1 5218 150 PREVENTION OF HEPATOCELLULAR CARCINOMA. PREVENTION IS THE ONLY REALISTIC APPROACH FOR REDUCING MORTALITY RATES ASSOCIATED WITH HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. VACCINATION AGAINST HEPATITIS B AND SCREENING OF BLOOD DONATIONS ARE EFFECTIVE MEASURES OF PRIMARY PREVENTION. SCREENING OF BLOOD DONATIONS HAS LED TO A SUBSTANTIAL REDUCTION IN VIRAL HEPATITIS TRANSMISSION AMONG THE GENERAL POPULATION, AND IN TAIWAN VACCINATION AGAINST HEPATITIS B CAUSED A SIGNIFICANT REDUCTION IN HCC INCIDENCE AMONG INFANTS. PRIMARY PREVENTION ALSO INCLUDES APPROACHES THAT ALTER EPIGENETIC AND GENETIC CHANGES IN HEPATOCYTES, KNOWN TO INCREASE SUSCEPTIBILITY TO HCC, AS WELL AS TREATMENTS SLOWING PROGRESSION TO CIRRHOSIS. THE ONLY EVIDENCE THAT CHEMOPREVENTION REDUCES HCC RISK IS A MULTICENTER RANDOMIZED PROSPECTIVE STUDY IN ASIAN PATIENTS WITH ADVANCED HEPATITIS B WHO RECEIVED THE ORAL NUCLEOSIDE ANALOGUE LAMIVUDINE. CIRCUMSTANTIAL EVIDENCE SUGGESTS THAT HCC RISK IS ALSO REDUCED IN PATIENTS WITH CHRONIC HEPATITIS C WHO HAVE HAD A SUSTAINED VIROLOGICAL RESPONSE TO INTERFERON THERAPY. HCC IS NOT SUBSTANTIALLY REDUCED IN PATIENTS WITH HEPATITIS B TREATED WITH INTERFERON AND PATIENTS WITH HEPATITIS C WHO DID NOT RESPOND TO INTERFERON. SECONDARY PREVENTION, THAT IS, PREVENTION OF TUMOR RECURRENCE AFTER HEPATIC RESECTION OR LOCAL ABLATIVE THERAPIES, HAS BEEN PURSUED WITH DIFFERENT APPROACHES. RETINOIDS, HEPATIC EMBOLIZATION WITH (131)I LIPIODOL, AND ADOPTIVE ADJUVANT IMMUNOTHERAPY HAVE YIELDED ENCOURAGING RESULTS. OTHER APPROACHES, INCLUDING THOSE BASED ON INTERFERON ALFA OR BETA, PROVIDED INCONCLUSIVE EVIDENCE FOR SECONDARY PROPHYLAXIS OF HCC, MAINLY BECAUSE OF THE POOR METHODOLOGIES AND SCIENTIFIC BACKGROUND OF THE STUDIES. DIETARY INTERVENTIONS AND ANTIAFLATOXIN AGENTS MIGHT HELP TO PREVENT HCC IN SUSCEPTIBLE INDIVIDUALS, BUT THE REAL EFFICACY OF THESE APPROACHES IS FAR FROM BEING DEMONSTRATED. 2005 2 6707 37 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 5211 34 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 4 3263 37 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 5 6798 36 [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 6 6356 27 THE ROLE OF HOST IN THE SPECTRUM OF OUTCOMES IN FAMILY CLUSTERS OF HEPATITIS INFECTION: FROM ASYMPTOMATIC TO HEPATOCELLULAR CARCINOMA. HEPATITIS B VIRUS INFECTIONS ARE PREVALENT WORLDWIDE, BUT THE OUTCOMES OF INFECTION VARY GREATLY FROM HOST TO HOST. IN MANY ENDEMIC REGIONS, VERTICAL TRANSMISSION FROM MOTHER TO CHILD IS MOST COMMON. IN THIS TRANSMISSION SETTING, VIRUS GENOTYPE AND SHARED PATIENT GENETICS MAKE FOR AN INTERESTING COMPARISON OF OUTCOME OF CHRONIC HEPATITIS B INFECTION. THIS CASE SERIES DEMONSTRATES FOUR FAMILY CLUSTERS WHICH DISPLAY DISPARATE OUTCOMES AMONG FAMILY MEMBERS WITH HEPATITIS B VIRUS INFECTIONS, FURTHER STRESSING THE ROLE OF HOST AND NON-GENETIC FACTORS IN THE NATURAL HISTORY OF THE DISEASE. MANY HOST FACTORS HAVE BEEN THEORIZED, FROM EPIGENETIC MECHANISMS TO THE ROLE OF CHRONIC STRESS, BUT MORE RESEARCH IS NEEDED TO BETTER UNDERSTAND THOSE AT HIGHER RISK OF FEARED COMPLICATIONS SUCH AS HEPATOCELLULAR CARCINOMA AND CIRRHOSIS. 2023 7 309 26 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 8 5233 29 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 9 3927 35 LIVER ABNORMALITIES AFTER ELIMINATION OF HCV INFECTION: PERSISTENT EPIGENETIC AND IMMUNOLOGICAL PERTURBATIONS POST-CURE. CHRONIC HEPATITIS C (CHC) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC) WORLDWIDE. WHILE DIRECTLY ACTING ANTIVIRAL (DAA) DRUGS ARE NOW ABLE TO CURE VIRTUALLY ALL HEPATITIS C VIRUS (HCV) INFECTIONS, EVEN IN SUBJECTS WITH ADVANCED LIVER DISEASE, WHAT HAPPENS TO THE LIVER AND PROGRESSION OF THE DISEASE AFTER DAA-INDUCED CURE OF VIREMIA IS ONLY BEGINNING TO EMERGE. SEVERAL LARGE-SCALE CLINICAL STUDIES IN DIFFERENT PATIENT POPULATIONS HAVE SHOWN THAT PATIENTS WITH ADVANCED LIVER DISEASE MAINTAIN A RISK FOR DEVELOPING HCC EVEN WHEN THE ORIGINAL INSTIGATOR, THE VIRUS, IS ELIMINATED BY DAAS. HERE WE REVIEW EMERGING STUDIES DERIVED FROM MULTIPLE, COMPLEMENTARY EXPERIMENTAL SYSTEMS INVOLVING PATIENT LIVER TISSUES, HUMAN LIVER CELL CULTURES, HUMAN LIVER SLICE CULTURES, AND ANIMAL MODELS, SHOWING THAT HCV INFECTION INDUCES EPIGENETIC, SIGNALING, AND GENE EXPRESSION CHANGES IN THE LIVER ASSOCIATED WITH ALTERED HEPATIC INNATE IMMUNITY AND LIVER CANCER RISK. OF CRITICAL IMPORTANCE IS THE FACT THAT THESE VIRUS-INDUCED ABNORMALITIES PERSIST AFTER DAA CURE OF HCV. THESE NASCENT FINDINGS PORTEND THE DISCOVERY OF PATHWAYS INVOLVED IN POST-HCV IMMUNOPATHOGENESIS, WHICH MAY BE CLINICALLY ACTIONABLE TARGETS FOR MORE COMPREHENSIVE CARE OF DAA-CURED INDIVIDUALS. 2021 10 3266 30 HEPATOCELLULAR CANCER AND GUT MICROBIOME: TIME TO UNTIE GORDIAN'S KNOT. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE LEADING CAUSES OF CANCER DEATH WORLDWIDE AND THE INCIDENCE IS GROWING ON A GLOBAL SCALE. ABOUT 90% OF CASES DEVELOP ON THE CIRRHOTIC LIVER AND THE ETIOLOGY IS MULTIFACTORIAL. INCREASING NUMBER OF STUDIES SUGGEST THAT GUT MICROBIOTA INFLUENCES THE DEVELOPMENT AND PROGRESSION OF LIVER DISEASES, INCLUDING CHRONIC HEPATIC INFLAMMATION, FIBROSIS, CIRRHOSIS, AND HCC. THE KEY ROLE OF GUT MICROBIOTA IN CARCINOGENESIS SEEMS TO BE ASSOCIATED WITH GENOMIC INSTABILITY OF HOST CELLS AND IMMUNE DYSREGULATION. RECENT CLINICAL STUDIES SHOWED THAT A STABLE AND HEALTHY MICROBIOTA INITIALLY COULD HAVE THE ABILITY TO RESIST THE EMERGENCE OF CHRONIC INFLAMMATION AND, THEREFORE, PREVENT THE INDUCTION OF CARCINOGENIC CELLS IN VARIOUS ORGANS SUCH AS THE ESOPHAGUS, STOMACH, COLON, AND LIVER. THE PROGRESSION FROM INFLAMMATION TO CANCER IS A STEPWISE PROCESS OCCURRING BY THE CONCERTED ACTION OF SEVERAL FACTORS SUCH AS DYSBIOSIS, INCREASED GUT PERMEABILITY, DIET, METABOLOMIC, GENETIC, AND EPIGENETIC CHANGES. IN THIS ARTICLE, WE AIMED TO REVIEW THE POSSIBLE ROLE OF GUT MICROBIOTA IN THE DEVELOPMENT, PROGRESSION, AND TREATMENT OF HCC. 2021 11 4687 30 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 12 3392 33 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 13 3277 31 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 14 3265 39 HEPATOCARCINOMA: GENETIC AND EPIGENETIC FEATURES. HCC IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATHS WORLDWIDE, ACCOUNTING FOR ABOUT 1 MILLION DEATHS ANNUALLY. THE INCIDENCE OF HCC IS HIGHEST IN ASIA AND AFRICA, WHERE THE ENDEMIC HIGH PREVALENCE OF HEPATITIS B AND HEPATITIS C STRONGLY PREDISPOSES TO THE DEVELOPMENT OF CHRONIC LIVER DISEASE AND SUBSEQUENT DEVELOPMENT OF HCC. PATIENTS WITH HCC GENERALLY PRESENT AT AN ADVANCED STAGE DUE TO COMPENSATED CIRRHOSIS DEFINED BY THE ABSENCE OF PATHOGNOMONIC SYMPTOMS, RESULTING IN DEATH WITHIN 6 TO 20 MONTHS, SUGGESTING AN URGENT NEED IN TREATMENT MODALITIES THAT WILL DRAMATICALLY DECREASE THE MORTALITY RATE OF HCC. THE MOLECULAR HEPATOCARCINOGENESIS IS, HOWEVER, A GRADUAL PROCESS DURING WHICH GENETIC ALTERATIONS PROGRESSIVELY ACCUMULATE AND LEAD TO HCC THROUGH INTERMEDIATE PRENEOPLASTIC STAGES. WITH THE ADVENT OF WHOLE GENOME SEQUENCING TOOLS, VARIOUS MUTATIONS ASSOCIATED WITH HCC HAVE BEEN IDENTI FI ED, WHICH HAVE ADVANCED OUR MOLECULAR UNDERSTANDING OF HCC. HOWEVER, THE FREQUENCY OF THESE MUTATIONS IS RARE, AND THESE GENETIC MUTATIONS ONLY PARTLY EXPLAIN THE ETIOLOGY OF THE DISEASE. BETTER UNDERSTANDING AND CHARACTERIZATION OF NOVEL GENETIC AND EPIGENETIC ALTERATIONS, WHICH ARE IMPORTANT TO HEPATOCARCINOGENESIS, MAY HELP UNDERSTAND THE MOLECULAR PATHOGENESIS OF HCC, AS WELL AS PROVIDING NOVEL THERAPEUTIC TARGETS FOR HCC TREATMENT. FURTHER CONSIDERATION SHOULD BE GIVEN TO DEVELOPING MORE EFFECTIVE MOLECULAR DIAGNOSTIC MARKERS AND TARGETED DRUG THERAPY. 2018 15 5622 33 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 16 4421 25 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 17 4449 27 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 18 6092 31 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 19 6797 36 [EPIDEMIOLOGY, NATURAL HISTORY AND PATHOGENESIS OF HEPATOCELLULAR CARCINOMA]. HEPATOCELLULAR CARCINOMA (HCC) IS THE MAIN TYPE OF PRIMARY LIVER CANCERS AND THE THIRD MOST COMMON CAUSE OF CANCER MORTALITY WORLDWIDE. IN FRANCE, RISING NUMBER BETWEEN 5000 AND 6000 CASES ARE DIAGNOSED EACH YEAR. THE MAJOR RISK FACTOR FOR HEPATOCELLULAR CARCINOMA IS CHRONIC HEPATITIS: VIRAL HEPATITIS B, VIRAL HEPATITIS C, CONSUMPTION OF ALCOHOL, HEMOCHROMATOSIS. HEPATOCELLULAR CARCINOMA IS CLOSELY ASSOCIATED TO LIVER CIRRHOSIS, WHICH IS A TRUE PRECANCEROUS STATE. BECAUSE HEPATOCARCINOGENESIS IS A LONG AND HETEROGENEOUS PROCESS, THERE IS STILL MUCH TO UNDERSTAND. MANY GENETIC AND EPIGENETIC ALTERATIONS ARE DESCRIBED LEADING TO CHANGES IN CELLULAR SIGNALLING CASCADES INVOLVED IN REGULATION OF GROWTH, DIFFERENTIATION, APOPTOSIS, MOTILITY. HEPATITIS VIRUSES PLAY A DIRECT ONCOGENIC ROLE THROUGH THE INTERACTION BETWEEN VIRAL AND CELLULAR PROTEINS, WHICH CONTROL CELL HOMEOSTASIS, OR BY THE INTEGRATION OF HEPATITIS B VIRUS GENOME INTO THE HOST GENOME. FURTHERMORE, HEPATITIS VIRUSES PLAY AN INDIRECT ONCOGENIC ROLE BY CAUSING CHRONIC INFLAMMATION AND HEPATOCYTE REGENERATION RELATED TO VIRAL HEPATOPATHY. IN EXPECTATION OF A BETTER UNDERSTANDING OF HEPATOCARCINOGENESIS AND NEW TREATMENTS, PREVENTION FROM RISK FACTORS AND ULTRASONOGRAPHIC SCREENING OF PATIENTS WITH CIRRHOSIS SHOULD INCREASE PROGNOSIS. 2011 20 915 32 CHRONIC HEPATITIS B VIRUS AND HEPATITIS C VIRUS INFECTIONS AND CANCER: SYNERGY BETWEEN VIRAL AND HOST FACTORS. HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) INFECTIONS REPRESENT MAJOR CAUSES OF CHRONIC LIVER DISEASE AND HEPATOCELLULAR CARCINOMA. DESPITE INDUCING SHARED PATHOLOGICAL EVENTS LEADING TO ONCOGENIC TRANSFORMATION, THESE TWO VIRUSES PRESENT PROFOUND DIFFERENCES IN THEIR MOLECULAR FEATURES, LIFE CYCLE AND INTERPLAY WITH HOST FACTORS, WHICH SIGNIFICANTLY DIFFERENTIATE THE PROGNOSTIC AND THERAPEUTIC APPROACH TO THE RELATED DISEASES. IN THE PRESENT REVIEW, WE REPORT THE MAIN MECHANISMS INVOLVED IN THE MULTISTEP PROCESS LEADING FROM HCV/HBV INFECTION AND CANCER DEVELOPMENT, DISCUSSING SIDE-BY-SIDE THE ANALOGIES AND DIFFERENCES BETWEEN THE TWO VIRUSES. SUCH EVENTS CAN BE BROADLY CATEGORIZED INTO (A) DIRECT ONCOGENIC EFFECTS, INVOLVING INTEGRATION IN THE HOST GENOME (IN THE CASE OF HBV) AND CHROMOSOMAL INSTABILITY, INTERFERENCE WITH ONCOSUPPRESSOR PATHWAYS, INDUCTION OF OXIDATIVE STRESS, PROMOTION OF ANGIOGENESIS, EPITHELIAL-MESENCHYMAL TRANSITION, ALTERATIONS IN THE EPIGENETIC ASSET AND INTERACTION WITH NON-CODING RNAS; AND (B) INDIRECT ACTIVITIES MOSTLY MEDIATED BY HOST EVENTS, INCLUDING CHRONIC INFLAMMATION SUSTAINED BY PECULIAR CYTOKINE NETWORKS (SUCH AS INTERLEUKIN-6 AND LYMPHOTOXINS), METABOLIC DYSFUNCTIONS PROMOTED BY STEATOHEPATITIS, INTERPLAY WITH GUT MICROBIOTA AND FIBROTIC EVENTS (MAINLY IN HCV INFECTION). THIS SCENARIO SUGGESTS THAT THE INTEGRATED STUDY OF VIRAL AND HOST FACTORS MAY LEAD TO THE SUCCESSFUL DEVELOPMENT OF NOVEL BIOMARKERS AND TARGETS FOR THERAPY. 2015