1 268 135 AFLATOXIN B1 INDUCES PERSISTENT EPIGENOMIC EFFECTS IN PRIMARY HUMAN HEPATOCYTES ASSOCIATED WITH HEPATOCELLULAR CARCINOMA. CHRONIC EXPOSURE TO AFLATOXIN B1 (AFB1) HAS, IN CERTAIN REGIONS IN THE WORLD, BEEN STRONGLY ASSOCIATED WITH HEPATOCELLULAR CARCINOMA (HCC) DEVELOPMENT. AFB1 IS A VERY POTENT HEPATOTOXIC AND CARCINOGENIC MYCOTOXIN WHICH IS FREQUENTLY REPORTED AS A FOOD CONTAMINANT. EPIGENETIC MODIFICATIONS PROVOKED BY ENVIRONMENTAL EXPOSURES, SUCH AS AFB1, MAY CREATE A PERSISTENT EPIGENETIC FOOTPRINT. DEREGULATION OF EPIGENETIC MECHANISMS HAS ACTUALLY BEEN REPORTED IN HCC PATIENTS FOLLOWING AFB1 EXPOSURE; HOWEVER, NO ATTEMPTS HAVE YET BEEN MADE TO INVESTIGATE EARLY EFFECTS ON THE EPIGENOME LEVEL WHICH MAY BE PERSISTENT ON LONGER TERM, THEREBY POSSIBLY INITIATING CARCINOGENIC EVENTS. IN THIS STUDY, WE AIM TO IDENTIFY METHYL DNA-MRNA-INTERACTIONS REPRESENTATIVE FOR A PERSISTENT EPIGENETIC FOOTPRINT ASSOCIATED WITH THE EARLY ONSET OF AFB1-INDUCED HCC. FOR THIS, PRIMARY HUMAN HEPATOCYTES WERE EXPOSED TO 0.3MUM OF AFB1 FOR 5 DAYS. PERSISTENT EPIGENETIC EFFECTS WERE MEASURED 3 DAYS AFTER TERMINATING THE CARCINOGENIC EXPOSURE. WHOLE GENOME DNA METHYLATION CHANGES AND WHOLE GENOME TRANSCRIPTOMIC ANALYSIS WERE ANALYZED APPLYING MICROARRAY TECHNOLOGIES, AND CROSS-OMICS INTERACTIONS WERE EVALUATED. UPON COMBINING TRANSCRIPTOMICS DATA WITH RESULTS ON DNA METHYLATION, A RANGE OF PERSISTENT HYPER- AND HYPO-METHYLATED GENES WAS IDENTIFIED WHICH ALSO APPEARED AFFECTED ON THE TRANSCRIPTOME LEVEL. FOR SIX OF THE HYPO-METHYLATED AND UP-REGULATED GENES, NAMELY TXNRD1, PCNA, CCNK, DIAPH3, RAB27A AND HIST1H2BF, A CLEAR ROLE IN CARCINOGENIC EVENTS COULD BE IDENTIFIED. THIS STUDY IS THE FIRST TO REPORT ON A CARCINOGEN-INDUCED PERSISTENT IMPACT ON THE EPIGENETIC FOOTPRINT IN RELATION WITH THE TRANSCRIPTOME WHICH COULD BE INDICATIVE FOR THE EARLY ONSET OF AFB1-RELATED DEVELOPMENT OF HCC. 2016 2 1545 38 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 3 1615 33 DNA METHYLTRANSFERASE 3B PLAYS A PROTECTIVE ROLE AGAINST HEPATOCARCINOGENESIS CAUSED BY CHRONIC INFLAMMATION VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. MOST HEPATOCELLULAR CARCINOMAS (HCCS) DEVELOP ON THE BASIS OF CHRONIC HEPATITIS, BUT THE MECHANISM OF EPIGENETIC REGULATION IN INFLAMMATORY HEPATOCARCINOGENESIS HAS YET TO BE ELUCIDATED. AMONG DE NOVO DNA METHYLTRANSFERASES (DNMTS), DNMT3B HAS LATELY BEEN REPORTED TO ACT SPECIFICALLY ON ACTIVELY TRANSCRIBED GENES, SUGGESTING THE POSSIBILITY THAT IT PLAYS A ROLE IN THE PATHOGENESIS OF CANCER. WE CONFIRMED THAT DNMT3B ISOFORMS LACKING ITS CATALYTIC DOMAIN WERE HIGHLY EXPRESSED IN HCCS COMPARED WITH NON-TUMOROUS LIVER TISSUE. TO ELUCIDATE THE ROLE OF DNMT3B IN HEPATOCARCINOGENESIS, WE GENERATED A GENETICALLY ENGINEERED MOUSE MODEL WITH HEPATOCYTE-SPECIFIC DNMT3B DELETION. THE LIVER OF THE DNMT3B-DEFICIENT MICE EXHIBITED AN EXACERBATION OF THIOACETAMIDE-INDUCED HEPATITIS, PROGRESSION OF LIVER FIBROSIS AND A HIGHER INCIDENCE OF HCC COMPARED WITH THE LIVER OF THE CONTROL MICE. WHOLE-GENOME BISULFITE SEQUENCING VERIFIED A LOWER CG METHYLATION LEVEL IN THE DNMT3B-DEFICIENT LIVER, DEMONSTRATING DIFFERENTIALLY METHYLATED REGIONS THROUGHOUT THE GENOME. TRANSCRIPTOME ANALYSIS REVEALED DECREASED EXPRESSION OF GENES RELATED TO OXIDATIVE PHOSPHORYLATION IN THE DNMT3B-DEFICIENT LIVER. MOREOVER, PRIMARY HEPATOCYTES ISOLATED FROM THE DNMT3B-DEFICIENT MICE SHOWED REDUCED MITOCHONDRIAL RESPIRATORY CAPACITY, LEADING TO THE ENHANCEMENT OF OXIDATIVE STRESS IN THE LIVER TISSUE. OUR FINDINGS SUGGEST THE PROTECTIVE ROLE OF DNMT3B AGAINST CHRONIC INFLAMMATION AND HCC DEVELOPMENT VIA MAINTAINING MITOCHONDRIAL HOMEOSTASIS. 2020 4 6488 37 TP53 R72P POLYMORPHISM MODULATES DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS CHARACTERIZED BY WIDESPREAD EPIDEMIOLOGICAL AND MOLECULAR HETEROGENEITY. PREVIOUS WORK SHOWED THAT IN THE WESTERN PART OF NORTH AFRICA, A REGION OF LOW INCIDENCE OF HCC, MUTATIONS ARE SCARCE FOR THIS TUMOR TYPE. AS EPIGENETIC CHANGES ARE CONSIDERED POSSIBLE SURROGATES TO MUTATIONS IN HUMAN CANCERS, WE DECIDED, THUS, TO CHARACTERIZE DNA METHYLATION IN HCC FROM NORTH-AFRICAN PATIENTS. METHODS: A SET OF 11 LOCI WAS INVESTIGATED IN A SERIES OF 45 TUMOR SPECIMENS USING METHYLATION-SPECIFIC AND COMBINED-BISULFITE RESTRICTION ASSAY PCR. RESULTS OBTAINED ON CLINICAL SAMPLES WERE SUBSEQUENTLY VALIDATED IN LIVER CANCER CELL LINES. RESULTS: DNA METHYLATION AT TUMOR SUPPRESSOR LOCI IS SIGNIFICANTLY HIGHER IN SAMPLES DISPLAYING CHROMOSOME INSTABILITY. MORE IMPORTANTLY, DNA METHYLATION WAS SIGNIFICANTLY HIGHER IN ARG/ARG WHEN COMPARED TO PRO/PRO GENOTYPE CARRIERS AT CODON 72 RS1042522 OF TP53 (65% VS 20% METHYLATED LOCI, P = 0.0006), A POLYMORPHISM ALREADY KNOWN TO AFFECT SOMATIC MUTATION RATE IN HUMAN CARCINOMAS. IN VITRO EXPERIMENTS IN CELL LINES INDICATED THAT ENZYMES CONTROLLING DNA METHYLATION WERE DIFFERENTIALLY REGULATED BY CODON 72 ARG OR PRO ISOFORMS OF P53. FURTHERMORE, THE ARG72-CARRYING VERSION OF P53 WAS SHOWN TO RE-METHYLATE DNA MORE RAPIDLY THAN THE PRO-HARBORING ISOFORM. FINALLY, PRO-CARRYING CELL LINES WERE SHOWN TO BE SIGNIFICANTLY MORE RESISTANT TO DECITABINE TREATMENT (TWO-FOLD, P = 0.005). CONCLUSIONS: OUR DATA SUGGEST THAT ARG72PRO POLYMORPHISM IN A WT P53 CONTEXT MAY ACT AS A PRIMARY DRIVER OF EPIGENETIC CHANGES IN HCC. IT SUGGESTS, IN ADDITION, THAT RS1042522 GENOTYPE MAY PREDICT SENSITIVITY TO EPIGENETIC-TARGETED THERAPY. THIS MODEL OF LIVER TUMORIGENESIS THAT ASSOCIATES LOW PENETRANCE GENETIC PREDISPOSITION TO EPIGENETIC CHANGES EMERGES FROM A REGION OF LOW HCC INCIDENCE AND IT MAY, THEREFORE, APPLY ESSENTIALLY TO POPULATION LIVING IN SIMILAR AREAS. SURVEYS ON POPULATIONS SUBMITTED TO HIGHLY MUTAGENIC CONDITIONS AS PERINATALLY-ACQUIRED CHRONIC HEPATITIS B OR AFLATOXIN B1 EXPOSURE REMAINED TO BE CONDUCTED TO VALIDATE OUR OBSERVATIONS AS A GENERAL MODEL. 2015 5 416 36 ANALYSIS OF THE DYNAMIC ABERRANT LANDSCAPE OF DNA METHYLATION AND GENE EXPRESSION DURING ARSENIC-INDUCED CELL TRANSFORMATION. INORGANIC ARSENIC IS A WELL-KNOWN CARCINOGEN ASSOCIATED WITH SEVERAL TYPES OF CANCER, BUT THE MECHANISMS INVOLVED IN ARSENIC-INDUCED CARCINOGENESIS ARE NOT FULLY UNDERSTOOD. RECENT EVIDENCE POINTS TO EPIGENETIC DYSREGULATION AS AN IMPORTANT MECHANISM IN THIS PROCESS; HOWEVER, THE EFFECTS OF EPIGENETIC ALTERATIONS IN GENE EXPRESSION HAVE NOT BEEN EXPLORED IN DEPTH. USING MICROARRAY DATA AND APPLYING A MULTIVARIATE CLUSTERING ANALYSIS IN A GAUSSIAN MIXTURE MODEL, WE DESCRIBE THE ALTERATIONS IN DNA METHYLATION AROUND THE PROMOTER REGION AND THE IMPACT ON GENE EXPRESSION IN HACAT CELLS DURING THE TRANSFORMATION PROCESS CAUSED BY CHRONIC EXPOSURE TO ARSENIC. USING THIS CLUSTERING APPROACH, THE GENES WERE GROUPED ACCORDING TO THEIR METHYLATION AND EXPRESSION STATUS IN THE EPIGENETIC LANDSCAPE, AND THE CHANGES THAT OCCURRED DURING THE CELLULAR TRANSFORMATION WERE IDENTIFIED ADEQUATELY. THUS, WE PRESENT A VALUABLE METHOD FOR IDENTIFYING EPIGENOMIC DYSREGULATION. 2019 6 3824 37 INVESTIGATING THE EPIGENETIC EFFECTS OF A PROTOTYPE SMOKE-DERIVED CARCINOGEN IN HUMAN CELLS. GLOBAL LOSS OF DNA METHYLATION AND LOCUS/GENE-SPECIFIC GAIN OF DNA METHYLATION ARE TWO DISTINCT HALLMARKS OF CARCINOGENESIS. ABERRANT DNA METHYLATION IS IMPLICATED IN SMOKING-RELATED LUNG CANCER. IN THIS STUDY, WE HAVE COMPREHENSIVELY INVESTIGATED THE MODULATION OF DNA METHYLATION CONSEQUENT TO CHRONIC EXPOSURE TO A PROTOTYPE SMOKE-DERIVED CARCINOGEN, BENZO[A]PYRENE DIOL EPOXIDE (B[A]PDE), IN GENOMIC REGIONS OF SIGNIFICANCE IN LUNG CANCER, IN NORMAL HUMAN CELLS. WE HAVE USED A PULLDOWN ASSAY FOR ENRICHMENT OF THE CPG METHYLATED FRACTION OF CELLULAR DNA COMBINED WITH MICROARRAY PLATFORMS, FOLLOWED BY EXTENSIVE VALIDATION THROUGH CONVENTIONAL BISULFITE-BASED ANALYSIS. HERE, WE DEMONSTRATE STRIKINGLY SIMILAR PATTERNS OF DNA METHYLATION IN NON-TRANSFORMED B[A]PDE-TREATED CELLS VS CONTROL USING HIGH-THROUGHPUT MICROARRAY-BASED DNA METHYLATION PROFILING CONFIRMED BY CONVENTIONAL BISULFITE-BASED DNA METHYLATION ANALYSIS. THE ABSENCE OF ABERRANT DNA METHYLATION IN OUR MODEL SYSTEM WITHIN A TIMEFRAME THAT PRECEDES CELLULAR TRANSFORMATION SUGGESTS THAT FOLLOWING CARCINOGEN EXPOSURE, OTHER AS YET UNKNOWN FACTORS (SECONDARY TO CARCINOGEN TREATMENT) MAY HELP INITIATE GLOBAL LOSS OF DNA METHYLATION AND REGION-SPECIFIC GAIN OF DNA METHYLATION, WHICH CAN, IN TURN, CONTRIBUTE TO LUNG CANCER DEVELOPMENT. UNVEILING THE INITIATING EVENTS THAT CAUSE ABERRANT DNA METHYLATION IN LUNG CANCER HAS TREMENDOUS PUBLIC HEALTH RELEVANCE, AS IT CAN HELP DEFINE FUTURE STRATEGIES FOR EARLY DETECTION AND PREVENTION OF THIS HIGHLY LETHAL DISEASE. 2010 7 1587 32 DNA METHYLATION PROFILING IDENTIFIES NOVEL MARKERS OF PROGRESSION IN HEPATITIS B-RELATED CHRONIC LIVER DISEASE. BACKGROUND: CHRONIC HEPATITIS B INFECTION IS CHARACTERIZED BY HEPATIC IMMUNE AND INFLAMMATORY RESPONSE WITH CONSIDERABLE VARIATION IN THE RATES OF PROGRESSION TO CIRRHOSIS. GENETIC VARIANTS AND ENVIRONMENTAL CUES INFLUENCE PREDISPOSITION TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE; HOWEVER, IT REMAINS UNKNOWN IF ABERRANT DNA METHYLATION IS ASSOCIATED WITH FIBROSIS PROGRESSION IN CHRONIC HEPATITIS B. RESULTS: TO IDENTIFY EPIGENETIC MARKS ASSOCIATED WITH INFLAMMATORY AND FIBROTIC PROCESSES OF THE HEPATITIS B-INDUCED CHRONIC LIVER DISEASE, WE CARRIED OUT HEPATIC GENOME-WIDE METHYLATION PROFILING USING ILLUMINA INFINIUM BEADARRAYS COMPARING MILD AND SEVERE FIBROTIC DISEASE IN A DISCOVERY COHORT OF 29 PATIENTS. WE OBTAINED 310 DIFFERENTIALLY METHYLATED REGIONS AND SELECTED FOUR LOCI COMPRISING THREE GENES FROM THE TOP DIFFERENTIALLY METHYLATED REGIONS: HYPERMETHYLATION OF HOXA2 AND HDAC4 ALONG WITH HYPOMETHYLATION OF PPP1R18 WERE SIGNIFICANTLY LINKED TO SEVERE FIBROSIS. WE REPLICATED THE PROMINENT METHYLATION MARKS IN AN INDEPENDENT COHORT OF 102 PATIENTS BY BISULFITE MODIFICATION AND PYROSEQUENCING. THE TIMING AND CAUSAL RELATIONSHIP OF EPIGENETIC MODIFICATIONS WITH DISEASE SEVERITY WAS FURTHER INVESTIGATED USING A COHORT OF PATIENTS WITH SERIAL BIOPSIES. CONCLUSIONS: OUR FINDINGS SUGGEST A LINKAGE OF WIDESPREAD EPIGENETIC DYSREGULATION WITH DISEASE PROGRESSION IN CHRONIC HEPATITIS B INFECTION. CPG METHYLATION AT NOVEL GENES SHEDS LIGHT ON NEW MOLECULAR PATHWAYS, WHICH CAN BE POTENTIALLY EXPLOITED AS A BIOMARKER OR TARGETED TO ATTENUATE INFLAMMATION AND FIBROSIS. 2016 8 1567 36 DNA METHYLATION OF THE KLF14 GENE REGION IN WHOLE BLOOD CELLS PROVIDES PREDICTION FOR THE CHRONIC INFLAMMATION IN THE ADIPOSE TISSUE. KRUPPEL-LIKE FACTOR 14 (KLF14) GENE, WHICH APPEARS TO BE A MASTER REGULATOR OF GENE EXPRESSION IN THE ADIPOSE TISSUE AND HAVE PREVIOUSLY BEEN ASSOCIATED WITH BMI AND TYPE 2 DIABETES (T2D) BY LARGE GENOME-WIDE ASSOCIATION STUDIES. IN ORDER TO FIND PREDICTIVE BIOMARKERS FOR THE DEVELOPMENT OF T2D, IT IS NECESSARY TO TAKE EPIGENOMIC CHANGES AFFECTED BY ENVIRONMENTAL FACTORS INTO ACCOUNT. THIS STUDY FOCUSES ON AGEING AND OBESITY, WHICH ARE T2D RISK FACTORS, AND EXAMINES EPIGENETIC CHANGES AND INFLAMMATORY CHANGES. WE INVESTIGATED DNA METHYLATION CHANGES IN THE KLF14 PROMOTER REGION IN DIFFERENT ORGANS OF MICE FOR COMPARING AGING AND WEIGHT. WE FOUND THAT METHYLATION LEVELS OF THESE SITES WERE INCREASED WITH AGING AND WEIGHT IN THE SPLEEN, THE ADIPOSE TISSUE, THE KIDNEY, THE LUNG, THE COLON AND THE WHOLE BLOOD CELLS. IN ADDITION, IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD, THESE EPIGENETIC CHANGES WERE ALSO SIGNIFICANTLY ASSOCIATED WITH INFLAMMATORY LEVELS. MOREOVER, NOT ONLY KLF14, BUT ALSO EXPRESSION LEVELS OF SOME DOWNSTREAM GENES WERE DECREASED WITH METHYLATION IN THE SPLEEN, THE ADIPOSE TISSUE AND THE WHOLE BLOOD CELLS. TAKEN TOGETHER, OUR RESULTS SUGGEST THAT METHYLATION CHANGES OF KLF14 IN THOSE TISSUES MAY BE ASSOCIATED WITH CHANGES IN GENE EXPRESSION AND INFLAMMATION ON THE ADIPOSE TISSUE OF OBESITY AND T2D. IN ADDITION, THE METHYLATION CHANGES IN THE WHOLE BLOOD CELLS MAY SERVE AS A PREDICTIVE EPIGENETIC BIOMARKER FOR THE DEVELOPMENT OF T2D. 2018 9 309 23 ALCOHOL AND HEPATOCELLULAR CARCINOMA: ADDING FUEL TO THE FLAME. PRIMARY TUMORS OF THE LIVER REPRESENT THE FIFTH MOST COMMON TYPE OF CANCER IN THE WORLD AND THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH. CASE-CONTROL STUDIES FROM DIFFERENT COUNTRIES REPORT THAT CHRONIC ETHANOL CONSUMPTION IS ASSOCIATED WITH AN APPROXIMATELY 2-FOLD INCREASED ODDS RATIO FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE THE SUBSTANTIAL EPIDEMIOLOGIC DATA IN HUMANS DEMONSTRATING THAT CHRONIC ALCOHOL CONSUMPTION IS A MAJOR RISK FACTOR FOR HCC DEVELOPMENT, THE PATHWAYS CAUSING ALCOHOL-INDUCED LIVER CANCER ARE POORLY UNDERSTOOD. IN THIS OVERVIEW, WE SUMMARIZE THE EPIDEMIOLOGICAL EVIDENCE FOR THE ASSOCIATION BETWEEN ALCOHOL AND LIVER CANCER, REVIEW THE GENETIC, ONCOGENIC, AND EPIGENETIC FACTORS THAT DRIVE HCC DEVELOPMENT SYNERGISTICALLY WITH ETHANOL INTAKE AND DISCUSS THE ESSENTIAL MOLECULAR AND METABOLIC PATHWAYS INVOLVED IN ALCOHOL-INDUCED LIVER TUMORIGENESIS. 2017 10 332 44 ALTERATION OF EPIGENETIC PROFILE IN HUMAN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL IMPLICATIONS. HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON CANCER WORLDWIDE AND DEVELOPS AGAINST A BACKGROUND OF CHRONIC LIVER DAMAGE. A VARIETY OF HCC-RELATED GENES ARE KNOWN TO BE ALTERED BY GENETIC AND EPIGENETIC MECHANISMS. THEREFORE, INFORMATION REGARDING ALTERATION OF THE GENETIC AND EPIGENETIC PROFILES IN HCC IS ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF THIS TYPE OF TUMOR. METHYLATION AT CPG SITES IN GENE PROMOTERS IS KNOWN TO AFFECT THE TRANSCRIPTION OF THE CORRESPONDING GENES. ABNORMAL REGIONAL HYPERMETHYLATION IS OBSERVED IN THE 5' REGION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) IN HCC, AND THIS HYPERMETHYLATION MAY PROMOTE CARCINOGENESIS THROUGH THE TRANSCRIPTIONAL INACTIVATION OF DOWNSTREAM TSGS. THE DNA DAMAGE INDUCED BY OXIDATION IS A TRIGGER OF ABNORMAL DNA METHYLATION AND INACTIVATION OF TSGS THROUGH RECRUITMENT OF THE POLYCOMB REPRESSIVE COMPLEX TO THE PROMOTER SEQUENCE. THUS, OXIDATIVE STRESS MAY BE RESPONSIBLE FOR THE EMERGENCE OF HCC FROM CHRONIC HEPATITIS AND LIVER CIRRHOSIS THROUGH THE EPIGENETIC ALTERATION OF TSGS. THERE HAVE BEEN SEVERAL ATTEMPTS TO APPLY EPIGENETIC INFORMATION TO THE DIAGNOSIS AND TREATMENT OF HCC. THE PREDICTIVE VALUE OF SELECTED METHYLATION EVENTS ON SURVIVAL IN HCC PATIENTS HAS BEEN REPORTED, AND THE METHYLATION PROFILE OF BACKGROUND LIVER COULD BE ASSOCIATED WITH RECURRENCE-FREE SURVIVAL OF HCC PATIENTS WHO HAVE UNDERGONE HEPATECTOMY. ANOTHER STUDY DETECTED METHYLATED DNA FROM HCC CELLS IN SERUM, AND THE CIRCULATING TUMOR DNA WAS REGARDED AS A POTENTIAL TUMOR MARKER. IN ADDITION, SEVERAL TRIALS OF HCC THERAPY HAVE TARGETED THE EPIGENETIC MACHINERY AND WERE BASED UPON COMPREHENSIVE ANALYSES OF DNA METHYLATION OF THIS TYPE OF TUMOR. HERE, WE PRESENT AN OVERVIEW OF RESEARCH REGARDING DNA METHYLATION STATUS IN HUMAN HCC AND DESCRIBE THE CLINICAL APPLICATION OF EPIGENETIC INFORMATION TO HCC. 2014 11 1655 33 DOSE-DEPENDENCE, SEX- AND TISSUE-SPECIFICITY, AND PERSISTENCE OF RADIATION-INDUCED GENOMIC DNA METHYLATION CHANGES. RADIATION IS A WELL-KNOWN GENOTOXIC AGENT AND HUMAN CARCINOGEN THAT GIVES RISE TO A VARIETY OF LONG-TERM EFFECTS. ITS DETRIMENTAL INFLUENCE ON CELLULAR FUNCTION IS ACTIVELY STUDIED NOWADAYS. ONE OF THE MOST ANALYZED, YET LEAST UNDERSTOOD LONG-TERM EFFECTS OF IONIZING RADIATION IS TRANSGENERATIONAL GENOMIC INSTABILITY. THE INHERITANCE OF GENOMIC INSTABILITY SUGGESTS THE POSSIBLE INVOLVEMENT OF EPIGENETIC MECHANISMS, SUCH AS CHANGES OF THE METHYLATION OF CYTOSINE RESIDUES LOCATED WITHIN CPG DINUCLEOTIDES. IN THE CURRENT STUDY WE EVALUATED THE DOSE-DEPENDENCE OF THE RADIATION-INDUCED GLOBAL GENOME DNA METHYLATION CHANGES. WE ALSO ANALYZED THE EFFECTS OF ACUTE AND CHRONIC HIGH DOSE (5GY) EXPOSURE ON DNA METHYLATION IN LIVER, SPLEEN, AND LUNG TISSUES OF MALE AND FEMALE MICE AND EVALUATED THE POSSIBLE PERSISTENCE OF THE RADIATION-INDUCED DNA METHYLATION CHANGES. HERE WE REPORT THAT RADIATION-INDUCED DNA METHYLATION CHANGES WERE SEX- AND TISSUE-SPECIFIC, DOSE-DEPENDENT, AND PERSISTENT. IN PARALLEL WE HAVE STUDIED THE LEVELS OF DNA DAMAGE IN THE EXPOSED TISSUES. BASED ON THE CORRELATION BETWEEN THE LEVELS OF DNA METHYLATION AND DNA DAMAGE WE PROPOSE THAT RADIATION-INDUCED GLOBAL GENOME DNA HYPOMETHYLATION IS DNA REPAIR-RELATED. 2004 12 5785 29 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 6848 37 [MOLECULAR GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR TYPE OF PRIMARY LIVER CANCER AND ONE OF THE MOST FREQUENT HUMAN MALIGNANT NEOPLASMS. COMMON RISK FACTORS OF HUMAN HCC INCLUDE CHRONIC HEPATITIS VIRUS (HBV AND HCV) INFECTION, DIETARY AFLATOXIN B1 (AFB1) INGESTION, CHRONIC ALCOHOL ABUSE, AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES. HEPATOCARCINOGENESIS IS THE RESULT OF INTERACTION BETWEEN HEREDITARY AND ENVIRONMENTAL FACTORS. INHERITANCE DETERMINES INDIVIDUAL SUSCEPTIBILITY TO CANCER; ENVIRONMENT DETERMINES WHICH SUSCEPTIBLE INDIVIDUALS EXPRESS CANCER. STUDIES OF GENETIC AND EPIGENETIC MECHANISMS OF HEPATOCARCINOGENESIS SHOWED THAT HCC DEVELOPMENT IS A COMPLEX POLYGENE AND MULTIPATHWAY PROCESS; THE ACTIVATION OF PROTO-ONCOGENES AND THE INACTIVATION OF TUMOR SUPPRESSOR GENES INDUCED BY GENETIC AND EPIGENETIC ALTERATIONS ARE CORE BIOLOGICAL PROCESSES OF HEPATOCARCINOGENESIS; RB1, P53, AND WNT PATHWAYS ARE COMMONLY AFFECTED IN HCCS OF DIFFERENT ETIOLOGIES, WHICH MAY REFLECT COMMON PATHOLOGIC SEQUENCE OF HCC: CHRONIC LIVER INJURY, CIRRHOSIS, ATYPICAL HYPERPLASTIC NODULES, AND HCC OF EARLY STAGES. HEPATITIS VIRUS INFECTION-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN RB1 PATHWAY, INCLUDING METHYLATION OF P16INK4A AND RB1 GENES AND AMPLIFICATION OF CYCLIN D1. AFB1 EXPOSURE-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN P53 PATHWAY; THE G-->T MUTATION OF P53 GENE AT CODON 249 HAS BEEN IDENTIFIED AS A GENETIC HALLMARK OF HCC CAUSED BY AFB1. ALCOHOLISM-ASSOCIATED HCCS HAVE FREQUENT ALTERATIONS IN BOTH RB1 AND P53 PATHWAYS. THE ROLES OF SOME IMPORTANT GENES RELATED TO CELL APOPTOSIS, DNA REPAIR, DRUG METABOLISM, AND TUMOR METASTASIS IN HEPATOCARCINOGENESIS HAD BEEN DISCUSSED. 2005 14 2653 40 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 15 6092 28 THE EFFECTS OF EPIGENETIC MODIFICATION ON THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES AND THE INVOLVED MECHANISM. INTRODUCTION: EPIGENETIC MODIFICATION IS A TYPE OF GENE EXPRESSION AND REGULATION THAT DOES NOT INVOLVE CHANGES IN DNA SEQUENCES. AN INCREASING NUMBER OF STUDIES HAVE PROVEN THAT EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES THROUGH THE GENE REGULATION AND PROTEIN EXPRESSIONS OF HEPATOCELLULAR LIPID METABOLISM, INFLAMMATORY REACTION, CELL PROLIFERATION, AND ACTIVATION, ETC.AREAS COVERED: IN THIS STUDY, WE ELABORATED AND ANALYZED THE UNDERLYING FUNCTIONAL MECHANISM OF EPIGENETIC MODIFICATION IN ALCOHOLIC LIVER DISEASE (ALD), NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), LIVER FIBROSIS (LF), VIRAL HEPATITIS, HEPATOCELLULAR CARCINOMA (HCC), AND RESEARCH PROGRESS OF RECENT YEARS.EXPERT OPINION: THE FURTHER UNDERSTANDING OF EPIGENETIC MECHANISMS THAT CAN REGULATE GENE EXPRESSION AND CELL PHENOTYPE LEADS TO NEW INSIGHTS IN EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE. CURRENTLY, HEPATOLOGISTS ARE EXPLORING THE ROLE OF DNA METHYLATION, HISTONE/CHROMATIN MODIFICATION, AND NON-CODING RNA IN SPECIFIC LIVER PATHOLOGY. THESE FINDINGS HAVE LED TO ADVANCES IN DIRECT EPIGENETIC BIOMARKER TESTING OF PATIENT TISSUE OR BODY FLUID SPECIMENS, AS WELL AS QUANTITATIVE ANALYSIS. BASED ON THESE FINDINGS, DRUG VALIDATION OF SOME TARGETS INVOLVED IN THE EPIGENETIC MECHANISM OF LIVER DISEASE IS GRADUALLY BEING CARRIED OUT CLINICALLY. 2020 16 6798 28 [EPIDEMIOLOGY, RISK FACTORS AND MOLECULAR PATHOGENESIS OF PRIMARY LIVER CANCER]. PRIMARY LIVER CANCER IS THE FIFTH MOST COMMON CANCER WORLDWIDE. HEPATOCELLULAR CARCINOMA ACCOUNTS FOR 85-90% OF PRIMARY LIVER CANCERS. DISTRIBUTION OF HEPATOCELLULAR CARCINOMA SHOWS VARIATIONS AMONG GEOGRAPHIC REGIONS AND ETHNIC GROUPS. MALES HAVE HIGHER LIVER CANCER RATES THAN FEMALES. HEPATOCELLULAR CARCINOMA OCCURS WITHIN AN ESTABLISHED BACKGROUND OF CHRONIC LIVER DISEASE AND CIRRHOSIS (70-90%). MAJOR CAUSES (80%) OF HEPATOCELLULAR CARCINOMA ARE HEPATITIS B, C VIRUS INFECTION, AND AFLATOXIN EXPOSITION. ITS DEVELOPMENT IS A MULTISTEP PROCESS. WE HAVE A GROWING UNDERSTANDING ON THE MOLECULAR PATHOGENESIS. GENETIC AND EPIGENETIC CHANGES ACTIVATE ONCOGENES, INHIBIT TUMORSUPPRESSOR GENES, WHICH RESULT IN AUTONOMOUS CELL PROLIFERATION. THE CHROMOSOMAL INSTABILITY CAUSED BY TELOMERE DYSFUNCTION, THE GROWTH-RETRAINED ENVIRONMENT AND THE ALTERATIONS OF THE MICRO- AND MACROENVIRONMENT HELP THE EXPANSION OF THE MALIGNANT CELLS. UNDERSTANDING THE MOLECULAR MECHANISMS COULD IMPROVE THE SCREENING OF PATIENTS WITH CHRONIC LIVER DISEASE, OR CIRRHOSIS, AND THE PREVENTION AS WELL AS TREATMENT OF HEPATOCELLULAR CARCINOMA. 2008 17 4056 40 MAPPING THE HETEROGENEITY OF HISTONE MODIFICATIONS ON HEPATITIS B VIRUS DNA USING LIVER NEEDLE BIOPSIES OBTAINED FROM CHRONICALLY INFECTED PATIENTS. COVALENTLY CLOSED CIRCULAR DNA (CCCDNA) FORMS THE BASIS FOR REPLICATION AND PERSISTENCE OF HEPATITIS B VIRUS (HBV) IN THE CHRONICALLY INFECTED LIVER. WE HAVE PREVIOUSLY SHOWN THAT VIRAL TRANSCRIPTION IS SUBJECT TO REGULATION BY POSTTRANSLATIONAL MODIFICATIONS (PTMS) OF HISTONE PROTEINS BOUND TO CCCDNA THROUGH ANALYSIS OF DE NOVO HBV-INFECTED CELL LINES. WE NOW REPORT THE SUCCESSFUL ADAPTATION OF THIS CHROMATIN IMMUNOPRECIPITATION SEQUENCING (CHIPSEQ) APPROACH FOR ANALYSIS OF FINE-NEEDLE PATIENT LIVER BIOPSY SPECIMENS TO INVESTIGATE THE ROLE OF HISTONE PTMS IN CHRONICALLY HBV-INFECTED PATIENTS. USING 18 SPECIMENS FROM PATIENTS IN DIFFERENT STAGES OF CHRONIC HBV INFECTION, OUR WORK SHOWS THAT THE PROFILE OF HISTONE PTMS IN CHRONIC INFECTION IS MORE NUANCED THAN PREVIOUSLY OBSERVED IN IN VITRO MODELS OF ACUTE INFECTION. IN LINE WITH OUR PREVIOUS FINDINGS, WE FIND THAT THE MAJORITY OF HBV-DERIVED SEQUENCES ARE ASSOCIATED WITH THE ACTIVATING HISTONE PTM H3K4ME3. HOWEVER, WE SHOW A STRIKING INTERPATIENT VARIABILITY OF ITS DEPOSITION IN THIS PATIENT COHORT CORRELATED WITH VIRAL TRANSCRIPTION AND PATIENT HBV EARLY ANTIGEN (HBEAG) STATUS. UNEXPECTEDLY, WE DETECTED DEPOSITION OF THE CLASSICAL INHIBITORY HISTONE PTM H3K9ME3 ON HBV-DNA IN AROUND HALF OF THE PATIENT BIOPSY SPECIMENS, WHICH COULD NOT BE LINKED TO REDUCED LEVELS OF VIRAL TRANSCRIPTS. OUR RESULTS SHOW THAT CURRENT IN VITRO MODELS ARE UNABLE TO FULLY RECAPITULATE THE COMPLEX EPIGENETIC LANDSCAPE OF CHRONIC HBV INFECTION OBSERVED IN VIVO AND DEMONSTRATE THAT FINE-NEEDLE LIVER BIOPSY SPECIMENS CAN PROVIDE SUFFICIENT MATERIAL TO FURTHER INVESTIGATE THE INTERACTION OF VIRAL AND HOST PROTEINS ON HBV-DNA.IMPORTANCE HEPATITIS B VIRUS (HBV) IS A MAJOR GLOBAL HEALTH CONCERN, CHRONICALLY INFECTING MILLIONS OF PATIENTS AND CONTRIBUTING TO A RISING BURDEN OF LIVER DISEASE. THE VIRAL GENOME FORMS THE BASIS FOR CHRONIC INFECTION AND HAS BEEN SHOWN TO BE SUBJECT TO REGULATION BY EPIGENETIC MECHANISMS, SUCH AS POSTTRANSLATIONAL MODIFICATION OF HISTONE PROTEINS. HERE, WE CONFIRM AND EXPAND ON PREVIOUS RESULTS BY ADAPTING A HIGH-RESOLUTION TECHNIQUE FOR ANALYSIS OF HISTONE MODIFICATIONS FOR USE WITH PATIENT-DERIVED FINE-NEEDLE LIVER BIOPSY SPECIMENS. OUR WORK HIGHLIGHTS THAT THE SITUATION IN VIVO IS MORE COMPLEX THAN PREDICTED BY CURRENT IN VITRO MODELS, FOR EXAMPLE, BY SUGGESTING A NOVEL, NONCANONICAL ROLE OF THE HISTONE MODIFICATION H3K9ME3 IN THE HBV LIFE CYCLE. IMPORTANTLY, ENABLING THE USE OF FINE-NEEDLE LIVER BIOPSY SPECIMENS FOR SUCH HIGH-RESOLUTION ANALYSES MAY FACILITATE FURTHER RESEARCH INTO THE EPIGENETIC REGULATION OF THE HBV GENOME. 2019 18 6707 29 VIRAL HEPATITIS AND HEPATOCELLULAR CARCINOMA: STATE OF THE ART. VIRAL HEPATITIS IS ONE OF THE MAIN CAUSES LEADING TO HEPATOCELLULAR CARCINOMA (HCC). THE CONTINUED RISE IN INCIDENCE OF HCC SUGGESTS ADDITIONAL FACTORS FOLLOWING INFECTION MAY BE INVOLVED. THIS REVIEW EXAMINES RECENT STUDIES INVESTIGATING THE MOLECULAR MECHANISMS OF CHRONIC HEPATITIS AND ITS ASSOCIATION WITH HEPATOCARCINOGENESIS. HEPATITIS B VIRUS PATIENTS WITH GENOTYPE C DISPLAY AN AGGRESSIVE DISEASE COURSE LEADING TO HCC MORE THAN OTHER GENOTYPES. FURTHERMORE, HEPATITIS B EXCRETORY ANTIGEN (HBEAG) SEEMS TO BE A MORE SENSITIVE PREDICTIVE TUMOR MARKER EXHIBITING A SIX-FOLD HIGHER RELATIVE RISK IN PATIENTS WITH POSITIVE HBSAG AND HBEAG THAN THOSE WITH HBSAG ONLY. SINGLE OR COMBINED MUTATIONS OF VIRAL GENOME CAN PREDICT HCC DEVELOPMENT IN UP TO 80% OF PATIENTS. SEVERAL MUTATIONS IN HBX-GENE ARE RELATED WITH HIGHER HCC INCIDENCE. OVEREXPRESSION OF THE CORE PROTEIN IN HCV LEADS TO HEPATOCELLULAR LIPID ACCUMULATION ASSOCIATED WITH ONCOGENESIS. REDUCED NUMBER AND DECREASED FUNCTIONALITY OF NATURAL KILLER CELLS IN CHRONIC HCV INDIVIDUALS DYSREGULATE THEIR SURVEILLANCE FUNCTION IN TUMOR AND VIRAL CELLS RESULTING IN HCC. FURTHERMORE, HIGH T-CELL IMMUNOGLOBULIN AND MUCIN 3 LEVELS SUPRESS CD8+ T-CELLS, WHICH LEAD TO IMMUNOLOGICAL DYSREGULATION. HEPATITIS D PROMOTES HCC DEVELOPMENT INDIRECTLY VIA MODIFICATIONS TO INNATE IMMUNITY, EPIGENETIC ALTERATIONS AND PRODUCTION OF REACTIVE OXYGEN SPECIES WITH THE LHDAG BEING THE MOST HIGHLY ASSOCIATED WITH HCC DEVELOPMENT. SUMMARIZING THE RESULTS, HBV AND HCV INFECTION REPRESENT THE MOST ASSOCIATED FORMS OF VIRAL HEPATITIS CAUSING HCC. FURTHER STUDIES ARE WARRANTED TO FURTHER IMPROVE THE PREDICTION OF HIGH-RISK PATIENTS AND DEVELOPMENT OF TARGETED THERAPEUTICS PREVENTING THE TRANSITION FROM HEPATIC INFLAMMATION-FIBROSIS TO CANCER. 2021 19 3508 30 IDENTIFYING A PANEL OF GENES/PROTEINS/MIRNAS MODULATED BY ARSENICALS IN BLADDER, PROSTATE, KIDNEY CANCERS. ARSENIC AND ARSENIC-DERIVATIVE COMPOUNDS, NAMED AS ARSENICALS, REPRESENT A WORLDWIDE PROBLEM FOR THEIR EFFECT ON THE HUMAN HEALTH AND, IN PARTICULAR, FOR THEIR CAPABILITY TO INCREASE THE RISK OF DEVELOPING CANCER SUCH AS KIDNEY, BLADDER AND PROSTATE CANCER. THE MAIN SOURCE OF ARSENICAL EXPOSURE IS DRINKING WATER. NOWADAYS, IT IS WELL KNOWN THAT THE CHRONIC EXPOSURE TO ARSENICALS LEADS TO A SERIES OF EPIGENETIC ALTERATIONS THAT HAVE A ROLE IN ARSENIC-INDUCED EFFECTS ON HUMAN HEALTH INCLUDING CANCER. BASED ON THESE OBSERVATIONS, THE AIM OF OUR STUDY WAS TO SELECT BY NETWORK ANALYSIS THE GENES/PROTEINS/MIRNAS IMPLICATED IN KIDNEY, BLADDER AND PROSTATE CANCER DEVELOPMENT UPON ARSENICAL EXPOSURE. FROM THIS ANALYSIS WE IDENTIFIED: (I) THE NODES LINKING THE THREE MOLECULAR NETWORKS SPECIFIC FOR KIDNEY, BLADDER AND PROSTATE CANCER; (II) THE RELATIVE HUB NODES (RXRA, MAP3K7, NR3C1, PABPC1, NDRG1, RELA AND CTNNB1) THAT LINK THE THREE CANCER NETWORKS; (III) THE MIRNAS ABLE TO TARGET THESE HUB NODES. IN CONCLUSION, WE HIGHLIGHTED A PANEL OF POTENTIAL MOLECULES RELATED TO THE MOLECULAR MECHANISMS OF ARSENICAL-INDUCED CANCEROGENESIS AND SUGGEST THEIR UTILITY AS BIOMARKERS OR THERAPEUTIC TARGETS. 2018 20 2182 31 EPIGENETIC MECHANISMS REGULATING THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA AND THEIR PROMISE FOR THERAPEUTICS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS AROUND THE GLOBE AND THIRD MOST FATAL MALIGNANCY. CHRONIC LIVER DISORDERS SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS OFTEN LEAD TO THE DEVELOPMENT OF HCC. ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS ARE INVOLVED IN THE DEVELOPMENT OF HCC. GENETIC RESEARCH SPARKED BY RECENT DEVELOPMENTS IN NEXT GENERATION SEQUENCING HAS IDENTIFIED THE FREQUENCY OF GENETIC ALTERATIONS THAT OCCUR IN HCC AND HAS LED TO THE IDENTIFICATION OF GENETIC HOTSPOTS. EMERGING EVIDENCE SUGGESTS THAT EPIGENETIC ABERRATIONS ARE STRONGLY ASSOCIATED WITH THE INITIATION AND DEVELOPMENT OF HCC. VARIOUS IMPORTANT GENES ENCODING TUMOR SUPPRESSORS INCLUDING P16, RASSF1A, DLC-1, RUNX3 AND SOCS-1 ARE TARGETS OF EPIGENETIC DYSREGULATION DURING THE DEVELOPMENT OF HCC. THE PRESENT REVIEW DISCUSSES THE IMPORTANCE OF EPIGENETIC REGULATIONS INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND MICRORNA MEDIATED REGULATION OF GENE EXPRESSION DURING TUMORIGENESIS AND THEIR USE AS DISEASE BIOMARKERS. FURTHERMORE, THESE EPIGENETIC ALTERATIONS HAVE BEEN DISCUSSED IN RELATIONSHIP WITH PROMISING THERAPEUTIC PERSPECTIVES FOR HCC AND RELATED CANCERS. 2017