEMOTHERAPY AND SHOULD NOT BE INTERPRETED IN ISOLATION. FURTHERMORE, WHEN PREDICTING TUMOR RESPONSE TO CHEMOTHERAPY BASED ON THE P53 STATUS, THE DRUGS USED SHOULD ALSO BE TAKEN INTO CONSIDERATION. THESE CONCEPTS REQUIRE FURTHER INVESTIGATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
15 2469  16 EPIGENETIC TRAJECTORIES OF THE PREMALIGNANT-TO-MALIGNANT TRANSITION OF CHRONIC LYMPHOCYTIC LEUKEMIA. KRETZMER AND COLLEAGUES SHOW THAT THE TRANSITION TO ALTERED METHYLOME OCCURS VERY EARLY IN CHRONIC LYMPHOCYTIC LEUKEMIA, AND ONCE ACQUIRED, IT IS A CLONAL AND EXTREMELY STABLE CHANGE. HOWEVER, THE PRECISE TIME POINT WHEN THE LEUKEMIC CLONE STARTS DEVIATING SIGNIFICANTLY FROM THE NORMAL B-CELL DIFFERENTIATION TRAJECTORY IS STILL ELUSIVE. SEE RELATED ARTICLE BY KRETZMER ET AL., P. 54.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
16 3764  31 INTEGRATIVE ANALYSIS OF DNA METHYLATION AND GENE EXPRESSION DATA IDENTIFIES EPAS1 AS A KEY REGULATOR OF COPD. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMPLEX DISEASE. GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS ARE KNOWN TO CONTRIBUTE TO COPD RISK AND DISEASE PROGRESSION. THEREFORE WE DEVELOPED A SYSTEMATIC APPROACH TO IDENTIFY KEY REGULATORS OF COPD THAT INTEGRATES GENOME-WIDE DNA METHYLATION, GENE EXPRESSION, AND PHENOTYPE DATA IN LUNG TISSUE FROM COPD AND CONTROL SAMPLES. OUR INTEGRATIVE ANALYSIS IDENTIFIED 126 KEY REGULATORS OF COPD. WE IDENTIFIED EPAS1 AS THE ONLY KEY REGULATOR WHOSE DOWNSTREAM GENES SIGNIFICANTLY OVERLAPPED WITH MULTIPLE GENES SETS ASSOCIATED WITH COPD DISEASE SEVERITY. EPAS1 IS DISTINCT IN COMPARISON WITH OTHER KEY REGULATORS IN TERMS OF METHYLATION PROFILE AND DOWNSTREAM TARGET GENES. GENES PREDICTED TO BE REGULATED BY EPAS1 WERE ENRICHED FOR BIOLOGICAL PROCESSES INCLUDING SIGNALING, CELL COMMUNICATIONS, AND SYSTEM DEVELOPMENT. WE CONFIRMED THAT EPAS1 PROTEIN LEVELS ARE LOWER IN HUMAN COPD LUNG TISSUE COMPARED TO NON-DISEASE CONTROLS AND THAT EPAS1 GENE EXPRESSION IS REDUCED IN MICE CHRONICALLY EXPOSED TO CIGARETTE SMOKE. AS EPAS1 DOWNSTREAM GENES WERE SIGNIFICANTLY ENRICHED FOR HYPOXIA RESPONSIVE GENES IN ENDOTHELIAL CELLS, WE TESTED EPAS1 FUNCTION IN HUMAN ENDOTHELIAL CELLS. EPAS1 KNOCKDOWN BY SIRNA IN ENDOTHELIAL CELLS IMPACTED GENES THAT SIGNIFICANTLY OVERLAPPED WITH EPAS1 DOWNSTREAM GENES IN LUNG TISSUE INCLUDING HYPOXIA RESPONSIVE GENES, AND GENES ASSOCIATED WITH EMPHYSEMA SEVERITY. OUR FIRST INTEGRATIVE ANALYSIS OF GENOME-WIDE DNA METHYLATION AND GENE EXPRESSION PROFILES ILLUSTRATES THAT NOT ONLY DOES DNA METHYLATION PLAY A 'CAUSAL' ROLE IN THE MOLECULAR PATHOPHYSIOLOGY OF COPD, BUT IT CAN BE LEVERAGED TO DIRECTLY IDENTIFY NOVEL KEY MEDIATORS OF THIS PATHOPHYSIOLOGY.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
17 6595  24 TUMOR-SPECIFIC GROWTH FACTOR (TSGF): A FUTURISTIC TUMOR BIOMARKER IN EARLY DIAGNOSIS OF CANCER. DESPITE THE SIGNIFICANT IMPROVEMENT IN THE TREATMENT MODALITIES, CANCER IS ONE OF THE FASTEST-GROWING CHRONIC DISEASE CONDITIONS ALL OVER THE WORLD. GENETIC AND EPIGENETIC ALTERATIONS IN THE NORMAL PHYSIOLOGY OF THE CELL ARE THE KEY FACTOR FOR TUMOR DEVELOPMENT. THESE CHANGES CAN TRIGGER THE PRODUCTION OF ABNORMAL PROTEIN EXPRESSIONS THROUGH STIMULATION OF DIFFERENT SIGNALING PATHWAYS AND CAN DEEPLY AFFECT NORMAL CELL GROWTH AND PROLIFERATION. ANY ALTERED PROTEIN EXPRESSION, GENETIC VARIATION, MICRO-RNA OR POST-TRANSLATIONAL PROTEIN MODIFICATIONS THAT INDICATE TUMORIGENESIS CAN ACT AS AN EARLY SIGNAL TERMED AS BIOMARKER. CANCER, BEING A MULTISTEP PROCESS WITH ACCUMULATING GENETIC AND EPIGENETIC ALTERATIONS, COULD BE DETECTED EARLY WITH SUITABLE BIOMARKERS. THERE ARE SEVERAL PROTEINS SUCH AS AFP, CA-125, PSA, TROPONIN, CEA, OSTEOPONTIN, CA 19-9 THAT ACT AS BIOMARKERS WHICH HELP IN EARLY DETECTION, PROGNOSIS, AND MONITORING OF DISEASE PROGRESSION, A HUNT FOR NEWER BIOMARKERS WITH HIGHER SPECIFICITY AND SENSITIVITY IS STILL ONGOING. TUMOR-SPECIFIC GROWTH FACTOR (TSGF) IS ONE SUCH BUDDING AND PREVAILING TUMOR BIOMARKER USED FOR THE EARLY-STAGE DETECTION OF SEVERAL TYPES OF CARCINOMAS. TSGF IS A GENE THAT HELPS IN TUMOR ANGIOGENESIS AND GETS RELEASED DURING THE PRELIMINARY STAGES FROM CANCER CELLS THAT ENSURE THE VASCULAR PROLIFERATION OF THE SAME. IN THIS REVIEW, THE CLINICAL INVESTIGATIONS OF TSGF IN DIFFERENT KINDS OF MALIGNANCY IS DISCUSSED IN DETAIL AND SUGGESTS THE POSSIBILITY OF USING TSGF AS A BIOMARKER IN EARLY DIAGNOSIS OF CANCER.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
18 3959  23 LONG NON-CODING RNAS TARGET PATHOGENETICALLY RELEVANT GENES AND PATHWAYS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE DRIVEN BY GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS. LONG NON-CODING RNAS (LNCRNAS) ARE A KEY COMPONENT OF THE EPIGENETIC MECHANISMS AND ARE KNOWN TO BE INVOLVED IN THE DEVELOPMENT OF AUTOIMMUNE DISEASES. IN THIS WORK WE AIMED TO IDENTIFY SIGNIFICANTLY DIFFERENTIALLY EXPRESSED LNCRNAS (DE-LNCRNAS) THAT ARE FUNCTIONALLY CONNECTED TO MODULATED GENES STRICTLY ASSOCIATED WITH RA. IN TOTAL, 542,500 TRANSCRIPTS HAVE BEEN PROFILED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) FROM FOUR PATIENTS WITH EARLY ONSET RA PRIOR ANY TREATMENT AND FOUR HEALTHY DONORS USING CLARIOM D ARRAYS. RESULTS WERE CONFIRMED BY REAL-TIME PCR IN 20 PATIENTS AND 20 CONTROLS. SIX DE-LNCRNAS TARGET EXPERIMENTALLY VALIDATED MIRNAS ABLE TO REGULATE DIFFERENTIALLY EXPRESSED GENES (DEGS) IN RA; AMONG THEM, ONLY FTX, HNRNPU-AS1 AND RP11-498C9.15 TARGETED A LARGE NUMBER OF DEGS. MOST IMPORTANTLY, RP11-498C9.15 TARGETED THE LARGEST NUMBER OF SIGNALLING PATHWAYS THAT WERE FOUND TO BE ENRICHED BY THE GLOBAL AMOUNT OF RA-DEGS AND THAT HAVE ALREADY BEEN ASSOCIATED WITH RA AND RA-SYNOVIOCYTES. MOREOVER, RP11-498C9.15 TARGETED THE MOST HIGHLY CONNECTED GENES IN THE RA INTERACTOME, THUS SUGGESTING ITS INVOLVEMENT IN CRUCIAL GENE REGULATION. THESE RESULTS INDICATE THAT, BY MODULATING BOTH MICRORNAS AND GENE EXPRESSION, RP11-498C9.15 MAY PLAY A PIVOTAL ROLE IN RA PATHOGENESIS.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  493  22 ASSESSMENT OF P53 AND ATM FUNCTIONALITY IN CHRONIC LYMPHOCYTIC LEUKEMIA BY MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION. THE ATM-P53 DNA-DAMAGE RESPONSE (DDR) PATHWAY HAS A CRUCIAL ROLE IN CHEMORESISTANCE IN CLL, AS INDICATED BY THE ADVERSE PROGNOSTIC IMPACT OF GENETIC ABERRATIONS OF TP53 AND ATM. IDENTIFYING AND DISTINGUISHING TP53 AND ATM FUNCTIONAL DEFECTS HAS BECOME RELEVANT AS EPIGENETIC AND POSTTRANSCRIPTIONAL DYSREGULATION OF THE ATM/P53 AXIS IS INCREASINGLY BEING RECOGNIZED AS THE UNDERLYING CAUSE OF CHEMORESISTANCE. ALSO, SPECIFIC TREATMENTS SENSITIZING TP53- OR ATM-DEFICIENT CLL CELLS ARE EMERGING. WE THEREFORE DEVELOPED A NEW ATM-P53 FUNCTIONAL ASSAY WITH THE AIM TO (I) IDENTIFY AND (II) DISTINGUISH ABNORMALITIES OF TP53 VERSUS ATM AND (III) ENABLE THE IDENTIFICATION OF ADDITIONAL DEFECTS IN THE ATM-P53 PATHWAY. REVERSED TRANSCRIPTASE MULTIPLEX LIGATION-DEPENDENT PROBE AMPLIFICATION (RT-MLPA) WAS USED TO MEASURE ATM AND/OR P53-DEPENDENT GENES AT THE RNA LEVEL FOLLOWING DNA DAMAGE USING IRRADIATION. HERE, WE SHOWED THAT THIS ASSAY IS ABLE TO IDENTIFY AND DISTINGUISH THREE SUBGROUPS OF CLL TUMORS (I.E., TP53-DEFECTIVE, ATM-DEFECTIVE AND WT) AND IS ALSO ABLE TO DETECT ADDITIONAL SAMPLES WITH A DEFECTIVE DDR, WITHOUT MOLECULAR ABERRATIONS IN TP53 AND/OR ATM. THESE FINDINGS MAKE THE ATM-P53 RT-MLPA FUNCTIONAL ASSAY A PROMISING PROGNOSTIC TOOL FOR PREDICTING TREATMENT RESPONSES IN CLL.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 2653  28 EPIGENOTYPING IN PERIPHERAL BLOOD CELL DNA AND BREAST CANCER RISK: A PROOF OF PRINCIPLE STUDY. BACKGROUND: EPIGENETIC CHANGES ARE EMERGING AS ONE OF THE MOST IMPORTANT EVENTS IN CARCINOGENESIS. TWO ALTERATIONS IN THE PATTERN OF DNA METHYLATION IN BREAST CANCER (BC) HAVE BEEN PREVIOUSLY REPORTED; ACTIVE ESTROGEN RECEPTOR-ALPHA (ER-ALPHA) IS ASSOCIATED WITH DECREASED METHYLATION OF ER-ALPHA TARGET (ERT) GENES, AND POLYCOMB GROUP TARGET (PCGT) GENES ARE MORE LIKELY THAN OTHER GENES TO HAVE PROMOTER DNA HYPERMETHYLATION IN CANCER. HOWEVER, WHETHER DNA METHYLATION IN NORMAL UNRELATED CELLS IS ASSOCIATED WITH BC RISK AND WHETHER THESE IMPRINTS CAN BE RELATED TO FACTORS WHICH CAN BE MODIFIED BY THE ENVIRONMENT, IS UNCLEAR. METHODOLOGY/PRINCIPAL FINDINGS: USING QUANTITATIVE METHYLATION ANALYSIS IN A CASE-CONTROL STUDY (N = 1,083) WE FOUND THAT DNA METHYLATION OF PERIPHERAL BLOOD CELL DNA PROVIDES GOOD PREDICTION OF BC RISK. WE ALSO REPORT THAT INVASIVE DUCTAL AND INVASIVE LOBULAR BC IS CHARACTERIZED BY TWO DIFFERENT SETS OF GENES, THE LATTER PARTICULAR BY GENES INVOLVED IN THE DIFFERENTIATION OF THE MESENCHYME (PITX2, TITF1, GDNF AND MYOD1). FINALLY WE DEMONSTRATE THAT ONLY ERT GENES PREDICT ER POSITIVE BC; LACK OF PERIPHERAL BLOOD CELL DNA METHYLATION OF ZNF217 PREDICTED BC INDEPENDENT OF AGE AND FAMILY HISTORY (ODDS RATIO 1.49; 95% CONFIDENCE INTERVAL 1.12-1.97; P = 0.006) AND WAS ASSOCIATED WITH ER-ALPHA BIOACTIVITY IN THE CORRESPONDING SERUM. CONCLUSION/SIGNIFICANCE: THIS FIRST LARGE-SCALE EPIGENOTYPING STUDY DEMONSTRATES THAT DNA METHYLATION MAY SERVE AS A LINK BETWEEN THE ENVIRONMENT AND THE GENOME. FACTORS THAT CAN BE MODULATED BY THE ENVIRONMENT (LIKE ESTROGENS) LEAVE AN IMPRINT IN THE DNA OF CELLS THAT ARE UNRELATED TO THE TARGET ORGAN AND INDICATE THE PREDISPOSITION TO DEVELOP A CANCER. FURTHER RESEARCH WILL NEED TO DEMONSTRATE WHETHER DNA METHYLATION PROFILES WILL BE ABLE TO SERVE AS A NEW TOOL TO PREDICT THE RISK OF DEVELOPING CHRONIC DISEASES WITH SUFFICIENT ACCURACY TO GUIDE PREVENTIVE MEASURES.	2008