1 6849 88 [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 2 3392 29 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 3 3256 27 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 4 6421 26 THE THERAPEUTIC PROPERTIES OF RESMINOSTAT FOR HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON FORM OF PRIMARY LIVER CANCER WITH INCREASES IN NEW CASES BEING REPORTED ANNUALLY. HISTOPATHOLOGISTS HAVE IDENTIFIED HEPATIC STEATOSIS AS A CHARACTERISTIC OF A BROAD RANGE OF CHRONIC LIVER DISEASES THAT ARE ASSOCIATED WITH THE ONSET AND DEVELOPMENT OF HCC. IN THIS CONTEXT, EPIGENETIC MODIFICATIONS MAY SERVE AS PRECANCEROUS FACTORS PREDISPOSING NORMAL CELLS TO THE INITIATION OF CARCINOGENESIS. THIS STUDY DEMONSTRATED THAT HEPATIC TUMORIGENESIS AND DIFFERENTIATED ADIPOCYTES MAY MODULATE BOTH GLOBAL HISTONE DEACETYLASE (HDAC) EXPRESSION AND SPECIFIC CLASS I HDAC GENES IN THE TUMOUR MICROENVIRONMENT. THE NOVEL CLASS I HDAC INHIBITOR RESMINOSTAT WAS SHOWN TO REDUCE THE PROLIFERATION OF HCC CELLS ALONG WITH ITS SPECIFICITY IN TARGETING CLASS I HDACS AND ONCOGENES. THE COMBINED EFFECT OF RESMINOSTAT WITH SEVERAL PHARMACEUTICAL AGENTS SUCH AS SORAFENIB, CISPLATIN AND DOXORUBICIN WAS ALSO DEMONSTRATED. THE INHIBITION OF HEAT SHOCK PROTEIN 90 (HSP90) HAS BEEN DEMONSTRATED AS A POTENTIAL THERAPEUTIC OPTION FOR HCC. IN LINE WITH THIS, THE SPECIFIC HSP90 INHIBITOR 17-(ALLYLAMINO)-17-DEMETHOXYGELDANAMYCIN (17-AAG) WAS SELECTED AND IT WAS FOUND THAT THE COMBINATION OF RESMINOSTAT AND 17-AAG MAY PROVIDE A "SMART" CLINICAL STRATEGY FOR HCC PATIENTS BY TARGETING CELLULAR COMMUNICATION WITHIN THE TUMOUR MICROENVIRONMENT. THIS STUDY PROVIDES AN INSIGHT INTO THE USE OF RESMINOSTAT AS AN EPIGENETIC BASED THERAPEUTIC FOR HCC ALONG WITH OTHER PHARMACEUTICAL OPTIONS, IN PARTICULAR BY TARGETING THE CELL-TO-CELL COMMUNICATION THAT OCCURS BETWEEN HEPATOMA AND ADIPOCYTES. 2018 5 3243 30 HEPATIC STEATOSIS IN HEPATITIS C IS A STORAGE DISEASE DUE TO HCV INTERACTION WITH MICROSOMAL TRIGLYCERIDE TRANSFER PROTEIN (MTP). LIVER STEATOSIS IS A FREQUENT HISTOLOGICAL FEATURE IN PATIENTS CHRONICALLY INFECTED WITH HEPATITIS C VIRUS (HCV). THE RELATIONSHIP BETWEEN HCV AND HEPATIC STEATOSIS SEEMS TO BE THE RESULT OF BOTH EPIGENETIC AND GENETIC FACTORS. IN VIVO AND IN VITRO STUDIES HAVE SHOWN THAT HCV CAN ALTER INTRAHEPATIC LIPID METABOLISM BY AFFECTING LIPID SYNTHESIS, OXIDATIVE STRESS, LIPID PEROXIDATION, INSULIN RESISTANCE AND THE ASSEMBLY AND SECRETION OF VLDL. MANY STUDIES SUGGEST THAT HCV-RELATED STEATOSIS MIGHT BE THE RESULT OF A DIRECT INTERACTION BETWEEN THE VIRUS AND MTP. IT HAS BEEN DEMONSTRATED THAT MTP IS CRITICAL FOR THE SECRETION OF HCV PARTICLES AND THAT INHIBITION OF ITS LIPID TRANSFER ACTIVITY REDUCES HCV PRODUCTION. HOWEVER, HIGHER DEGREES OF HEPATIC STEATOSIS WERE FOUND IN CHRONIC HEPATITIS C PATIENTS CARRYING THE T ALLELE OF MTP -493G/T POLYMORPHISM THAT SEEMS TO BE ASSOCIATED WITH INCREASED MTP TRANSCRIPTION. WE PROPOSE HERE THAT LIVER STEATOSIS IN HEPATITIS C COULD BE A STORAGE DISEASE INDUCED BY THE EFFECTS OF THE VIRUS AND OF ITS PROTEINS ON THE INTRACELLULAR LIPID MACHINERY AND ON MTP. AVAILABLE DATA SUPPORT THE HYPOTHESIS THAT HCV MAY MODULATE MTP EXPRESSION AND ACTIVITY THROUGH A NUMBER OF MECHANISMS SUCH AS INHIBITION OF ITS ACTIVITY AND TRANSCRIPTIONAL CONTROL. INITIAL UP REGULATION COULD FAVOUR PROPAGATION OF HCV WHILE DOWN REGULATION IN CHRONIC PHASE COULD CAUSE IMPAIRMENT OF TRIGLYCERIDE SECRETION AND EXCESSIVE LIPID ACCUMULATION, WITH ABNORMAL LIPID DROPLETS FACILITATING THE "STORAGE" OF VIRUS PARTICLES FOR PERSISTENT INFECTION. 2010 6 3307 29 HIGH-RESOLUTION GENOMIC PROFILING OF LIVER CANCER LINKS ETIOLOGY WITH MUTATION AND EPIGENETIC SIGNATURES. BACKGROUND & AIMS: HEPATOCELLULAR CARCINOMA (HCC) IS A MODEL OF A DIVERSE SPECTRUM OF CANCERS BECAUSE IT IS INDUCED BY WELL-KNOWN ETIOLOGIES, MAINLY HEPATITIS C VIRUS (HCV) AND HEPATITIS B VIRUS. HERE, WE AIMED TO IDENTIFY HCV-SPECIFIC MUTATIONAL SIGNATURES AND EXPLORED THE LINK BETWEEN THE HCV-RELATED REGIONAL VARIATION IN MUTATIONS RATES AND HCV-INDUCED ALTERATIONS IN GENOME-WIDE CHROMATIN ORGANIZATION. METHODS: TO IDENTIFY AN HCV-SPECIFIC MUTATIONAL SIGNATURE IN HCC, WE PERFORMED HIGH-RESOLUTION TARGETED SEQUENCING TO DETECT PASSENGER MUTATIONS ON 64 HCC SAMPLES FROM 3 ETIOLOGY GROUPS: HEPATITIS B VIRUS, HCV, OR OTHER. TO EXPLORE THE LINK BETWEEN THE GENOMIC SIGNATURE AND GENOME-WIDE CHROMATIN ORGANIZATION WE PERFORMED CHROMATIN IMMUNOPRECIPITATION SEQUENCING FOR THE TRANSCRIPTIONALLY PERMISSIVE H3K4ME3, H3K9AC, AND SUPPRESSIVE H3K9ME3 MODIFICATIONS AFTER HCV INFECTION. RESULTS: REGIONAL VARIATION IN MUTATION RATE ANALYSIS SHOWED SIGNIFICANT ETIOLOGY-DEPENDENT REGIONAL MUTATION RATES IN 12 GENES: LRP2, KRT84, TMEM132B, DOCK2, DMD, INADL, JAK2, DNAH6, MTMR9, ATM, SLX4, AND ARSD. WE FOUND AN ENRICHMENT OF C->T TRANSVERSION MUTATIONS IN THE HCV-ASSOCIATED HCC CASES. FURTHERMORE, THESE CASES SHOWED REGIONAL VARIATION IN MUTATION RATES ASSOCIATED WITH GENOMIC INTERVALS IN WHICH HCV INFECTION DICTATED EPIGENETIC ALTERATIONS. THIS SIGNATURE MAY BE RELATED TO THE HCV-INDUCED DECREASED EXPRESSION OF GENES ENCODING KEY ENZYMES IN THE BASE EXCISION REPAIR PATHWAY. CONCLUSIONS: WE IDENTIFIED NOVEL DISTINCT HCV ETIOLOGY-DEPENDENT MUTATION SIGNATURES IN HCC ASSOCIATED WITH HCV-INDUCED ALTERATIONS IN HISTONE MODIFICATION. THIS STUDY PRESENTS A LINK BETWEEN CANCER-CAUSING MUTAGENESIS AND THE INCREASED PREDISPOSITION TO LIVER CANCER IN CHRONIC HCV-INFECTED INDIVIDUALS, AND UNVEILS NOVEL ETIOLOGY-SPECIFIC MECHANISMS LEADING TO HCC AND CANCER IN GENERAL. 2023 7 3263 26 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 8 6707 26 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 9 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 10 3742 19 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 11 758 26 CAS9-TARGETED NANOPORE SEQUENCING REVEALS EPIGENETIC HETEROGENEITY AFTER DE NOVO ASSEMBLY OF NATIVE FULL-LENGTH HEPATITIS B VIRUS GENOMES. HEPATITIS B VIRUS (HBV) CONTAINS A 3.2 KB DNA GENOME AND CAUSES ACUTE AND CHRONIC HEPATITIS. HBV INFECTION IS A GLOBAL HEALTH PROBLEM, WITH 350 MILLION CHRONICALLY INFECTED PEOPLE AT INCREASED RISK OF DEVELOPING LIVER DISEASE AND HEPATOCELLULAR CARCINOMA (HCC). METHYLATION OF HBV DNA IN A CPG CONTEXT (5MCPG) CAN ALTER THE EXPRESSION PATTERNS OF VIRAL GENES RELATED TO INFECTION AND CELLULAR TRANSFORMATION. MOREOVER, IT MAY ALSO PROVIDE CLUES AS TO WHY CERTAIN INFECTIONS ARE CLEARED OR PERSIST WITH OR WITHOUT PROGRESSION TO CANCER. THE DETECTION OF 5MCPG OFTEN REQUIRES TECHNIQUES THAT DAMAGE DNA OR INTRODUCE BIAS THROUGH A MYRIAD OF LIMITATIONS. THEREFORE, WE DEVELOPED A METHOD FOR THE DETECTION OF 5MCPG ON THE HBV GENOME THAT DOES NOT RELY ON BISULFITE CONVERSION OR PCR. WITH CAS9-GUIDED RNPS TO SPECIFICALLY TARGET THE HBV GENOME, WE ENRICHED IN HBV DNA FROM PRIMARY HUMAN HEPATOCYTES (PHHS) INFECTED WITH DIFFERENT HBV GENOTYPES, AS WELL AS ENRICHING IN HBV FROM INFECTED PATIENT LIVER TISSUE, FOLLOWED BY SEQUENCING WITH OXFORD NANOPORE TECHNOLOGIES MINION. DETECTION OF 5MCPG BY NANOPORE SEQUENCING WAS BENCHMARKED WITH BISULFITE-QUANTITATIVE METHYL-SPECIFIC QPCR (BS-QMSP). THE 5MCPG LEVELS IN HBV DETERMINED BY BS-QMSP AND NANOPORE SEQUENCING WERE HIGHLY CORRELATED. OUR NANOPORE SEQUENCING APPROACH ACHIEVED A COVERAGE OF ~2000X OF HBV DEPENDING ON INFECTION EFFICIENCY, SUFFICIENT COVERAGE TO PERFORM A DE NOVO ASSEMBLY AND DETECT SMALL FLUCTUATIONS IN HBV METHYLATION, PROVIDING THE FIRST DE NOVO ASSEMBLY OF NATIVE HBV DNA, AS WELL AS THE FIRST LANDSCAPE OF 5MCPG FROM NATIVE HBV SEQUENCES. MOREOVER, BY CAPTURING ENTIRE HBV GENOMES, WE EXPLORED THE EPIGENETIC HETEROGENEITY OF HBV IN INFECTED PATIENTS AND IDENTIFIED FOUR EPIGENETICALLY DISTINCT CLUSTERS BASED ON METHYLATION PROFILES. THIS METHOD IS A NOVEL APPROACH THAT ENABLES THE ENRICHMENT OF VIRAL DNA IN A MIXTURE OF NUCLEIC ACID MATERIAL FROM DIFFERENT SPECIES AND WILL SERVE AS A VALUABLE TOOL FOR INFECTIOUS DISEASE MONITORING. 2021 12 3278 29 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 13 6798 27 [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 14 3254 21 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 15 4449 38 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 16 3728 24 INHIBITION OF REPLICATION OF HEPATITIS B VIRUS USING TRANSCRIPTIONAL REPRESSORS THAT TARGET THE VIRAL DNA. BACKGROUND: CHRONIC INFECTION WITH HEPATITIS B VIRUS (HBV) IS A SERIOUS GLOBAL HEALTH PROBLEM. PERSISTENCE OF THE VIRUS OCCURS AS A RESULT OF STABILITY OF THE REPLICATION INTERMEDIATE COMPRISING COVALENTLY CLOSED CIRCULAR DNA (CCCDNA). DEVELOPMENT OF DRUGS THAT ARE CAPABLE OF DISABLING THIS CCCDNA IS VITAL. METHODS: TO INVESTIGATE AN EPIGENETIC APPROACH TO INACTIVATING VIRAL DNA, WE ENGINEERED TRANSCRIPTIONAL REPRESSORS THAT COMPRISE AN HBV DNA-BINDING DOMAIN OF TRANSCRIPTION ACTIVATOR LIKE EFFECTORS (TALES) AND A FUSED KRUPPEL ASSOCIATED BOX (KRAB). THESE REPRESSOR TALES (RTALES) TARGETED THE VIRAL SURFACE OPEN READING FRAME AND WERE PLACED UNDER TRANSCRIPTION CONTROL OF CONSTITUTIVELY ACTIVE OR LIVER-SPECIFIC PROMOTERS. RESULTS: EVALUATION IN CULTURED CELLS AND FOLLOWING HYDRODYNAMIC INJECTION OF MICE REVEALED THAT THE RTALES SIGNIFICANTLY INHIBITED PRODUCTION OF MARKERS OF HBV REPLICATION WITHOUT EVIDENCE OF HEPATOTOXICITY. INCREASED METHYLATION OF HBV DNA AT CPG ISLAND II SHOWED THAT THE RTALES CAUSED INTENDED EPIGENETIC MODIFICATION. CONCLUSIONS: EPIGENETIC MODIFICATION OF HBV DNA IS A NEW AND EFFECTIVE MEANS OF INACTIVATING THE VIRUS IN VIVO. THE APPROACH HAS THERAPEUTIC POTENTIAL AND AVOIDS POTENTIALLY PROBLEMATIC UNINTENDED MUTAGENESIS OF GENE EDITING. 2019 17 6829 30 [HEPATITIS C VIRUS INFECTION AND HEPATOCARCINOGENESIS]. HEPATITIS C VIRUS INFECTION CAUSES APPROXIMATELY 4 MILLION NEW INFECTIONS WORLDWIDE, AND 399 000 DEATHS DUE TO ITS COMPLICATIONS, CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC). MICROENVIRONMENTAL CHANGES, CHRONIC INFLAMMATION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM STRESS CAUSED BY HCV INFECTION, VIA GENETIC AND EPIGENETIC CHANGES CAN RESULT IN PRIMARY LIVER CANCER DURING DECADES. THE DIRECT ONCOGENIC PROPERTY OF HCV IS WELLKNOWN. THE TRANSFORMING EFFECT OF FOUR HCV PROTEINS (CORE, NS3, NS4B, NS5A) HAS BEEN PROVEN. EFFECTIVE ANTIVIRAL THERAPY, SUSTAINED VIRAL RESPONSE DECREASES THE HCV-RELATED GENERAL AND LIVER-RELATED MORTALITY. INTERFERON-BASED THERAPY REDUCES THE RISK OF HCC DEVELOPMENT. SHORTER THERAPY WITH DIRECT ACTING ANTIVIRAL AGENTS (DAA) HAS HIGHER EFFICACY, FEWER SIDE-EFFECTS. PUBLICATIONS HAVE REPORTED THE UNEXPECTED EFFECTS OF DAA. THE AUTHORS REVIEW THE ARTICLES FOCUSING ON THE OCCURRENCE OF HCC IN CONNECTION WITH DAA THERAPIES. THERE IS A NEED FOR PROSPECTIVE, MULTICENTRIC STUDIES WITH LONGER FOLLOW-UP TO EXAMINE THE RISK OF HCC FORMATION. AFTER ANTIVIRAL THERAPY, HCC SURVEILLANCE IS OF HIGH IMPORTANCE WHICH MEANS ABDOMINAL ULTRASOUND EVERY 3-6-12 MONTHS IN SUSTAINED VIRAL RESPONSE PATIENTS AS WELL. ORV HETIL. 2019; 160(22): 846-853. 2019 18 6584 17 TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 : OUR NEW PARTNER IN HUMAN ONCOLOGY? INFLAMMATION IS RECOGNIZED AS ONE OF THE HALLMARKS OF CANCER. INDEED, STRONG EVIDENCE INDICATES THAT CHRONIC INFLAMMATION PLAYS A MAJOR ROLE IN ONCOGENESIS, PROMOTING GENOME INSTABILITY, EPIGENETIC ALTERATIONS, PROLIFERATION AND DISSEMINATION OF CANCER CELLS. MONONUCLEAR PHAGOCYTES (MPS) HAVE BEEN IDENTIFIED AS KEY CONTRIBUTORS OF THE INFLAMMATORY INFILTRATE IN SEVERAL SOLID HUMAN NEOPLASIA, PROMOTING ANGIOGENESIS AND CANCER PROGRESSION. ONE OF THE MOST DESCRIBED AMPLIFIERS OF MPS PRO-INFLAMMATORY INNATE IMMUNE RESPONSE IS THE TRIGGERING RECEPTORS EXPRESSED ON MYELOID CELLS 1 (TREM-1). GROWING EVIDENCE SUGGESTS TREM-1 INVOLVEMENT IN ONCOGENESIS THROUGH CANCER RELATED INFLAMMATION AND THE SURROUNDING TUMOR MICROENVIRONMENT. IN HUMAN ONCOLOGY, HIGH LEVELS OF TREM-1 AND/OR ITS SOLUBLE FORM HAVE BEEN ASSOCIATED WITH POORER SURVIVAL DATA IN SEVERAL SOLID MALIGNANCIES, ESPECIALLY IN HEPATOCELLULAR CARCINOMA AND LUNG CANCER. TREM-1 SHOULD BE CONSIDERED AS A POTENTIAL BIOMARKER IN HUMAN ONCOLOGY AND COULD BE USED AS A NEW THERAPEUTIC TARGET OF INTEREST IN HUMAN ONCOLOGY (TREM-1 INHIBITORS, TREM-1 AGONISTS). MORE CLINICAL STUDIES ARE URGENTLY NEEDED TO CONFIRM TREM-1 (AND TREM FAMILY) ROLES IN THE PROGNOSIS AND THE TREATMENT OF HUMAN SOLID CANCERS. 2022 19 5844 26 STUDY OF PROMOTER HYPOMETHYLATION PROFILES OF RAS ONCOGENES IN HEPATOCELLULAR CARCINOMA DERIVED FROM HEPATITIS C VIRUS GENOTYPE 3A IN PAKISTANI POPULATION. EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION CONTRIBUTE TO PROGRESSION OF HEPATITIS C VIRUS (HCV) INFECTION TO LIFE-THREATENING HEPATOCELLULAR CARCINOMA (HCC) BY PROMOTING THE SILENCING OF TUMOR SUPPRESSOR GENES THROUGH DNA HYPERMETHYLATION AND BY CAUSING GENOMIC INSTABILITY THROUGH GLOBAL HYPOMETHYLATION. HOWEVER FEW STUDIES HAVE ADDRESSED THE PROMOTER REGION HYPOMETHYLATION STATUS OF THE ONCOGENES INVOLVED IN HCV DERIVED HCC. IN THIS STUDY, WE ANALYZED THE PROMOTER REGION METHYLATION PATTERN OF RAS ONCOGENES (HRAS, KRAS, AND NRAS) USING METHYLATION-SPECIFIC PCR FOR 50 CHRONIC HCV PATIENTS INFECTED WITH GENOTYPE 3A (27 HCC PATIENTS AND 23 CONTROL NON-HCC PATIENTS). METHYLATION-SPECIFIC POLYMERASE CHAIN REACTION ANALYSIS REVEALED THAT THE NRAS ONCOGENE PROMOTER (P = .0025) WAS SIGNIFICANTLY HYPOMETHYLATED IN HCC PATIENTS COMPARED TO THE NON-HCC PATIENTS SUGGESTING ITS CONTRIBUTION TO THE PROGRESSION OF HCV TOWARDS HCC. TO IDENTIFY THE AGENT FOR ALTERATION IN THE RAS ONCOGENE EXPRESSION, 7 HCV GENES WERE EXPRESSED IN THE HUH-7 CELL LINE FOLLOWED BY MEASUREMENT OF THE NRAS EXPRESSION LEVEL IN HUH-7 BY A QUANTITATIVE REAL-TIME POLYMERASE CHAIN REACTION. AN INCREASE IN THE MESSENGER RNA LEVEL OF THE NRAS GENE WAS DETECTED WHEN HUH-7 WERE TRANSFECTED WITH CORE, NS5A, AND NS2 GENES. OUR FINDINGS SUGGEST THE INVOLVEMENT OF NRAS ONCOGENE IN THE PATHOGENESIS OF HCV3A DERIVED HCC IN PAKISTANI POPULATION AND ALSO IDENTIFIES THE HCV GENES RESPONSIBLE FOR ITS ENHANCED EXPRESSION. OUR STUDY RAISES THE HYPOTHESIS THAT A SINGLE HCV GENE MAY INCREASE THE CHANCES OF MALIGNANCY. THEREFORE, OUR STUDY MAY HAVE IDENTIFIED A USEFUL EPIGENETIC BIOMARKER OF HCC PROGRESSION IN HCV PATIENTS AND MAY HELP TO DEVELOP NOVEL DIAGNOSTIC TOOLS. 2018 20 1615 24 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