1 3392 133 HOST AND VIRAL GENETIC VARIATION IN HBV-RELATED HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER IN MEN AND THE SECOND LEADING CAUSE OF CANCER DEATHS GLOBALLY. THE HIGH PREVALENCE OF HCC IS DUE IN PART TO THE HIGH PREVALENCE OF CHRONIC HBV INFECTION AND THE HIGH MORTALITY RATE IS DUE TO THE LACK OF BIOMARKERS FOR EARLY DETECTION AND LIMITED TREATMENT OPTIONS FOR LATE STAGE HCC. THE OBSERVED INDIVIDUAL VARIANCE IN DEVELOPMENT OF HCC IS ATTRIBUTABLE TO DIFFERENCES IN HBV GENOTYPE AND MUTATIONS, HOST PREDISPOSING GERMLINE GENETIC VARIATIONS, THE ACQUISITION OF TUMOR-SPECIFIC SOMATIC MUTATIONS, AS WELL AS ENVIRONMENTAL FACTORS. HBV GENOTYPE C AND MUTATIONS IN THE PRES, BASIC CORE PROMOTER (BCP) OR HBX REGIONS ARE ASSOCIATED WITH AN INCREASED RISK OF HCC. GENOME-WIDE ASSOCIATION STUDIES HAVE IDENTIFIED COMMON POLYMORPHISMS IN KIF1B, HLA-DQ, STAT4, AND GRIK1 WITH ALTERED RISK OF HBV-RELATED HCC. HBV INTEGRATION INTO GROWTH CONTROL GENES (SUCH AS TERT), PRO-ONCOGENIC GENES, OR TUMOR SUPPRESSOR GENES AND THE ONCOGENIC ACTIVITY OF TRUNCATED HBX PROMOTE HEPATOCARCINOGENESIS. SOMATIC MUTATIONS IN THE TERT PROMOTER AND CLASSIC CANCER SIGNALING PATHWAYS, INCLUDING WNT (CTNNB1), CELL CYCLE REGULATION (TP53), AND EPIGENETIC MODIFICATION (ARID2 AND MLL4) ARE FREQUENTLY DETECTED IN HEPATIC TUMOR TISSUES. THE IDENTIFICATION OF HBV AND HOST VARIATION ASSOCIATED WITH TUMOR INITIATION AND PROGRESSION HAS CLINICAL UTILITY FOR IMPROVING EARLY DIAGNOSIS AND PROGNOSIS; WHEREAS THE IDENTIFICATION OF SOMATIC MUTATIONS DRIVING TUMORIGENESIS HOLD PROMISE TO INFORM PRECISION TREATMENT FOR HCC PATIENTS. 2018 2 6707 36 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 3 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 4 6798 35 [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 5 3263 33 HEPATITIS VIRUS AND HEPATOCELLULAR CARCINOMA: RECENT ADVANCES. HEPATOCELLULAR CARCINOMA (HCC) REMAINS A GLOBAL HEALTH CHALLENGE, CAUSING 600,000 DEATHS EACH YEAR. INFECTIOUS FACTORS, INCLUDING HEPATITIS B VIRUS (HBV), HEPATITIS C VIRUS (HCV) AND HEPATITIS D VIRUS (HDV), HAVE LONG BEEN CONSIDERED THE MAJOR RISK FACTORS FOR THE DEVELOPMENT AND PROGRESSION OF HCC. THESE PATHOGENS INDUCE HEPATOCYTE TRANSFORMATION THROUGH A VARIETY OF MECHANISMS, INCLUDING INSERTIONAL MUTATIONS CAUSED BY VIRAL GENE INTEGRATION, EPIGENETIC CHANGES, AND THE INDUCTION OF LONG-TERM IMMUNE DYSFUNCTION. THE DISCOVERY OF THESE MECHANISMS, WHILE ADVANCING OUR UNDERSTANDING OF THE DISEASE, ALSO PROVIDES TARGETS FOR NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES. IN ADDITION, THE DISCOVERY AND RESEARCH OF CHRONIC HEV INFECTION OVER THE PAST DECADE INDICATE THAT THIS COMMON HEPATITIS VIRUS ALSO SEEMS TO HAVE THE POTENTIAL TO INDUCE HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW OF RECENT STUDIES ON THE LINK BETWEEN HEPATITIS VIRUS AND HCC, AS WELL AS NEW DIAGNOSTIC AND THERAPEUTIC APPROACHES TO HCC BASED ON THESE FINDINGS. FINALLY, WE ALSO DISCUSS THE POTENTIAL RELATIONSHIP BETWEEN HEV AND HCC. IN CONCLUSION, THESE ASSOCIATIONS WILL FURTHER OPTIMIZE THE DIAGNOSIS AND TREATMENT OF INFECTION-ASSOCIATED HCC AND CALL FOR BETTER MANAGEMENT POLICIES. 2023 6 4449 37 MOLECULAR MECHANISM OF HEPATITIS B VIRUS-INDUCED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) INFECTION IS A GLOBAL PUBLIC HEALTH PROBLEM WITH APPROXIMATELY 2 BILLION PEOPLE THAT HAVE BEEN EXPOSED TO THE VIRUS. HBV IS A MEMBER OF A FAMILY OF SMALL, ENVELOPED DNA VIRUSES CALLED HEPADNAVIRUSES, AND HAS A PREFERENTIAL TROPISM FOR HEPATOCYTES OF MAMMALS AND BIRDS. EPIDEMIOLOGICAL STUDIES HAVE PROVED A STRONG CORRELATION BETWEEN CHRONIC HEPATITIS B VIRUS INFECTION AND THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). HCC IS THE FIFTH MOST COMMON MALIGNANCY WITH ABOUT 700000 NEW CASES EACH YEAR, AND MORE THAN 50% OF THEM ARISE IN HBV CARRIERS. A LARGE NUMBER OF STUDIES DESCRIBE THE WAY IN WHICH HBV CAN CONTRIBUTE TO HCC DEVELOPMENT. MULTIPLE MECHANISMS HAVE BEEN PROPOSED, INCLUDING THE ACCUMULATION OF GENETIC DAMAGE DUE TO IMMUNE-MEDIATED HEPATIC INFLAMMATION AND THE INDUCTION OF OXIDATIVE STRESS. THERE IS EVIDENCE OF THE DIRECT EFFECTS OF THE VIRAL PROTEINS HBX AND HBS ON THE CELL BIOLOGY. INTEGRATION OF HBV-DNA INTO THE HUMAN GENOME IS CONSIDERED AN EARLY EVENT IN THE CARCINOGENIC PROCESS AND CAN INDUCE, THROUGH INSERTIONAL MUTAGENESIS, THE ALTERATION OF GENE EXPRESSION AND CHROMOSOMAL INSTABILITY. HBV HAS ALSO EPIGENETIC EFFECTS THROUGH THE MODIFICATION OF THE GENOMIC METHYLATION STATUS. FURTHERMORE, THE VIRUS PLAYS AN IMPORTANT ROLE IN THE REGULATION OF MICRORNA EXPRESSION. THIS REVIEW WILL SUMMARIZE THE MANY MECHANISMS INVOLVED IN HBV-RELATED LIVER CARCINOGENESIS. 2014 7 3256 30 HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA AND HEPATIC CANCER STEM CELLS. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS LINKED TO HEPATOCELLULAR CARCINOMA (HCC) PATHOGENESIS. DESPITE THE AVAILABILITY OF A HBV VACCINE, CURRENT TREATMENTS FOR HCC ARE INADEQUATE. GLOBALLY, 257 MILLION PEOPLE ARE CHRONIC HBV CARRIERS, AND CHILDREN BORN FROM HBV-INFECTED MOTHERS BECOME CHRONIC CARRIERS, DESTINED TO DEVELOP LIVER CANCER. THUS, NEW THERAPEUTIC APPROACHES ARE NEEDED TO TARGET ESSENTIAL PATHWAYS INVOLVED IN HCC PATHOGENESIS. ACCUMULATING EVIDENCE SUPPORTS EXISTENCE OF HEPATIC CANCER STEM CELLS (HCSCS), WHICH CONTRIBUTE TO CHEMOTHERAPY RESISTANCE AND CANCER RECURRENCE AFTER TREATMENT OR SURGERY. UNDERSTANDING HOW HCSCS FORM WILL ENABLE DEVELOPMENT OF THERAPEUTIC STRATEGIES TO PREVENT THEIR FORMATION. RECENT STUDIES HAVE IDENTIFIED AN EPIGENETIC MECHANISM INVOLVING THE DOWNREGULATION OF THE CHROMATIN MODIFYING POLYCOMB REPRESSIVE COMPLEX 2 (PRC2) DURING HBV INFECTION, WHICH RESULTS IN RE-EXPRESSION OF HCSC MARKER GENES IN INFECTED HEPATOCYTES AND HBV-ASSOCIATED LIVER TUMORS. HOWEVER, THE GENESIS OF HCSCS REQUIRES, IN ADDITION TO THE EXPRESSION OF HCSC MARKERS CELLULAR CHANGES, REWIRING OF METABOLISM, CELL SURVIVAL, ESCAPE FROM PROGRAMMED CELL DEATH, AND IMMUNE EVASION. HOW THESE CHANGES OCCUR IN CHRONICALLY HBV-INFECTED HEPATOCYTES IS NOT YET UNDERSTOOD. IN THIS REVIEW, WE WILL PRESENT THE BASICS ABOUT HBV INFECTION AND HEPATOCARCINOGENESIS. NEXT, WE WILL DISCUSS STUDIES DESCRIBING THE MUTATIONAL LANDSCAPE OF LIVER CANCERS AND HOW EPIGENETIC MECHANISMS LIKELY ORCHESTRATE CELLULAR REPROGRAMING OF HEPATOCYTES TO ENABLE FORMATION OF HCSCS. 2018 8 2182 37 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 9 5761 42 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 10 3278 32 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 11 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 12 3254 27 HEPATITIS B VIRUS X PROTEIN AND HEPATOCARCINOGENESIS. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ONE OF THE MOST ASSOCIATED FACTORS IN HEPATOCARCINOGENESIS. HBV IS ABLE TO INTEGRATE INTO THE HOST GENOME AND ENCODE THE MULTI-FUNCTIONAL HEPATITIS B VIRUS X PROTEIN (HBX). ALTHOUGH THE MECHANISM BETWEEN HBX AND CARCINOGENESIS IS STILL ELUSIVE, RECENT STUDIES HAVE SHOWN THAT HBX WAS ABLE TO INFLUENCE VARIOUS SIGNALING PATHWAYS, AS WELL AS EPIGENETIC AND GENETIC PROCESSES. THIS REVIEW WILL EXAMINE AND SUMMARIZE RECENT LITERATURE ABOUT HBX'S ROLE IN THESE VARIOUS PROCESSES. 2016 13 4454 30 MOLECULAR MECHANISMS DRIVING PROGRESSION OF LIVER CIRRHOSIS TOWARDS HEPATOCELLULAR CARCINOMA IN CHRONIC HEPATITIS B AND C INFECTIONS: A REVIEW. ALMOST ALL PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC), A MAJOR TYPE OF PRIMARY LIVER CANCER, ALSO HAVE LIVER CIRRHOSIS, THE SEVERITY OF WHICH HAMPERS EFFECTIVE TREATMENT FOR HCC DESPITE RECENT PROGRESS IN THE EFFICACY OF ANTICANCER DRUGS FOR ADVANCED STAGES OF HCC. HERE, WE REVIEW RECENT KNOWLEDGE CONCERNING THE MOLECULAR MECHANISMS OF LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC FROM GENETIC AND EPIGENOMIC POINTS OF VIEW. BECAUSE ~70% OF PATIENTS WITH HCC HAVE HEPATITIS B VIRUS (HBV) AND/OR HEPATITIS C VIRUS (HCV) INFECTION, WE FOCUSED ON HBV- AND HCV-ASSOCIATED HCC. THE LITERATURE SUGGESTS THAT GENETIC AND EPIGENETIC FACTORS, SUCH AS MICRORNAS, PLAY A ROLE IN LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC, AND THAT HBV- AND HCV-ENCODED PROTEINS APPEAR TO BE INVOLVED IN HEPATOCARCINOGENESIS. FURTHER STUDIES ARE NEEDED TO ELUCIDATE THE MECHANISMS, INCLUDING IMMUNE CHECKPOINTS AND MOLECULAR TARGETS OF KINASE INHIBITORS, ASSOCIATED WITH LIVER CIRRHOSIS AND ITS PROGRESSION TO HCC. 2019 14 6229 32 THE LNCRNAS IN HBV-RELATED HCCS: TARGETING CHROMATIN DYNAMICS AND BEYOND. HEPATOCELLULAR CARCINOMA (HCC) REPRESENTS THE FOURTH LEADING AND FASTEST RISING CAUSE OF CANCER DEATH (841,000 NEW CASES AND 782,000 DEATHS ANNUALLY), AND HEPATITIS B (HBV), WITH 250 MILLION PEOPLE CHRONICALLY INFECTED AT RISK OF DEVELOPING HCC, ACCOUNTS FOR >50% OF THE CASES WORLDWIDE. LONG NON-CODING RNAS (LNCRNAS), UNTRANSLATED TRANSCRIPTS LONGER THAN 200 NUCLEOTIDES, ARE IMPLICATED IN GENE REGULATION AT THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS, EXERTING THEIR ACTIVITIES BOTH IN THE NUCLEAR AND CYTOPLASMIC COMPARTMENTS. THANKS TO HIGH-THROUGHPUT SEQUENCING TECHNIQUES, SEVERAL LNCRNAS HAVE BEEN SHOWN TO FAVOR THE ESTABLISHMENT OF CHRONIC HBV INFECTION, TO CHANGE THE HOST TRANSCRIPTOME TO ESTABLISH A PRO-CARCINOGENIC ENVIRONMENT, AND TO DIRECTLY PARTICIPATE IN HCC DEVELOPMENT AND PROGRESSION. IN THIS REVIEW, WE SUMMARIZE CURRENT KNOWLEDGE ON THE ROLE OF LNCRNAS IN HBV INFECTION AND HBV-RELATED LIVER CARCINOGENESIS AND DISCUSS THE POTENTIAL OF LNCRNAS AS PREDICTIVE OR DIAGNOSTIC BIOMARKERS. 2021 15 5233 35 PROFIBROTIC SIGNALING AND HCC RISK DURING CHRONIC VIRAL HEPATITIS: BIOMARKER DEVELOPMENT. DESPITE BREAKTHROUGHS IN ANTIVIRAL THERAPIES, CHRONIC VIRAL HEPATITIS B AND C ARE STILL THE MAJOR CAUSES OF LIVER FIBROSIS AND HEPATOCELLULAR CARCINOMA (HCC). IMPORTANTLY, EVEN IN PATIENTS WITH CONTROLLED INFECTION OR VIRAL CURE, THE CANCER RISK CANNOT BE FULLY ELIMINATED, HIGHLIGHTING A PERSISTING ONCOGENIC PRESSURE IMPOSED BY EPIGENETIC IMPRINTING AND ADVANCED LIVER DISEASE. RELIABLE AND MINIMALLY INVASIVE BIOMARKERS FOR EARLY FIBROSIS AND FOR RESIDUAL HCC RISK IN HCV-CURED PATIENTS ARE URGENTLY NEEDED. CHRONIC INFECTION WITH HBV AND/OR HCV DYSREGULATES ONCOGENIC AND PROFIBROGENIC SIGNALING WITHIN THE HOST, ALSO DISPLAYED IN THE SECRETION OF SOLUBLE FACTORS TO THE BLOOD. THE STUDY OF VIRUS-DYSREGULATED SIGNALING PATHWAYS MAY, THEREFORE, CONTRIBUTE TO THE IDENTIFICATION OF RELIABLE MINIMALLY INVASIVE BIOMARKERS FOR THE DETECTION OF PATIENTS AT EARLY-STAGE LIVER DISEASE POTENTIALLY COMPLEMENTING EXISTING NONINVASIVE METHODS IN CLINICS. WITH A FOCUS ON VIRUS-INDUCED SIGNALING EVENTS, THIS REVIEW PROVIDES AN OVERVIEW OF CANDIDATE BLOOD BIOMARKERS FOR LIVER DISEASE AND HCC RISK ASSOCIATED WITH CHRONIC VIRAL HEPATITIS AND EPIGENETIC VIRAL FOOTPRINTS. 2021 16 2980 37 GENETIC BASIS OF HEPATITIS VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA: LINKAGE BETWEEN INFECTION, INFLAMMATION, AND TUMORIGENESIS. HEPATITIS VIRUS INFECTION IS A LEADING CAUSE OF CHRONIC LIVER DISEASE, INCLUDING CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). ALTHOUGH ANTI-VIRAL THERAPIES AGAINST HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV) HAVE DRAMATICALLY PROGRESSED DURING THE PAST DECADE, THE ESTIMATED NUMBER OF PEOPLE CHRONICALLY INFECTED WITH HBV AND/OR HCV IS ~370 MILLION, AND HEPATITIS VIRUS-ASSOCIATED HEPATOCARCINOGENESIS IS A SERIOUS HEALTH CONCERN WORLDWIDE. UNDERSTANDING THE MECHANISM OF VIRUS-ASSOCIATED CARCINOGENESIS IS CRUCIAL TOWARD BOTH TREATMENT AND PREVENTION, AND THE RECENTLY DEVELOPED WHOLE GENOME/EXOME SEQUENCING ANALYSIS USING NEXT-GENERATION SEQUENCING TECHNOLOGIES HAS CONTRIBUTED TO UNVEILING THE LANDSCAPE OF GENETIC AND EPIGENETIC ABERRATIONS IN NOT ONLY TUMOR TISSUES BUT ALSO THE BACKGROUND LIVER TISSUES UNDERLYING CHRONIC LIVER DAMAGE CAUSED BY HEPATITIS VIRUS INFECTION. SEVERAL MAJOR MECHANISMS UNDERLIE THE GENETIC AND EPIGENETIC ABERRATIONS IN THE HEPATITIS VIRUS-INFECTED LIVER, SUCH AS THE GENERATION OF REACTIVE OXIDATIVE STRESS, ECTOPIC EXPRESSION OF DNA MUTATOR ENZYMES, AND DYSFUNCTION OF THE DNA REPAIR SYSTEM. IN ADDITION, DIRECT ONCOGENIC EFFECTS OF HEPATITIS VIRUS, REPRESENTED BY THE INTEGRATION OF HBV-DNA, ARE OBSERVED IN INFECTED HEPATOCYTES. ELUCIDATING THE WHOLE PICTURE OF GENETIC AND EPIGENETIC ALTERATIONS, AS WELL AS THE MECHANISMS OF TUMORIGENESIS, WILL FACILITATE THE DEVELOPMENT OF EFFICIENT TREATMENT AND PREVENTION STRATEGIES FOR HEPATITIS VIRUS-ASSOCIATED HCC. 2017 17 3742 21 INSIGHTS FOR HEPATITIS C VIRUS RELATED HEPATOCELLULAR CARCINOMA GENETIC BIOMARKERS: EARLY DIAGNOSIS AND THERAPEUTIC INTERVENTION. THE CURRENT REVIEW EXPLORES THE ROLE OF EMERGING MOLECULAR CONTRIBUTING FACTORS IN LIVER CARCINOGENESIS ON TOP OF HEPATITIS C VIRUS (HCV). HERE WE WILL TRY TO DISCUSS THE ROLE GENETIC AND EPIGENETIC FACTORS IN PATHOGENESIS OF HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE ROLE OF THESE FACTORS WILL HELP IN DISCOVERING THE MYSTERY OF LIVER CARCINOGENESIS ON TOP OF CHRONIC HCV INFECTION. MOREOVER, USE OF THE STUDIED MOLECULAR FACTORS WILL PROVIDE THE HEPATOLOGISTS WITH TAILORED DIAGNOSTIC PROMISING BIOMARKERS AND FLATTEN THE WAY FOR ESTABLISHMENT OF EMERGING MOLECULAR TREATMENT BASED ON EXPLORING THE MOLECULAR SUBSCRIPTION OF THIS AGGRESSIVE LIVER CANCER. 2016 18 5211 27 PRENEOPLASTIC LESIONS IN HUMAN HEPATOCARCINOGENESIS. THE EARLY STAGES OF HEPATOCARCINOGENESIS IN HUMAN CHRONIC LIVER DISEASES ARE CHARACTERIZED BY THE EMERGENCE OF PRENEOPLASTIC LESIONS OF WHICH SOME WILL EVENTUALLY DEVELOP INTO HEPATOCELLULAR CARCINOMA (HCC). BASIC STUDIES ON THE GENETIC AND EPIGENETIC ALTERATIONS OF THESE PRENEOPLASTIC LESIONS MAY EVENTUALLY LEAD TO NEW THERAPEUTIC STRATEGIES. CLINICOPATHOLOGICAL STUDIES ARE ALSO IMPORTANT IN ORDER TO DETERMINE OPTIMAL MANAGEMENT OF PATIENTS WITH A PRENEOPLASTIC LESION. THIS ARTICLE AIMS TO PROVIDE A COMPREHENSIVE REVIEW OF THE CURRENT CONCEPTS OF PRENEOPLASTIC LESION IN CHRONIC LIVER DISEASES. THE MICROSCOPICAL SMALL-CELL DYSPLASTIC FOCUS IS THE SMALLEST MORPHOLOGICALLY RECOGNIZABLE PRECURSOR LESION OF HCC AND THEREFORE IS A LOGICAL TARGET OF STUDY TO ELUCIDATE THE EARLIEST EVENTS IN HEPATOCARCINOGENESIS. IN CONTRAST, LARGE-CELL DYSPLASIA IS NOT A PRECURSOR LESION, BUT APPEARS TO BE OF CLINICAL VALUE BECAUSE OF ITS GOOD PREDICTIVE VALUE FOR DEVELOPMENT OF HCC. DYSPLASTIC NODULES (DNS) ARE MACROSCOPICALLY RECOGNIZABLE PRECURSOR LESIONS OF HCC AND HIGH-GRADE DNS (HGDNS) HAVE A RISK OF MALIGNANT TRANSFORMATION. DETECTION OF DNS AND CORRECT DIFFERENTIATION FROM SMALL HCC (<2 CM) IS SOMETIMES DIFFICULT, ESPECIALLY WHEN ONLY IMAGING TECHNIQUES ARE USED. ADDITIONAL CLINICOPATHOLOGICAL STUDIES ON IDENTIFICATION AND OPTIMAL TREATMENT OF DNS ARE NECESSARY. MOLECULAR STUDIES ON HGDNS AND SMALL HCCS MAY YIELD MUCH INFORMATION ON THE GENETIC MECHANISMS INVOLVED IN THE TRANSITION FROM SEVERE DYSPLASIA TO EARLY MALIGNANCY. IN CONTRAST, CURRENTLY AVAILABLE DATA INDICATE THAT (LARGE) REGENERATIVE NODULES DO NOT REPRESENT A DISTINCT STEP IN HEPATOCARCINOGENESIS. ANIMAL MODELS WILL BE HELPFUL IN THE FURTHER UNRAVELLING OF HUMAN HCC DEVELOPMENT, PROVIDED THAT STUDIES ARE PERFORMED ON MODELS THAT ARE GOOD REPRESENTATIVES OF HUMAN HEPATOCARCINOGENESIS. WE PROPOSE THREE CRITERIA BY WHICH GOOD MIMICKERS CAN BE IDENTIFIED. 2005 19 6849 29 [MOLECULAR MECHANISM OF HEPATOCARCINOGENESIS]. HEPATOCELLULAR CARCINOMA (HCC) IN JAPAN IS CLOSELY ASSOCIATED WITH THE CHRONIC LIVER DISEASES OF INFECTION WITH THE HEPATITIS B OR C VIRUSES. ANALYSIS OF HCC TISSUES FREQUENTLY DETECTS LOSS OF HETEROZYGOSITY AT CHROMOSOMES 1P, 4, 6Q, 8P, 10Q, 13Q, 16Q, 17P, AND MANY GENOMIC AND EPIGENOMIC ABNORMALITIES HAVE BEEN FOUND IN P53, BETA-CATENIN, P16CDKI, DNA MISMATCH REPAIR GENES, AND OTHERS. HOWEVER, NO SPECIFIC ABNORMAL GENETIC OR EPIGENETIC CHANGES FOR HCC HAVE BEEN FOUND SO FAR. THE DEVELOPMENT OF HCC HAS BEEN REPORTED IN MICE TRANSGENIC FOR THE HEPATITIS B VIRUS X GENE OR THE HEPATITIS C VIRUS CORE GENE, AND THESE VIRAL PROTEINS MIGHT PLAY ESSENTIAL ROLES IN HEPATOCARCINOGENESIS. CHRONIC HEPATITIS AND FIBROSIS DUE TO PERSISTENT VIRAL INFECTION MIGHT ALSO INFLUENCE THE GENOMIC INSTABILITY OF HEPATOCYTES, LEADING TO ACCUMULATION OF GENOMIC CHANGES. 1999 20 4476 27 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