1 2182 100 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 2 4421 31 MOLECULAR AND FUNCTIONAL GENETICS OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER AND ONE OF THE LEADING CAUSES OF CANCER DEATH WORLDWIDE. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS DEVELOPING FROM NORMAL THROUGH CHRONIC HEPATITIS/CIRRHOSIS AND DYSPLASTIC NODULES TO HCC. ALTHOUGH WE HAVE INSUFFICIENT UNDERSTANDING TO PROPOSE A ROBUST GENERAL MODEL, WITH ADVANCES IN MOLECULAR METHODS, THERE IS A GROWING UNDERSTANDING OF THE MOLECULAR MECHANISMS IN THE DEVELOPMENT OF HCC. HEPATOCARCINOGENESIS IS STRONGLY LINKED TO INCREASES IN ALLELIC LOSSES, CHROMOSOMAL CHANGES, GENE MUTATIONS, EPIGENETIC ALTERATIONS, AND ALTERATIONS IN MOLECULAR CELLULAR PATHWAYS. SPECIAL EMPHASIS IN THIS REVIEW IS GIVEN TO THE GENETICS, EPIGENETICS, AND REGULATION OF MAJOR SIGNALING PATHWAYS INVOLVED IN HCC SUCH AS WNT/B-CATENIN, RAS, AND PI3K/AKT/MTOR PATHWAYS. A DETAILED UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS INVOLVED IN THE PROGRESSION OF HCC CAN IMPROVE OUR PREVENTION AND DIAGNOSTIC TOOLS FOR HCC AND BE AN IMPORTANT POTENTIAL SOURCE OF NOVEL MOLECULAR TARGETS FOR NEW THERAPIES. 2010 3 2970 49 GENETIC AND EPIGENETIC SIGNATURES IN HUMAN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD MOST COMMON CAUSE OF CANCER DEATHS WORLDWIDE, AND THE INCIDENCE OF THIS FATAL DISEASE IS STILL ON RISE. THE MAJORITY OF HCCS EMERGE IN THE BACKGROUND OF A CHRONIC LIVER DISEASE, SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS. THE CURRENT UNDERSTANDING IS THAT MAJORITY OF HCCS EVOLVE AS A CONSEQUENCE OF CHRONIC INFLAMMATION AND DUE TO THE PRESENCE OF INFECTION WITH HEPATITIS VIRUSES. THESE UNDERLYING PATHOGENIC STIMULI SUBSEQUENTLY INDUCE A SPECTRUM OF GENETIC AND EPIGENETIC ALTERATIONS IN SEVERAL CANCER-RELATED GENES, WHICH ARE INVOLVED IN CELL-CYCLE REGULATION, CELL GROWTH AND ADHESION. SUCH WIDESPREAD GENOMIC ALTERATIONS CAUSE DISRUPTION OF NORMAL CELLULAR SIGNALING AND FINALLY LEAD TO THE ACQUISITION OF A MALIGNANT PHENOTYPE IN HCC. IN GENERAL, THE TYPE OF GENE ALTERATIONS, SUCH AS POINT MUTATIONS, DELETION OF CHROMOSOMAL REGIONS AND ABNORMAL METHYLATION OF GENE PROMOTERS DIFFER ACCORDING TO THE INDIVIDUAL TARGETED GENE. IN HCC, INCIDENCE OF GENETIC ALTERATIONS IS RELATIVELY RARE AND IS LIMITED TO A SUBSET OF FEW CANCER-SPECIFIC GENES, SUCH AS THE TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS THE CTNNB1. IN CONTRAST, EPIGENETIC CHANGES THAT INVOLVE ABERRANT METHYLATION OF GENES AND OTHER POST-TRANSCRIPTIONAL HISTONE MODIFICATIONS OCCUR FAR MORE FREQUENTLY, AND SOME OF THESE EPIGENETIC ALTERATIONS ARE NOW BEING EXPLOITED FOR THE DEVELOPMENT OF MOLECULAR DIAGNOSTIC SIGNATURES FOR HCC. IN ADDITION, RECENT FINDINGS OF UNIQUE MICRORNA EXPRESSION PROFILES ALSO PROVIDE AN EVIDENCE FOR THE EXISTENCE OF NOVEL MECHANISMS FOR GENE EXPRESSION REGULATION IN HCC. IN THIS REVIEW ARTICLE, WE WILL REVIEW THE CURRENT STATE OF KNOWLEDGE ON THE ACTIVATION OF VARIOUS ONCOGENIC PATHWAYS AND THE INACTIVATION OF TUMOR SUPPRESSOR PATHWAYS IN HCC THAT RESULT IN THE DISRUPTION OF CANCER-RELATED GENE FUNCTION. IN ADDITION, WE WILL SPECIFICALLY EMPHASIZE THE CLINICAL IMPLICATION OF SOME OF THESE GENETIC AND EPIGENETIC ALTERATIONS IN THE MANAGEMENT OF HEPATOCARCINOGENESIS. 2011 4 2166 48 EPIGENETIC MECHANISMS IN HEPATOCELLULAR CARCINOMA: HOW ENVIRONMENTAL FACTORS INFLUENCE THE EPIGENOME. EPIGENETIC MECHANISMS MAINTAIN HERITABLE CHANGES IN GENE EXPRESSION AND CHROMATIN ORGANIZATION OVER MANY CELL GENERATIONS. IMPORTANTLY, DEREGULATED EPIGENETIC MECHANISMS PLAY A KEY ROLE IN A WIDE RANGE OF HUMAN MALIGNANCIES, INCLUDING LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC), WHICH ORIGINATES FROM THE HEPATOCYTES, IS BY FAR THE MOST COMMON LIVER CANCER, WITH RATES AND AETIOLOGY THAT SHOW CONSIDERABLE GEOGRAPHIC VARIATION. VARIOUS ENVIRONMENTAL AGENTS AND LIFESTYLES KNOWN TO BE RISK FACTORS FOR HCC (SUCH AS INFECTION BY HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), CHRONIC ALCOHOL INTAKE, AND AFLATOXINS) ARE SUSPECTED TO PROMOTE ITS DEVELOPMENT BY ELICITING EPIGENETIC CHANGES, HOWEVER THE PRECISE GENE TARGETS AND UNDERLYING MECHANISMS HAVE NOT BEEN ELUCIDATED. MANY RECENT STUDIES HAVE EXPLOITED CONCEPTUAL AND TECHNOLOGICAL ADVANCES IN EPIGENETICS AND EPIGENOMICS TO INVESTIGATE THE ROLE OF EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN HCC TUMORS AND NON-TUMOR PRECANCEROUS (CIRRHOTIC) LESIONS. THESE STUDIES HAVE IDENTIFIED A LARGE NUMBER OF GENES AND PATHWAYS THAT ARE TARGETED BY EPIGENETIC DEREGULATION (CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-MEDIATED GENE SILENCING) DURING THE DEVELOPMENT AND PROGRESSION OF HCC. FREQUENT IDENTIFICATION OF ABERRANT EPIGENETIC CHANGES IN SPECIFIC GENES IN CIRRHOTIC TISSUE IS CONSISTENT WITH THE NOTION THAT EPIGENETIC DEREGULATION OF SELECTED GENES IN PRE-MALIGNANT LESIONS PRECEDES AND PROMOTES THE DEVELOPMENT OF HCC. IN ADDITION, SEVERAL LINES OF EVIDENCE ARGUE THAT SOME ENVIRONMENTAL FACTORS (SUCH AS HBV VIRUS) MAY ABROGATE CELLULAR DEFENSE SYSTEMS, INDUCE SILENCING OF HOST GENES AND PROMOTE HCC DEVELOPMENT VIA AN "EPIGENETIC STRATEGY". FINALLY, PROFILING STUDIES REVEAL THAT HCC TUMORS AND PRE-CANCEROUS LESIONS MAY EXHIBIT EPIGENETIC SIGNATURES ASSOCIATED WITH SPECIFIC RISK FACTORS AND TUMOR PROGRESSION STAGE. TOGETHER, RECENT EVIDENCE UNDERSCORES THE IMPORTANCE OF ABERRANT EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN LIVER CANCER AND HIGHLIGHTS POTENTIAL TARGETS FOR BIOMARKER DISCOVERY AND FUTURE PREVENTIVE AND THERAPEUTIC STRATEGIES. 2011 5 4476 28 MOLECULAR PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER AND THE THIRD LEADING CAUSE OF CANCER DEATH WORLDWIDE. HEPATOCARCINOGENESIS IS A MULTISTEP PROCESS EVOLVING FROM NORMAL THROUGH CHRONIC HEPATITIS/CIRRHOSIS AND DYSPLASTIC NODULES TO HCC. WITH ADVANCES IN MOLECULAR METHODS, THERE IS A GROWING UNDERSTANDING OF THE MOLECULAR MECHANISMS IN HEPATOCARCINOGENESIS. HEPATOCARCINOGENESIS IS STRONGLY LINKED TO INCREASES IN ALLELIC LOSSES, CHROMOSOMAL CHANGES, GENE MUTATIONS, EPIGENETIC ALTERATIONS AND ALTERATIONS IN MOLECULAR CELLULAR PATHWAYS. SOME OF THESE ALTERATIONS ARE ACCOMPANIED BY A STEPWISE INCREASE IN THE DIFFERENT PATHOLOGICAL DISEASE STAGES IN HEPATOCARCINOGENESIS. OVERALL, A DETAILED UNDERSTANDING OF THE UNDERLYING MOLECULAR MECHANISMS INVOLVED IN THE PROGRESSION OF HCC IS OF FUNDAMENTAL IMPORTANCE TO THE DEVELOPMENT OF EFFECTIVE PREVENTION AND TREATMENT REGIMES FOR HCC. 2008 6 2538 29 EPIGENETICS IN HEPATOCELLULAR CARCINOMA: AN UPDATE AND FUTURE THERAPY PERSPECTIVES. HEPATOCELLULAR CARCINOMA (HCC), THE PREDOMINANT FORM OF ADULT LIVER MALIGNANCIES, IS A GLOBAL HEALTH CONCERN. ITS DISMAL PROGNOSIS HAS PROMPTED RECENT SIGNIFICANT ADVANCES IN THE UNDERSTANDING OF ITS ETIOLOGY AND PATHOGENESIS. THE DEREGULATION OF EPIGENETIC MECHANISMS, WHICH MAINTAIN HERITABLE GENE EXPRESSION CHANGES AND CHROMATIN ORGANIZATION, IS IMPLICATED IN THE DEVELOPMENT OF MULTIPLE CANCERS, INCLUDING HCC. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF HCC, WITH AN EMPHASIS ON HCC MEDIATED BY CHRONIC HEPATITIS B VIRUS INFECTION. THIS REVIEW ALSO DISCUSSES THE ENCOURAGING OUTCOMES AND LESSONS LEARNT FROM EPIGENETIC THERAPIES FOR HEMATOLOGICAL AND OTHER SOLID CANCERS, AND HIGHLIGHTS THE FUTURE POTENTIAL OF SIMILAR THERAPIES IN THE TREATMENT OF HCC. 2014 7 4687 33 NEW TOOLS FOR MOLECULAR THERAPY OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER, ARISING FROM NEOPLASTIC TRANSFORMATION OF HEPATOCYTES OR LIVER PRECURSOR/STEM CELLS. HCC IS OFTEN ASSOCIATED WITH PRE-EXISTING CHRONIC LIVER PATHOLOGIES OF DIFFERENT ORIGIN (MAINLY SUBSEQUENT TO HBV AND HCV INFECTIONS), SUCH AS FIBROSIS OR CIRRHOSIS. CURRENT THERAPIES ARE ESSENTIALLY STILL INEFFECTIVE, DUE BOTH TO THE TUMOR HETEROGENEITY AND THE FREQUENT LATE DIAGNOSIS, MAKING NECESSARY THE CREATION OF NEW THERAPEUTIC STRATEGIES TO INHIBIT TUMOR ONSET AND PROGRESSION AND IMPROVE THE SURVIVAL OF PATIENTS. A PROMISING STRATEGY FOR TREATMENT OF HCC IS THE TARGETED MOLECULAR THERAPY BASED ON THE RESTORATION OF TUMOR SUPPRESSOR PROTEINS LOST DURING NEOPLASTIC TRANSFORMATION. IN PARTICULAR, THE DELIVERY OF MASTER GENES OF EPITHELIAL/HEPATOCYTE DIFFERENTIATION, ABLE TO TRIGGER AN EXTENSIVE REPROGRAMMING OF GENE EXPRESSION, COULD ALLOW THE INDUCTION OF AN EFFICIENT ANTITUMOR RESPONSE THROUGH THE SIMULTANEOUS ADJUSTMENT OF MULTIPLE GENETIC/EPIGENETIC ALTERATIONS CONTRIBUTING TO TUMOR DEVELOPMENT. HERE, WE REPORT RECENT LITERATURE DATA SUPPORTING THE USE OF MEMBERS OF THE LIVER ENRICHED TRANSCRIPTION FACTOR (LETF) FAMILY, IN PARTICULAR HNF4ALPHA, AS TOOLS FOR GENE THERAPY OF HCC. 2015 8 1543 34 DNA METHYLATION IN HEPATOCELLULAR CARCINOMA. AS FOR MANY OTHER TUMORS, DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES, LEADING TO ACTIVATION OF ONCOGENES AND INACTIVATION OR LOSS OF TUMOR SUPPRESSOR GENES (TSG). IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC INACTIVATION OF (TUMOR SUPPRESSOR) GENES BY PROMOTER HYPERMETHYLATION HAS BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMORIGENESIS. IN HCC, ABERRANT METHYLATION OF PROMOTER SEQUENCES OCCURS NOT ONLY IN ADVANCED TUMORS, IT HAS BEEN ALSO OBSERVED IN PREMALIGNANT CONDITIONS JUST AS CHRONIC VIRAL HEPATITIS B OR C AND CIRRHOTIC LIVER. THIS REVIEW DISCUSSES THE EPIGENETIC ALTERATIONS IN HEPATOCELLULAR CARCINOMA FOCUSING DNA METHYLATION. 2008 9 5622 37 SEARCH FOR USEFUL BIOMARKERS IN HEPATOCELLULAR CARCINOMA, TUMOR FACTORS AND BACKGROUND LIVER FACTORS (REVIEW). HEPATOCARCINOGENESIS IS A COMPLEX AND MULTISTEP PROCESS THAT INVOLVES THE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS IN REGULATORY GENES. TO UNDERSTAND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC), CURRENT RESEARCH HAS UTILIZED IMPROVED ARRAY TECHNOLOGIES. THE IDENTIFICATION OF CANCER-RELATED MOLECULES COULD LEAD TO THE DEVELOPMENT OF NOVEL MOLECULAR TARGETS FOR TREATMENT AND BIOMARKERS FOR PREDICTING PROGNOSIS. HOWEVER, PROGNOSTIC PREDICTION IS INSUFFICIENT WHEN CONSIDERING ONLY TUMOR FACTORS, SINCE HEPATOCARCINOGENESIS IS ALSO GREATLY INFLUENCED BY THE STATUS OF THE BACKGROUND LIVER. CLINICAL BACKGROUND LIVER FACTORS, SUCH AS THE PRESENCE OF CHRONIC ACTIVE HEPATITIS OR CIRRHOSIS, ARE WELL KNOWN AS RISK FACTORS FOR DEVELOPING HCC. IN CONTRAST, GENETIC OR EPIGENETIC BACKGROUND LIVER FACTORS REMAIN UNKNOWN, ALBEIT THOSE ARE IMPORTANT TO UNDERSTAND THE DEVELOPING PROCESS OF HCC. INVESTIGATING BACKGROUND LIVER FACTORS COULD CONTRIBUTE TO THE DEVELOPMENT OF CARCINOGENIC MARKERS OF HCC AND TO THE PREVENTION OF THE DEVELOPMENT OF HCC. IN THE PRESENT STUDY, WE REVIEW THE CURRENTLY IDENTIFIED TUMOR FACTORS AND BACKGROUND LIVER FACTORS FROM A MOLECULAR BIOLOGICAL VIEWPOINT AND ALSO INTRODUCE OUR COMBINATION ARRAY ANALYSIS. 2017 10 3932 30 LIVER REGENERATION, LIVER CANCERS AND CYCLINS. ACCUMULATING EVIDENCE HAS REVEALED THAT MALIGNANT CELL GROWTH IS REGULATED BY COMPLEX MECHANISMS INVOLVED IN GENETIC AND EPIGENETIC FACTORS. AMONG HUMAN CANCERS, CANCER IN THE LIVER (HEPATOCELLULAR CARCINOMA (HCC)) IS CHARACTERIZED BY THE EVIDENCE THAT IT IS USUALLY BASED ON CHRONIC LIVER DISEASES SUCH AS LIVER CIRRHOSIS OR CHRONIC HEPATITIS, IN WHICH THE LIVER IS PERSISTENTLY REGENERATING FOLLOWING HEPATIC INJURY. THIS RAISES THE POSSIBILITY THAT REPEATED HEPATOCYTE PROLIFERATION MAY CAUSE DISORDER OF GENES THAT ARE REGULATING THE CELL CYCLE IN HEPATOCYTES, THUS CAUSING HCC. IN THIS ARTICLE, RECENT STUDIES FOCUSING ON LIVER REGENERATION AND CANCER ARE REVIEWED FROM THE VIEWPOINT OF THE CELL CYCLE THAT IS REGULATED BY CYCLIN AND THE ASSOCIATED PROTEINS. 1998 11 5360 35 RECENT ADVANCEMENTS IN COMPREHENSIVE GENETIC ANALYSES FOR HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) TYPICALLY DEVELOPS IN THE LIVER WITH CHRONIC HEPATITIS AND CIRRHOSIS, AND ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS DURING CARCINOGENESIS VIA GENETIC AND EPIGENETIC MECHANISMS. RECENT ADVANCEMENTS IN THE DEVELOPMENT OF ANALYSES FOR EXAMINING THE CANCER GENOME HAVE REVEALED INFORMATION REGARDING GENETIC ALTERATIONS IN HCC TISSUES. ACCORDING TO PREVIOUS STUDIES, THE INCIDENCE OF RECURRENT GENETIC ALTERATIONS IN INDIVIDUAL GENES WAS THOUGHT TO BE RELATIVELY RARE AND LIMITED TO A SUBSET OF A FEW CANCER-SPECIFIC GENES SUCH AS TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS CTNNB1. HOWEVER, RECENT WHOLE-GENOME ANALYSES AND EXOME SEQUENCING OF TUMOR DNA HAVE REVEALED NUMEROUS NOVEL ALTERATIONS OF CANCER-RELATED GENES AND PATHWAYS CRITICAL FOR HCC DEVELOPMENT. IN ADDITION, VARIOUS RISK FACTORS FOR HCC, SUCH AS THE PRESENCE OR ABSENCE OF HEPATITIS B AND C VIRUS, MAY AFFECT THE MUTATION PROFILE OF THE CORRESPONDING CANCER GENOME. ON THE OTHER HAND, GENOME-WIDE ASSOCIATION STUDIES HAVE ALSO IDENTIFIED IMPORTANT SINGLE-NUCLEOTIDE POLYMORPHISMS INVOLVED IN HCC DEVELOPMENT, WHICH MAY ALLOW DETECTION OF A GROUP AT HIGH RISK OF HCC EMERGENCE. SUCH ANALYSES WILL CLARIFY HOW THIS MALIGNANCY CAN BE TREATED, DIAGNOSED AND PREVENTED MORE EFFECTIVELY. 2013 12 2014 34 EPIGENETIC BIOMARKERS FOR THE DIAGNOSIS AND TREATMENT OF LIVER DISEASE. RESEARCH IN THE LAST DECADES HAS DEMONSTRATED THE RELEVANCE OF EPIGENETICS IN CONTROLLING GENE EXPRESSION TO MAINTAIN CELL HOMEOSTASIS, AND THE IMPORTANT ROLE PLAYED BY EPIGENOME ALTERATIONS IN DISEASE DEVELOPMENT. MOREOVER, THE REVERSIBILITY OF EPIGENETIC MARKS CAN BE HARNESSED AS A THERAPEUTIC STRATEGY, AND EPIGENETIC MARKS CAN BE USED AS DIAGNOSIS BIOMARKERS. EPIGENETIC ALTERATIONS IN DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS), AND NON-CODING RNA (NCRNA) EXPRESSION HAVE BEEN ASSOCIATED WITH THE PROCESS OF HEPATOCARCINOGENESIS. HERE, WE SUMMARIZE EPIGENETIC ALTERATIONS INVOLVED IN THE PATHOGENESIS OF CHRONIC LIVER DISEASE (CLD), PARTICULARLY FOCUSING ON DNA METHYLATION. WE ALSO DISCUSS THEIR UTILITY AS EPIGENETIC BIOMARKERS IN LIQUID BIOPSY FOR THE DIAGNOSIS AND PROGNOSIS OF HEPATOCELLULAR CARCINOMA (HCC). FINALLY, WE DISCUSS THE POTENTIAL OF EPIGENETIC THERAPEUTIC STRATEGIES FOR HCC TREATMENT. 2021 13 2172 40 EPIGENETIC MECHANISMS INVOLVED IN HCV-INDUCED HEPATOCELLULAR CARCINOMA (HCC). HEPATOCELLULAR CARCINOMA (HCC), IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS, WHICH IS LARGELY CAUSED BY VIRUS INFECTION. ABOUT 80% OF THE VIRUS-INFECTED PEOPLE DEVELOP A CHRONIC INFECTION THAT EVENTUALLY LEADS TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). WITH APPROXIMATELY 71 MILLION HCV CHRONIC INFECTED PATIENTS WORLDWIDE, THEY STILL HAVE A HIGH RISK OF HCC IN THE NEAR FUTURE. HOWEVER, THE MECHANISMS OF CARCINOGENESIS IN CHRONIC HCV INFECTION HAVE NOT BEEN STILL FULLY UNDERSTOOD, WHICH INVOLVE A COMPLEX EPIGENETIC REGULATION AND CELLULAR SIGNALING PATHWAYS. HERE, WE SUMMARIZE 18 SPECIFIC GENE TARGETS AND DIFFERENT SIGNALING PATHWAYS INVOLVED IN RECENT FINDINGS. WITH THESE EPIGENETIC ALTERATIONS REQUIRING HISTONE MODIFICATIONS AND DNA HYPER OR HYPO-METHYLATION OF THESE SPECIFIC GENES, THE DYSREGULATION OF GENE EXPRESSION IS ALSO ASSOCIATED WITH DIFFERENT SIGNALING PATHWAYS FOR THE HCV LIFE CYCLE AND HCC. THESE FINDINGS PROVIDE A NOVEL INSIGHT INTO A CORRELATION BETWEEN HCV INFECTION AND HCC TUMORIGENESIS, AS WELL AS POTENTIALLY PREVENTABLE APPROACHES. HEPATITIS C VIRUS (HCV) INFECTION LARGELY CAUSES HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE WITH 3 TO 4 MILLION NEWLY INFECTED CASES DIAGNOSED EACH YEAR. IT IS URGENT TO EXPLORE ITS UNDERLYING MOLECULAR MECHANISMS FOR THERAPEUTIC TREATMENT AND BIOMARKER DISCOVERY. HOWEVER, THE MECHANISMS OF CARCINOGENESIS IN CHRONIC HCV INFECTION HAVE NOT BEEN STILL FULLY UNDERSTOOD, WHICH INVOLVE A COMPLEX EPIGENETIC REGULATION AND CELLULAR SIGNALING PATHWAYS. HERE, WE SUMMARIZE 18 SPECIFIC GENE TARGETS AND DIFFERENT SIGNALING PATHWAYS INVOLVED IN RECENT FINDINGS. WITH THESE EPIGENETIC ALTERATIONS REQUIRING HISTONE MODIFICATIONS AND DNA HYPER OR HYPO-METHYLATION OF THESE SPECIFIC GENES, THE DYSREGULATION OF GENE EXPRESSION IS ALSO ASSOCIATED WITH DIFFERENT SIGNALING PATHWAYS FOR THE HCV LIFE CYCLE AND HCC. THESE FINDINGS PROVIDE A NOVEL INSIGHT INTO A CORRELATION BETWEEN HCV INFECTION AND HCC TUMORIGENESIS, AS WELL AS POTENTIALLY PREVENTABLE APPROACHES. 2021 14 3103 33 GENOMIC LANDSCAPE OF HCC. INTRODUCTION: HEPATOCELLULAR CARCINOMA (HCC) IS A LEADING CAUSE OF CANCER RELATED MORTALITY IN THE WORLD AND IT HAS LIMITED TREATMENT OPTIONS. UNDERSTANDING THE MOLECULAR DRIVERS OF HCC IS IMPORTANT TO DEVELOP NOVEL BIOMARKERS AND THERAPEUTICS. PURPOSE OF REVIEW: HCC ARISES IN A COMPLEX BACKGROUND OF CHRONIC HEPATITIS, FIBROSIS AND LIVER REGENERATION WHICH LEAD TO GENOMIC CHANGES. HERE, WE SUMMARIZE STUDIES THAT HAVE EXPANDED OUR UNDERSTANDING OF THE MOLECULAR LANDSCAPE OF HCC. RECENT FINDINGS: RECENT TECHNOLOGICAL ADVANCES IN NEXT GENERATION SEQUENCING (NGS) HAVE ELUCIDATED SPECIFIC GENETIC AND MOLECULAR PROGRAMS INVOLVED IN HEPATOCARCINOGENESIS. WE SUMMARIZE THE MAJOR SOMATIC MUTATIONS AND EPIGENETIC CHANGES HAVE BEEN IDENTIFIED IN NGS-BASED STUDIES. WE ALSO DESCRIBE PROMISING MOLECULAR THERAPIES AND IMMUNOTHERAPIES WHICH TARGET SPECIFIC GENETIC AND EPIGENETIC MOLECULAR EVENTS. SUMMARY: THE GENOMIC LANDSCAPE OF HCC IS INCREDIBLY COMPLEX AND HETEROGENEOUS. PROMISING NEW DEVELOPMENTS ARE HELPING US DECIPHER THE MOLECULAR DRIVERS OF HCC AND LEADING TO NEW THERAPIES. 2020 15 3277 36 HEPATOCYTE PLOIDY AND PATHOLOGICAL MUTATIONS IN HEPATOCELLULAR CARCINOMA: IMPACT ON ONCOGENESIS AND THERAPEUTICS. HEPATOCELLULAR CARCINOMA (HCC) OCCURS IN THE CHRONIC LIVER INFLAMMATION SUCH AS VIRAL HEPATITIS, ALCOHOLIC AND NON-ALCOHOLIC STEATOHEPATITIS. WHILE ANTI-VIRAL TREATMENT HAS BEEN SIGNIFICANTLY IMPROVED, THE PREVALENCE OF HCC REMAINS HIGH AND TREATMENT IS STILL CHALLENGING. THE CONTINUATION OF HEPATOCYTE DEATH, INFLAMMATION, AND FIBROSIS LEADS TO THE ACCUMULATION OF GENE ALTERATIONS, WHICH MAY TRIGGER CARCINOGENESIS. HEPATOCYTES ARE A UNIQUE CELL TYPE HAVING MORE THAN ONE COMPLETE SET OF 23 CHROMOSOMES, TERMED POLYPLOIDY. DUE TO GENE REDUNDANCY, HEPATOCYTES MAY TOLERATE LETHAL MUTATIONS. NEXT GENERATION SEQUENCING TECHNOLOGY HAS REVEALED GENE ALTERATIONS IN HCC RELATED TO TELOMERE MAINTENANCE, WNT/BETA-CATENIN PATHWAY, P53 CELL-CYCLE PATHWAY, EPIGENETIC MODIFIERS, OXIDATIVE STRESS PATHWAY, PI3K/AKT/MTOR, AND RAS/RAF/MAPK PATHWAY WITH OR WITHOUT A CHROMOSOMAL INSTABILITY. SOME TYPE OF DRIVER GENE MUTATIONS ACCUMULATES IN HEPATOCYTES AND BREAKS THE ORCHESTRATION OF EXCESSIVE COPIES OF CHROMOSOMES, WHICH MAY LEAD TO UNFAVORABLE GENE EXPRESSIONS AND FUEL TUMORIGENESIS. RECENTLY, MOLECULAR TARGETED DRUGS, DEVELOPED WITH THE AIM OF INTERFERING WITH THESE SIGNALING PATHWAYS, ARE BEING USED FOR HCC PATIENTS IN THE CLINICS. THEREFORE, A DEEPER UNDERSTANDING OF HEPATOCYTE PLOIDY AND GENETIC OR EPIGENETIC ALTERATIONS IS INDISPENSABLE FOR THE ESTABLISHMENT OF NOVEL THERAPEUTIC STRATEGIES AGAINST HCC. 2020 16 6092 34 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 17 3278 39 HEPATOEPIGENETIC ALTERATIONS IN VIRAL AND NONVIRAL-INDUCED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR PUBLIC HEALTH CONCERN AND ONE OF THE LEADING CAUSES OF TUMOUR-RELATED DEATHS WORLDWIDE. EXTENSIVE EVIDENCE ENDORSES THAT HCC IS A MULTIFACTORIAL DISEASE CHARACTERISED BY HEPATIC CIRRHOSIS MOSTLY ASSOCIATED WITH CHRONIC INFLAMMATION AND HEPATITIS B/C VIRAL INFECTIONS. INTERACTION OF VIRAL PRODUCTS WITH THE HOST CELL MACHINERY MAY LEAD TO INCREASED FREQUENCY OF GENETIC AND EPIGENETIC ABERRATIONS THAT CAUSE HARMFUL ALTERATIONS IN GENE TRANSCRIPTION. THIS MAY PROVIDE A PROGRESSIVE SELECTIVE ADVANTAGE FOR NEOPLASTIC TRANSFORMATION OF HEPATOCYTES ASSOCIATED WITH PHENOTYPIC HETEROGENEITY OF INTRATUMOUR HCC CELLS, THUS POSING EVEN MORE CHALLENGES IN HCC TREATMENT DEVELOPMENT. EPIGENETIC ABERRATIONS INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING MIRNA DYSREGULATION HAVE BEEN SHOWN TO BE INTIMATELY LINKED WITH AND PLAY A CRITICAL ROLE IN TUMOUR INITIATION, PROGRESSION, AND METASTASES. THE CURRENT REVIEW FOCUSES ON THE ABERRANT HEPATOEPIGENETICS EVENTS THAT PLAY IMPORTANT ROLES IN HEPATOCARCINOGENESIS AND THEIR UTILITIES IN THE DEVELOPMENT OF HCC THERAPY. 2016 18 4477 30 MOLECULAR PATHOGENESIS OF HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCARCINOGENESIS IS A SLOW PROCESS DURING WHICH GENOMIC CHANGES PROGRESSIVELY ALTER THE HEPATOCELLULAR PHENOTYPE TO PRODUCE CELLULAR INTERMEDIATES THAT EVOLVE INTO HEPATOCELLULAR CARCINOMA. DURING THE LONG PRENEOPLASTIC STAGE, IN WHICH THE LIVER IS OFTEN THE SITE OF CHRONIC HEPATITIS, CIRRHOSIS, OR BOTH, HEPATOCYTE CYCLING IS ACCELERATED BY UPREGULATION OF MITOGENIC PATHWAYS, IN PART THROUGH EPIGENETIC MECHANISMS. THIS LEADS TO THE PRODUCTION OF MONOCLONAL POPULATIONS OF ABERRANT AND DYSPLASTIC HEPATOCYTES THAT HAVE TELOMERE EROSION AND TELOMERASE RE-EXPRESSION, SOMETIMES MICROSATELLITE INSTABILITY, AND OCCASIONALLY STRUCTURAL ABERRATIONS IN GENES AND CHROMOSOMES. DEVELOPMENT OF DYSPLASTIC HEPATOCYTES IN FOCI AND NODULES AND EMERGENCE OF HEPATOCELLULAR CARCINOMA ARE ASSOCIATED WITH THE ACCUMULATION OF IRREVERSIBLE STRUCTURAL ALTERATIONS IN GENES AND CHROMOSOMES, BUT THE GENOMIC BASIS OF THE MALIGNANT PHENOTYPE IS HETEROGENEOUS. THE MALIGNANT HEPATOCYTE PHENOTYPE MAY BE PRODUCED BY THE DISRUPTION OF A NUMBER OF GENES THAT FUNCTION IN DIFFERENT REGULATORY PATHWAYS, PRODUCING SEVERAL MOLECULAR VARIANTS OF HEPATOCELLULAR CARCINOMA. NEW STRATEGIES SHOULD ENABLE THESE VARIANTS TO BE CHARACTERIZED. 2002 19 4920 33 PARALLEL EPIGENETIC AND GENETIC CHANGES IN THE PATHOGENESIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST FREQUENT TUMOR TYPES IN THE WORLD, WITH SHORT SURVIVAL TIMES AND FEW TREATMENT OPTIONS. HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) ARE MAJOR ETIOLOGIC AGENTS OF HCC, ALTHOUGH THE ASSOCIATED MECHANISMS ARE INCOMPLETELY UNDERSTOOD. THE AVAILABLE EVIDENCE SUGGESTS THAT BOTH VIRUSES PROMOTE TUMORIGENESIS BY UP-REGULATING GENES THAT PROMOTE HEPATOCELLULAR GROWTH AND SURVIVAL, AND BY DOWN-REGULATING OTHER GENES THAT ACT AS TUMOR SUPPRESSORS AND NEGATIVE GROWTH REGULATORY MOLECULES. SIGNIFICANTLY, A NUMBER OF THE PATHWAYS THAT ARE ALTERED BY THESE VIRUSES ARE THE SAME ONES THAT ACCUMULATE GENETIC ALTERATIONS DURING TUMOR PROGRESSION. THIS SUGGESTS THAT THE PATHWAYS THAT PROMOTE VIRUS PERSISTENCE AND REPLICATION MAY ALSO PROMOTE CELL GROWTH AND SURVIVAL. FROM THE PERSPECTIVE OF THE VIRUS, THIS PROMOTES CHRONIC INFECTION, WHILE FROM THE PERSPECTIVE OF THE HOST, THIS PROMOTES TUMORIGENESIS. 2006 20 5761 39 SOMATIC MUTATIONS, VIRAL INTEGRATION AND EPIGENETIC MODIFICATION IN THE EVOLUTION OF HEPATITIS B VIRUS-INDUCED HEPATOCELLULAR CARCINOMA. LIVER CANCER IN MEN IS THE SECOND LEADING CAUSE OF CANCER DEATH AND HEPATOCELLULAR CARCINOMA (HCC) ACCOUNTS FOR 70%-85% OF THE TOTAL LIVER CANCER WORLDWIDE. CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) IS THE MAJOR CAUSE OF HCC. CHRONIC, INTERMITTENTLY ACTIVE INFLAMMATION PROVIDES "FERTILE FIELD" FOR "MUTATION, SELECTION, AND ADAPTATION" OF HBV AND THE INFECTED HEPATOCYTES, A LONG-TERM EVOLUTIONARY PROCESS DURING HBV-INDUCED CARCINOGENESIS. HBV MUTATIONS, WHICH ARE POSITIVELY SELECTED BY INSUFFICIENT IMMUNITY, CAN PROMOTE AND PREDICT THE OCCURRENCE OF HCC. RECENTLY, ADVANCED SEQUENCING TECHNOLOGIES INCLUDING WHOLE GENOME SEQUENCING, EXOME SEQUENCING, AND RNA SEQUENCING PROVIDE OPPORTUNITIES TO BETTER UNDER-STAND THE INSIGHT OF HOW SOMATIC MUTATIONS, STRUCTURE VARIATIONS, HBV INTEGRATIONS, AND EPIGENETIC MODIFICATIONS CONTRIBUTE TO HCC DEVELOPMENT. GENOMIC VARIATIONS OF HCC CAUSED BY VARIOUS ETIOLOGICAL FACTORS MAY BE DIFFERENT, BUT THE COMMON DRIVER MUTATIONS ARE IMPORTANT TO ELUCIDATE THE HCC EVOLUTIONARY PROCESS. GENOME-WIDE ANALYSES OF HBV INTEGRATIONS ARE HELPFUL IN CLARIFYING THE TARGETED GENES OF HBV IN CARCINOGENESIS AND DISEASE PROGRESSION. RNA SEQUENCING CAN IDENTIFY KEY MOLECULES WHOSE EXPRESSIONS ARE EPIGENETICALLY MODIFIED DURING HCC EVOLUTION. IN THIS REVIEW, WE SUMMARIZED THE CURRENT FINDINGS OF NEXT GENERATION SEQUENCINGS FOR HBV-HCC AND PROPOSED A THEORY FRAMEWORK OF CANCER EVOLUTION AND DEVELOPMENT BASED ON THE CURRENT KNOWLEDGE OF HBV-INDUCED HCC TO CHARACTERIZE AND INTERPRET EVOLUTIONARY MECHANISMS OF HCC AND POSSIBLE OTHER CANCERS. UNDERSTANDING THE KEY VIRAL AND GENOMIC VARIATIONS INVOLVED IN HCC EVOLUTION IS ESSENTIAL FOR GENERATING EFFECTIVE DIAGNOSTIC, PROGNOSTIC, AND PREDICTIVE BIOMARKERS AS WELL AS THERAPEUTIC TARGETS FOR THE INTERVENTIONS OF HBV-HCC. 2014