1 3190 146 HCV-INDUCED EPIGENETIC CHANGES ASSOCIATED WITH LIVER CANCER RISK PERSIST AFTER SUSTAINED VIROLOGIC RESPONSE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION IS AN IMPORTANT RISK FACTOR FOR HEPATOCELLULAR CARCINOMA (HCC). DESPITE EFFECTIVE ANTIVIRAL THERAPIES, THE RISK FOR HCC IS DECREASED BUT NOT ELIMINATED AFTER A SUSTAINED VIROLOGIC RESPONSE (SVR) TO DIRECT-ACTING ANTIVIRAL (DAA) AGENTS, AND THE RISK IS HIGHER IN PATIENTS WITH ADVANCED FIBROSIS. WE INVESTIGATED HCV-INDUCED EPIGENETIC ALTERATIONS THAT MIGHT AFFECT RISK FOR HCC AFTER DAA TREATMENT IN PATIENTS AND MICE WITH HUMANIZED LIVERS. METHODS: WE PERFORMED GENOME-WIDE CHIPMENTATION-BASED CHIP-SEQ AND RNA-SEQ ANALYSES OF LIVER TISSUES FROM 6 PATIENTS WITHOUT HCV INFECTION (CONTROLS), 18 PATIENTS WITH CHRONIC HCV INFECTION, 8 PATIENTS WITH CHRONIC HCV INFECTION CURED BY DAA TREATMENT, 13 PATIENTS WITH CHRONIC HCV INFECTION CURED BY INTERFERON THERAPY, 4 PATIENTS WITH CHRONIC HEPATITIS B VIRUS INFECTION, AND 7 PATIENTS WITH NONALCOHOLIC STEATOHEPATITIS IN EUROPE AND JAPAN. HCV-INDUCED EPIGENETIC MODIFICATIONS WERE MAPPED BY COMPARATIVE ANALYSES WITH MODIFICATIONS ASSOCIATED WITH OTHER LIVER DISEASE ETIOLOGIES. UPA/SCID MICE WERE ENGRAFTED WITH HUMAN HEPATOCYTES TO CREATE MICE WITH HUMANIZED LIVERS AND GIVEN INJECTIONS OF HCV-INFECTED SERUM SAMPLES FROM PATIENTS; MICE WERE GIVEN DAAS TO ERADICATE THE VIRUS. PATHWAYS ASSOCIATED WITH HCC RISK WERE IDENTIFIED BY INTEGRATIVE PATHWAY ANALYSES AND VALIDATED IN ANALYSES OF PAIRED HCC TISSUES FROM 8 PATIENTS WITH AN SVR TO DAA TREATMENT OF HCV INFECTION. RESULTS: WE FOUND CHRONIC HCV INFECTION TO INDUCE SPECIFIC GENOME-WIDE CHANGES IN H3K27AC, WHICH CORRELATED WITH CHANGES IN EXPRESSION OF MRNAS AND PROTEINS. THESE CHANGES PERSISTED AFTER AN SVR TO DAAS OR INTERFERON-BASED THERAPIES. INTEGRATIVE PATHWAY ANALYSES OF LIVER TISSUES FROM PATIENTS AND MICE WITH HUMANIZED LIVERS DEMONSTRATED THAT HCV-INDUCED EPIGENETIC ALTERATIONS WERE ASSOCIATED WITH LIVER CANCER RISK. COMPUTATIONAL ANALYSES ASSOCIATED INCREASED EXPRESSION OF SPHK1 WITH HCC RISK. WE VALIDATED THESE FINDINGS IN AN INDEPENDENT COHORT OF PATIENTS WITH HCV-RELATED CIRRHOSIS (N = 216), A SUBSET OF WHICH (N = 21) ACHIEVED VIRAL CLEARANCE. CONCLUSIONS: IN AN ANALYSIS OF LIVER TISSUES FROM PATIENTS WITH AND WITHOUT AN SVR TO DAA THERAPY, WE IDENTIFIED EPIGENETIC AND GENE EXPRESSION ALTERATIONS ASSOCIATED WITH RISK FOR HCC. THESE ALTERATIONS MIGHT BE TARGETED TO PREVENT LIVER CANCER IN PATIENTS TREATED FOR HCV INFECTION.	2019	
                                                                                                                                                                                                                                          
2 3260  63 HEPATITIS C VIRUS LEAVES AN EPIGENETIC SIGNATURE POST CURE OF INFECTION BY DIRECT-ACTING ANTIVIRALS. THE INCREASING WORLDWIDE PREVALENCE OF HEPATOCELLULAR CARCINOMA (HCC), CHARACTERIZED BY RESISTANCE TO CONVENTIONAL CHEMOTHERAPY, POOR PROGNOSIS AND EVENTUALLY MORTALITY, PLACE IT AS A PRIME TARGET FOR NEW MODES OF PREVENTION AND TREATMENT. HEPATITIS C VIRUS (HCV) IS THE PREDOMINANT RISK FACTOR FOR HCC IN THE US AND EUROPE. MULTIPLE EPIDEMIOLOGICAL STUDIES SHOWED THAT SUSTAINED VIROLOGICAL RESPONSES (SVR) FOLLOWING TREATMENT WITH THE POWERFUL DIRECT ACTING ANTIVIRALS (DAAS), WHICH HAVE REPLACED INTERFERON-BASED REGIMES, DO NOT ELIMINATE TUMOR DEVELOPMENT. WE AIMED TO IDENTIFY AN HCV-SPECIFIC PATHOGENIC MECHANISM THAT PERSISTS POST SVR FOLLOWING DAAS TREATMENT. WE DEMONSTRATE THAT HCV INFECTION INDUCES GENOME-WIDE EPIGENETIC CHANGES BY PERFORMING CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT-GENERATION SEQUENCING (CHIP-SEQ) FOR HISTONE POST-TRANSLATIONAL MODIFICATIONS THAT ARE EPIGENETIC MARKERS FOR ACTIVE AND REPRESSED CHROMATIN. THE CHANGES IN HISTONE MODIFICATIONS CORRELATE WITH REPROGRAMED HOST GENE EXPRESSION AND ALTER SIGNALING PATHWAYS KNOWN TO BE ASSOCIATED WITH HCV LIFE CYCLE AND HCC. THESE EPIGENETIC ALTERATIONS REQUIRE THE PRESENCE OF HCV RNA OR/AND EXPRESSION OF THE VIRAL PROTEINS IN THE CELLS. IMPORTANTLY, THE EPIGENETIC CHANGES INDUCED FOLLOWING INFECTION PERSIST AS AN "EPIGENETIC SIGNATURE" AFTER VIRUS ERADICATION BY DAAS TREATMENT, AS DETECTED USING IN VITRO HCV INFECTION MODELS. THESE OBSERVATIONS LED TO THE IDENTIFICATION OF AN 8 GENE SIGNATURE THAT IS ASSOCIATED WITH HCC DEVELOPMENT AND DEMONSTRATE PERSISTENT EPIGENETIC ALTERATIONS IN HCV INFECTED AND POST SVR LIVER BIOPSY SAMPLES. THE EPIGENETIC SIGNATURE WAS REVERTED IN VITRO BY DRUGS THAT INHIBIT EPIGENETIC MODIFYING ENZYME AND BY THE EGFR INHIBITOR, ERLOTINIB. THIS EPIGENETIC "SCARRING" OF THE GENOME, PERSISTING FOLLOWING HCV ERADICATION, SUGGEST A NOVEL MECHANISM FOR THE PERSISTENT PATHOGENESIS OF HCV AFTER ITS ERADICATION BY DAAS. OUR STUDY OFFERS NEW AVENUES FOR PREVENTION OF THE PERSISTENT ONCOGENIC EFFECTS OF CHRONIC HEPATITIS INFECTIONS USING SPECIFIC DRUGS TO REVERT THE EPIGENETIC CHANGES TO THE GENOME.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
3   42  49 A COMPREHENSIVE GENOME-WIDE PROFILING COMPARISON BETWEEN HBV AND HCV INFECTED HEPATOCELLULAR CARCINOMA. BACKGROUND: HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON CANCERS WORLDWIDE, ESPECIALLY IN EAST ASIA. EVEN WITH THE PROGRESS IN THERAPY, 5-YEAR SURVIVAL RATES REMAIN UNSATISFIED. CHRONIC INFECTION WITH THE HEPATITIS B VIRUS (HBV) OR HEPATITIS C VIRUS (HCV) HAS BEEN EPIDEMIOLOGICALLY ASSOCIATED WITH HCC AND IS THE MAJOR ETIOLOGY IN THE EAST ASIAN POPULATION. THE DETAILED MECHANISM, ESPECIALLY THE CHANGES OF DNA METHYLATION AND GENE EXPRESSION BETWEEN THE TWO TYPES OF VIRUS-RELATED HCC, AND THEIR CONTRIBUTIONS TO THE HCC DEVELOPMENT, METASTASIS, AND RECURRENCE REMAIN LARGELY UNKNOWN. METHODS: IN THIS INTEGRATED ANALYSIS, WE CHARACTERIZED GENOME-SCALE PROFILES OF HBV AND HCV INFECTED HCC BY COMPARING THEIR GENE EXPRESSION PATTERN, METHYLATION PROFILES, AND COPY NUMBER VARIATIONS FROM THE PUBLICLY ACCESSIBLE DATA OF THE CANCER GENOME ATLAS PROGRAM (TCGA). RESULTS: THE HLA-A, STAT1, AND OAS2 GENES WERE HIGHLY ENRICHED AND UP-REGULATED DISCOVERED IN THE HCV-INFECTED HCC. HYPOMETHYLATION BUT NOT COPY NUMBER VARIATIONS MIGHT BE THE MAJOR FACTOR FOR THE UP-REGULATION OF THESE IMMUNE-RELATED GENES IN HCV-INFECTED HCC. CONCLUSIONS: THE RESULTS INDICATED THE DIFFERENT EPIGENETIC CHANGES OF HBV/HCV RELATED HEPATOCARCINOGENESIS. THE TOP UP-REGULATED GENES IN HCV GROUP WERE SIGNIFICANTLY CLUSTERED IN THE IMMUNE-RELATED AND DEFENSE RESPONSE PATHWAYS. THESE FINDINGS WILL HELP US TO UNDERSTAND THE PATHOGENESIS OF HBV/HCV ASSOCIATED HEPATOCELLULAR CARCINOMA.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
4 5521  50 RISK OF HEPATOCELLULAR CARCINOMA AFTER HCV CLEARANCE BY DIRECT-ACTING ANTIVIRALS TREATMENT PREDICTIVE FACTORS AND ROLE OF EPIGENETICS. DIRECT-ACTING ANTIVIRALS (DAAS) INDUCE A RAPID VIROLOGIC RESPONSE (SVR) IN UP TO 99% OF CHRONIC HEPATITIS C PATIENTS. THE ROLE OF SVR BY DAAS ON THE INCIDENCE OR RECURRENCE OF HEPATOCELLULAR CARCINOMA (HCC) IS STILL A MATTER OF DEBATE, ALTHOUGH IT IS KNOWN THAT SVR DOES NOT ELIMINATE THE RISK OF HCC. IN THIS REVIEW, WE MADE AN UPDATED ANALYSIS OF THE LITERATURE DATA ON THE IMPACT OF SVR BY DAAS ON THE RISK OF HCC AS WELL AS AN ASSESSMENT OF RISK FACTORS AND THE ROLE OF EPIGENETICS. DATA SHOWED THAT SVR HAS NO IMPACT ON THE OCCURRENCE OF HCC IN THE SHORT-MEDIUM TERM BUT REDUCES THE RISK OF HCC IN THE MEDIUM-LONG TERM. A DIRECT ROLE OF DAAS IN THE DEVELOPMENT OF HCC HAS NOT BEEN DEMONSTRATED, WHILE THE HYPOTHESIS OF A REDUCTION IN IMMUNE SURVEILLANCE IN RESPONSE TO THE RAPID CLEARANCE OF HCV AND CHANGES IN THE CYTOKINE PATTERN INFLUENCING EARLY CARCINOGENESIS REMAINS TO BE FURTHER ELUCIDATED. HCV INDUCES EPIGENETIC ALTERATIONS SUCH AS MODIFICATIONS OF THE HISTONE TAIL AND DNA METHYLATION, WHICH ARE RISK FACTORS FOR HCC, AND SUCH CHANGES ARE MAINTAINED AFTER HCV CLEARANCE. FUTURE EPIGENETIC STUDIES COULD LEAD TO IDENTIFY USEFUL BIOMARKERS AND THERAPEUTIC TARGETS. CIRRHOSIS HAS BEEN IDENTIFIED AS A RISK FACTOR FOR HCC, PARTICULARLY IF ASSOCIATED WITH HIGH LIVER STIFFNESS AND ALPHA-FETOPROTEIN VALUES, DIABETES AND THE MALE SEX. CURRENTLY, CONSIDERING THE HIGH NUMBER AND HEALTH COST TO FOLLOW SUBJECTS' POST-HCV CLEARANCE BY DAAS, IT IS MANDATORY TO IDENTIFY THOSE AT HIGH RISK OF HCC TO OPTIMIZE MANAGEMENT.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                           
5 3780  54 INTERFERON DRIVES HCV SCARRING OF THE EPIGENOME AND CREATES TARGETABLE VULNERABILITIES FOLLOWING VIRAL CLEARANCE. BACKGROUND AND AIMS: CHRONIC HCV INFECTION IS A LEADING ETIOLOGIC DRIVER OF CIRRHOSIS AND ULTIMATELY HCC. OF THE APPROXIMATELY 71 MILLION INDIVIDUALS CHRONICALLY INFECTED WITH HCV, 10%-20% ARE EXPECTED TO DEVELOP SEVERE LIVER COMPLICATIONS IN THEIR LIFETIME. EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS BECOME PROFOUNDLY DISRUPTED IN DISEASE PROCESSES INCLUDING LIVER DISEASE. APPROACH AND RESULTS: TO UNDERSTAND HOW HCV INFECTION INFLUENCES THE EPIGENOME AND WHETHER THESE EVENTS REMAIN AS "SCARS" FOLLOWING CURE OF CHRONIC HCV INFECTION, WE MAPPED GENOME-WIDE DNA METHYLATION, FOUR KEY REGULATORY HISTONE MODIFICATIONS (H3K4ME3, H3K4ME1, H3K27AC, AND H3K27ME3), AND OPEN CHROMATIN IN PARENTAL AND HCV-INFECTED IMMORTALIZED HEPATOCYTES AND THE HUH7.5 HCC CELL LINE, ALONG WITH DNA METHYLATION AND GENE-EXPRESSION ANALYSES FOLLOWING ELIMINATION OF HCV IN THESE MODELS THROUGH TREATMENT WITH INTERFERON-ALPHA (IFN-ALPHA) OR A DIRECT-ACTING ANTIVIRAL (DAA). OUR DATA DEMONSTRATE THAT HCV INFECTION PROFOUNDLY AFFECTS THE EPIGENOME (PARTICULARLY ENHANCERS); HCV SHARES EPIGENETIC TARGETS WITH INTERFERON-ALPHA TARGETS; AND AN OVERWHELMING MAJORITY OF EPIGENETIC CHANGES INDUCED BY HCV REMAIN AS "SCARS" ON THE EPIGENOME FOLLOWING VIRAL CURE. SIMILAR FINDINGS ARE OBSERVED IN PRIMARY HUMAN PATIENT SAMPLES CURED OF CHRONIC HCV INFECTION. SUPPLEMENTATION OF IFN-ALPHA/DAA ANTIVIRAL REGIMENS WITH DNA METHYLTRANSFERASE INHIBITOR 5-AZA-2'-DEOXYCYTIDINE SYNERGIZES IN REVERTING ABERRANT DNA METHYLATION INDUCED BY HCV. FINALLY, BOTH HCV-INFECTED AND CURED CELLS DISPLAYED A BLUNTED IMMUNE RESPONSE, DEMONSTRATING A FUNCTIONAL EFFECT OF EPIGENETIC SCARRING. CONCLUSIONS: INTEGRATION OF EPIGENETIC AND TRANSCRIPTIONAL DATA ELUCIDATE KEY GENE DEREGULATION EVENTS DRIVEN BY HCV INFECTION AND HOW THIS MAY UNDERPIN THE LONG-TERM ELEVATED RISK FOR HCC IN PATIENTS CURED OF HCV DUE TO EPIGENOME SCARRING.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
6 5486  57 REVERSE INFLAMMAGING: LONG-TERM EFFECTS OF HCV CURE ON BIOLOGICAL AGE. BACKGROUND & AIMS: CHRONIC HEPATITIS C VIRUS (HCV) INFECTION CAN BE CURED WITH DIRECT-ACTING ANTIVIRALS (DAAS). HOWEVER, NOT ALL SEQUELAE OF CHRONIC HEPATITIS C APPEAR TO BE COMPLETELY REVERSIBLE AFTER SUSTAINED VIROLOGIC RESPONSE (SVR). RECENTLY, CHRONIC VIRAL INFECTIONS HAVE BEEN SHOWN TO BE ASSOCIATED WITH BIOLOGICAL AGE ACCELERATION DEFINED BY THE EPIGENETIC CLOCK. THE AIM OF THIS STUDY WAS TO INVESTIGATE WHETHER CHRONIC HCV INFECTION IS ASSOCIATED WITH EPIGENETIC CHANGES AND BIOLOGICAL AGE ACCELERATION AND WHETHER THIS IS REVERSIBLE AFTER SVR. METHODS: WE INCLUDED 54 WELL-CHARACTERIZED INDIVIDUALS WITH CHRONIC HEPATITIS C WHO ACHIEVED SVR AFTER DAA THERAPY AT THREE TIME POINTS: DAA TREATMENT INITIATION, END OF TREATMENT, AND LONG-TERM FOLLOW-UP (MEDIAN 96 WEEKS AFTER END OF TREATMENT). GENOME-WIDE DNA METHYLATION STATUS WAS DETERMINED IN PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) AND USED TO CALCULATE EPIGENETIC AGE ACCELERATION (EAA) USING HORVATH'S CLOCK. RESULTS: INDIVIDUALS WITH HCV HAD AN OVERALL SIGNIFICANT EAA OF 3.12 YEARS AT BASELINE COMPARED WITH -2.61 YEARS IN THE AGE- AND SEX-MATCHED REFERENCE GROUP (P <0.00003). HCV ELIMINATION RESULTED IN A SIGNIFICANT LONG-TERM INCREASE IN DNA METHYLATION DOMINATED BY HYPERMETHYLATED CPGS IN ALL PATIENT GROUPS. ACCORDINGLY, EAA DECREASED TO 1.37 YEARS AT LONG-TERM FOLLOW-UP. THE DECREASE IN EAA WAS SIGNIFICANT ONLY BETWEEN THE END OF TREATMENT AND FOLLOW-UP (P = 0.01). INTERESTINGLY, EIGHT INDIVIDUALS WHO DEVELOPED HEPATOCELLULAR CARCINOMA AFTER SVR HAD THE HIGHEST EAA AND SHOWED NO EVIDENCE OF REVERSAL AFTER SVR. CONCLUSIONS: OUR DATA CONTRIBUTE TO THE UNDERSTANDING OF THE BIOLOGICAL IMPACT OF HCV ELIMINATION AFTER DAA THERAPY AND DEMONSTRATE THAT HCV ELIMINATION CAN LEAD TO "REVERSE INFLAMMAGING". IN ADDITION, OUR DATA SUPPORT THE POTENTIAL USE OF BIOLOGICAL AGE AS A BIOMARKER FOR HCV SEQUELAE AFTER SVR. IMPACT AND IMPLICATIONS: CHRONIC HEPATITIS C VIRUS INFECTION IS NOW CURABLE WITH DIRECT-ACTING ANTIVIRALS, BUT IT REMAINS UNCLEAR WHETHER HEPATITIS C SEQUELAE ARE FULLY REVERSIBLE AFTER VIRAL ELIMINATION. OUR RESULTS SUGGEST THAT EPIGENETIC CHANGES OR ACCELERATION OF BIOLOGICAL AGE ARE REVERSIBLE IN PRINCIPLE, BUT THIS REQUIRES TIME, WHILE A LACK OF REVERSIBILITY APPEARS TO BE ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. WHILE MOST CLINICAL RISK SCORES NOW TAKE CHRONOLOGICAL AGE INTO ACCOUNT, IT MAY BE WORTHWHILE TO EXPLORE HOW BIOLOGICAL AGE MIGHT IMPROVE THESE SCORES IN THE FUTURE. BIOLOGICAL AGE MAY BE A CORNERSTONE FOR THE INDIVIDUALIZED CLINICAL ASSESSMENT OF PATIENTS IN THE FUTURE, AS IT BETTER REFLECTS PATIENTS' LIFESTYLE AND ENVIRONMENTAL EXPOSURES OVER DECADES.	2023	

7 1042  37 CLINICAL AND MOLECULAR BASIS OF HEPATOCELLULAR CARCINOMA AFTER HEPATITIS C VIRUS ERADICATION. HEPATOCELLULAR CARCINOMA (HCC) ARISES IN THE BACKGROUND OF CHRONIC LIVER DISEASES, INCLUDING HEPATITIS AND LIVER CIRRHOSIS CAUSED BY HEPATITIS C VIRUS (HCV) INFECTION. IT IS WELL KNOWN THAT HCV ERADICATION USING ANTIVIRAL DRUGS CAN EFFICIENTLY INHIBIT HEPATOCARCINOGENESIS. RECENT ADVANCES IN AND DEVELOPMENT OF DIRECT-ACTING ANTIVIRAL (DAA) DRUGS HAS REVOLUTIONIZED THE TREATMENT OF HCV INFECTION, AND THE VAST MAJORITY OF HCV PATIENTS CAN ACHIEVE HCV ERADICATION USING DAAS. HOWEVER, MOUNTING EVIDENCE CLEARLY INDICATES THAT HCC INEVITABLY OCCURS IN A SUBSET OF PATIENTS AFTER SUCCESSFUL VIRAL ERADICATION USING DAA THERAPY. CANCER IS A GENETIC DISEASE, AND THE ACCUMULATION OF GENETIC AND EPIGENETIC ABERRATIONS MAY CAUSE HEPATOCARCINOGENESIS IN CHRONICALLY DAMAGED LIVER, EVEN AFTER VIRUS ELIMINATION. IN THIS REVIEW, WE HIGHLIGHT HCC DEVELOPMENT AFTER HCV ERADICATION AND DISCUSS THE CURRENT UNDERSTANDING OF THE MOLECULAR MECHANISMS OF TUMORIGENESIS AFTER VIRUS ELIMINATION, FOCUSING ON THE GENETIC AND EPIGENETIC BACKGROUND OF CHRONICALLY DAMAGED LIVER TISSUES.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
8 3264  51 HEPATITIS VIRUS INFECTION AFFECTS DNA METHYLATION IN MICE WITH HUMANIZED LIVERS. BACKGROUND & AIMS: CELLS OF TUMORS ASSOCIATED WITH CHRONIC INFLAMMATION FREQUENTLY HAVE ALTERED PATTERNS OF DNA METHYLATION, INCLUDING HEPATOCELLULAR CARCINOMAS. CHRONIC HEPATITIS HAS ALSO BEEN ASSOCIATED WITH ABERRANT DNA METHYLATION, BUT LITTLE IS KNOWN ABOUT THEIR RELATIONSHIP. METHODS: PYROSEQUENCING WAS USED TO DETERMINE THE METHYLATION STATUS OF CULTURED HUH7.5.1 HEPATOMA CELLS AFTER HEPATITIS C VIRUS (HCV) INFECTION. WE ALSO STUDIED MICE WITH SEVERE COMBINED IMMUNODEFICIENCY CARRYING THE UROKINASE-TYPE PLASMINOGEN ACTIVATOR TRANSGENE CONTROLLED BY AN ALBUMIN PROMOTER (UROKINASE-TYPE PLASMINOGEN ACTIVATOR/SEVERE COMBINED IMMUNODEFICIENT MICE), IN WHICH UP TO 85% OF HEPATOCYTES WERE REPLACED BY HUMAN HEPATOCYTES (CHIMERIC MICE). MICE WERE GIVEN INTRAVENOUS INJECTIONS OF HEPATITIS B VIRUS (HBV) OR HCV, LIVER TISSUES WERE COLLECTED, AND DNA METHYLATION PROFILES WERE DETERMINED AT DIFFERENT TIME POINTS AFTER INFECTION. WE ALSO COMPARED METHYLATION PATTERNS BETWEEN PAIRED SAMPLES OF HEPATOCELLULAR CARCINOMAS AND ADJACENT NONTUMOR LIVER TISSUES FROM PATIENTS. RESULTS: NO REPRODUCIBLE CHANGES IN DNA METHYLATION WERE OBSERVED AFTER INFECTION OF HUH7.5.1 CELLS WITH HCV. LIVERS FROM HBV- AND HCV-INFECTED MICE HAD GENOME-WIDE, TIME-DEPENDENT CHANGES IN DNA METHYLATION, COMPARED WITH UNINFECTED UROKINASE-TYPE PLASMINOGEN ACTIVATOR/SEVERE COMBINED IMMUNODEFICIENT MICE. THERE WERE CHANGES IN 160 +/- 63 GENES IN HBV-INFECTED AND 237 +/- 110 GENES IN HCV-INFECTED MICE. METHYLATION OF 149 COMMON GENES INCREASED IN HBV- AND HCV-INFECTED MICE; METHYLATION OF SOME OF THESE GENES ALSO INCREASED IN HEPATOCELLULAR CARCINOMA SAMPLES FROM PATIENTS COMPARED WITH NONTUMOR TISSUES. EXPRESSION OF IFNG, WHICH IS EXPRESSED BY NATURAL KILLER CELLS, INCREASED SIGNIFICANTLY IN CHIMERIC LIVERS, IN CONCORDANCE WITH INDUCTION OF DNA METHYLATION, AFTER INFECTION WITH HBV OR HCV. INDUCTION OF IFNG WAS REDUCED AFTER ADMINISTRATION OF AN INHIBITOR OF NATURAL KILLER CELL FUNCTION (ANTI-ASIALO GM1). CONCLUSIONS: IN CHIMERIC MICE WITH HUMANIZED LIVERS, INFECTION WITH HBV AND HCV APPEARS TO ACTIVATE A NATURAL KILL CELL-DEPENDENT INNATE IMMUNE RESPONSE. THIS CONTRIBUTES TO THE INDUCTION AND ACCUMULATION OF ABERRANT DNA METHYLATION IN HUMAN HEPATOCYTES.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                          
9 6640  47 UNRAVELING THE MOLECULAR MECHANISMS INVOLVED IN HCV-INDUCED CARCINOGENESIS. CANCER INDUCED BY A VIRAL INFECTION IS AMONG THE LEADING CAUSES OF CANCER. HEPATITIS C VIRUS (HCV) IS A HEPATOTROPIC ONCOGENIC POSITIVE-SENSE RNA VIRUS THAT LEADS TO CHRONIC INFECTION, EXPOSING THE LIVER TO A CONTINUOUS PROCESS OF DAMAGE AND REGENERATION AND PROMOTING HEPATOCARCINOGENESIS. THE VIRUS PROMOTES THE DEVELOPMENT OF CARCINOGENESIS THROUGH INDIRECT AND DIRECT MOLECULAR MECHANISMS SUCH AS CHRONIC INFLAMMATION, OXIDATIVE STRESS, STEATOSIS, GENETIC ALTERATIONS, EPITHELIAL-MESENCHYMAL TRANSITION, PROLIFERATION, AND APOPTOSIS, AMONG OTHERS. RECENTLY, DIRECT-ACTING ANTIVIRALS (DAAS) SHOWED SUSTAINED VIROLOGIC RESPONSE IN 95% OF CASES. NEVERTHELESS, PATIENTS TREATED WITH DAAS HAVE REPORTED AN UNEXPECTED INCREASE IN THE EARLY INCIDENCE OF HEPATOCELLULAR CARCINOMA (HCC). STUDIES SUGGEST THAT HCV INDUCES EPIGENETIC REGULATION THROUGH NON-CODING RNAS, DNA METHYLATION, AND CHROMATIN REMODELING, WHICH MODIFY GENE EXPRESSIONS AND INDUCE GENOMIC INSTABILITY RELATED TO HCC DEVELOPMENT THAT PERSISTS WITH THE INFECTION'S CLEARANCE. THE NEED FOR A BETTER UNDERSTANDING OF THE MOLECULAR MECHANISMS ASSOCIATED WITH THE DEVELOPMENT OF CARCINOGENESIS IS EVIDENT. THE AIM OF THIS REVIEW WAS TO UNRAVEL THE MOLECULAR PATHWAYS INVOLVED IN THE DEVELOPMENT OF CARCINOGENESIS BEFORE, DURING, AND AFTER THE VIRAL INFECTION'S RESOLUTION, AND HOW THESE PATHWAYS WERE REGULATED BY THE VIRUS, TO FIND CONTROL POINTS THAT CAN BE USED AS POTENTIAL THERAPEUTIC TARGETS.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
10 4677  43 NEW LNCRNAS IN CHRONIC HEPATITIS C PROGRESSION: FROM FIBROSIS TO HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD LEADING CAUSE OF CANCER-RELATED DEATH IN THE WORLD, AND ABOUT 80% OF THE CASES ARE ASSOCIATED WITH HEPATITIS B OR C. GENETIC AND EPIGENETIC ALTERATIONS ARE ACCUMULATED OVER DECADES OF CHRONIC INJURY AND MAY AFFECT THE FUNCTIONING OF TUMOR SUPPRESSOR GENES AND PROTOONCOGENES. STUDIES HAVE EVIDENCED THE ROLE OF LONG NON-CODING RNAS (LNCRNA) WITH ONCOGENIC OR TUMOR SUPPRESSOR ACTIVITIES, SUGGESTING A GREAT POTENTIAL IN THE TREATMENT, DIAGNOSIS OR INDICATOR OF PROGNOSIS IN CANCER. IN THIS CONTEXT, THE AIM OF THIS STUDY WAS TO EVALUATE THE GLOBAL EXPRESSION PROFILE LNCRNA IN HEPATIC TISSUE SAMPLES WITH DIFFERENT STAGES OF FIBROSIS ASSOCIATED WITH CHRONIC HEPATITIS C, HCC AND NORMAL LIVER, IN ORDER TO IDENTIFY NEW LNCRNAS THAT COULD CONTRIBUTE TO STUDY THE PROGRESSION OF HEPATIC FIBROSIS TO HCC ASSOCIATED WITH CHRONIC HEPATITIS C. RNA-SEQ WAS PERFORMED ON ILLUMINA NEXTSEQ PLATFORM TO IDENTIFY LNCRNAS EXPRESSED DIFFERENTLY IN 15 PATIENTS WITH CHRONIC HEPATITIS C, THREE PATIENTS WITH HCC AND THREE NORMAL LIVER SPECIMENS. WHEN THE PATHOLOGICAL TISSUES (FIBROSIS AND CARCINOMA) WERE COMPARED TO NORMAL HEPATIC TISSUE, WERE IDENTIFIED 2, 6 E 34 DIFFERENTIALLY EXPRESSED LNCRNAS IN MODERATE FIBROSIS, ADVANCED FIBROSIS AND HCC, RESPECTIVELY. THE CARCINOMA GROUP HAD THE HIGHEST PROPORTION OF DIFFERENTIALLY EXPRESSED LNCRNA (34) AND OF THESE, 29 WERE EXCLUSIVE IN THIS TYPE OF TISSUE. A HEAT MAP OF THE DEREGULATED LNCRNA REVEALED DIFFERENT EXPRESSION PATTERNS ALONG THE PROGRESSION OF FIBROSIS TO HCC. THE RESULTS SHOWED THE DEREGULATION OF SOME LNCRNA ALREADY CLASSIFIED AS TUMOR SUPPRESSORS IN HCC AND OTHER CANCERS, AS WELL AS SOME UNPUBLISHED LNCRNA WHOSE FUNCTION IS UNKNOWN. SOME OF THESE LNCRNAS ARE DYSREGULATED SINCE THE EARLY STAGES OF LIVER INJURY IN PATIENTS WITH HEPATITIS C, OTHERS OVEREXPRESSED ONLY IN TUMOR TISSUE, INDICATING THEMSELVES AS CANDIDATES OF MARKERS OF FIBROSIS PROGRESSION OR TUMOR, WITH POTENTIAL CLINICAL APPLICATIONS IN PROGNOSIS AS WELL AS A THERAPEUTIC TARGET. ALTHOUGH THERE ARE ALREADY STUDIES ON LNCRNA IN HEPATOCELLULAR CARCINOMA, THIS IS THE FIRST STUDY CONDUCTED IN SAMPLES EXCLUSIVELY OF HCV-RELATED LIVER AND HCV HCC.	2020	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
11 2172  44 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
12 3567  36 IMPACT OF HEPATITIS VIRUS AND AGING ON DNA METHYLATION IN HUMAN HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) USUALLY DEVELOPS ON THE BASIS OF CHRONIC HEPATITIS AND LIVER CIRRHOSIS, WHERE INACTIVATION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) TAKES PLACE VIA METHYLATION OF THE PROMOTER. INTERESTINGLY, THESE METHYLATION EVENTS ARE MORE PREVALENT IN A BACKGROUND LIVER AT HIGH RISK OF HCC THAN ONE AT LOW RISK. ABNORMAL METHYLATION IS ALSO OBSERVED IN PRECANCEROUS NODULES SUCH AS DYSPLASTIC NODULES AND ADENOMAS, SUGGESTING THAT EPIGENETIC ALTERATION IS AN EARLY EVENT FOR HCC CARCINOGENESIS. IT IS POSSIBLE THAT INFECTION WITH THE HEPATITIS VIRUS INDUCES ALTERATION OF METHYLATION AT PROMOTERS OF TSGS. SOME STUDIES SUGGESTED THAT VIRAL PROTEINS INTERFERE WITH DNA METHYLTRANSFERASE IN CHRONIC HEPATITIS B. INDUCTION OF EPIGENETIC ALTERATION IN CHRONIC HEPATITIS C MIGHT, HOWEVER, MIGHT BE A CONSEQUENCE OF OXIDATIVE STRESS. IN ADDITION, WE PROPOSED AGE SHOULD BE TAKEN INTO CONSIDERATION FOR HCC DEVELOPMENT VIA EPIGENETIC PATHWAYS. FURTHER INVESTIGATIONS ARE REQUIRED TO UNDERSTAND THE MECHANISM OF INDUCING EPIGENETIC INSTABILITY DURING HEPATOCARCINOGENESIS.	2010	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
13 2682  35 EVALUATION OF SERUM LINE-1 HYPOMETHYLATION AS A PROGNOSTIC MARKER FOR HEPATOCELLULAR CARCINOMA. BACKGROUND AND STUDY AIMS: GLOBAL HYPOMETHYLATION IS ONE OF THE MOST CONSISTENT EPIGENETIC CHANGES IN CANCER. DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC) MUST BE UNDERSTOOD AS A MULTISTEP PROCESS WITH ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS. IN THE LAST DECADES, IN ADDITION TO GENETIC ALTERATIONS, EPIGENETIC CHANGES HAVE BEEN RECOGNIZED AS AN IMPORTANT AND ALTERNATIVE MECHANISM IN TUMOURIGENESIS. WE INVESTIGATED THE CLINICAL IMPLICATIONS OF GLOBAL HYPOMETHYLATION IN THE SERA OF PATIENTS WITH HEPATOCELLULAR CARCINOMA (HCC). PATIENTS AND METHODS: PCR WAS USED TO ASSESS THE METHYLATION STATUS OF LONG INTERSPERSED NUCLEAR ELEMENT TYPE 1 (LINE-1) REPETITIVE SEQUENCES IN GENOMIC DNA DERIVED FROM SERA OF 50 PATIENTS WITH HCC, 20 PATIENTS WITH CIRRHOSIS, 20 PATIENTS WITH CHRONIC HEPATITIS C AND 10 HEALTHY SUBJECTS. RESULTS: SERUM GENOME HYPOMETHYLATION WAS SIGNIFICANTLY INCREASED IN PATIENTS WITH HCC (P<0.001). THE LEVELS OF SERUM LINE-1 HYPOMETHYLATION AT INITIAL PRESENTATION CORRELATED SIGNIFICANTLY WITH TUMOUR SIZE, TUMOUR NUMBER AND ALPHA-FOETOPROTEIN LEVEL. MOREOVER HIGH SERUM LINE-1 HYPOMETHYLATION CORRELATES SIGNIFICANTLY WITH POOR SURVIVAL. CONCLUSION: SERUM LINE-1 HYPOMETHYLATION MAY SERVE AS A PROGNOSTIC MARKER FOR PATIENTS WITH HCC.	2011	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
14 3248  37 HEPATITIS B VIRUS GENOME ASYMMETRY IN HEPATOCELLULAR CARCINOMA. BACKGROUND: THE ASSOCIATION BETWEEN HEPATITIS B VIRUS (HBV) MUTATIONS AND HEPATOCARCINOGENESIS WERE REPORTED IN THE LITERATURE. PREFERENCE FOR G OVER C IN THE LEADING DNA STRAND HAS BEEN REPORTED TO ACCOUNT FOR THE ASYMMETRY IN NUCLEOTIDE (NT) COMPOSITION. THE AIM OF THIS STUDY WAS TO ANALYZE THE COMPLETE GENOME SEQUENCE AND COMPOSITIONAL ASYMMETRY OF HBV IN DIFFERENT STAGES OF HEPATITIS B. METHODS: FULL GENOME SEQUENCING OF 24 PATIENTS WITH CHRONIC HEPATITIS B, SOME OF WHOM ALSO HAD CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC) WAS PERFORMED. MUTATIONS ANALYSIS WAS IMPLEMENTED IN A COMPARISON WITH A HBV GENOTYPE D REFERENCE FROM AN INTERNATIONAL DNA DATABASE. CPGPROD, A WEB-BASED APPLICATION, WAS USED TO EVALUATE CG CONTENT AND PREDICT CPG ISLANDS. RESULTS: ALL STRAINS WERE 3182 BASE PAIRS (BP) IN LENGTH, EXCEPT FOR TWO CASES OF HCC IN WHICH 9 AND 21 NT, RESPECTIVELY, WERE DELETED IN PRES2. THE GENETIC RELATEDNESS OF THESE ISOLATES WAS 97%-100%. THERE WERE COMMON CPG-RICH REGIONS IN ALL 24 ISOLATED FULL GENOME SEQUENCES, HOWEVER A STRONG NEGATIVE GC SKEW FOR FORMING A CPG ISLAND IN THE MINUS STRAND WERE EXHIBITED IN OVERLAP WITH ENHANCER I IN THREE HCC PATIENTS, A CIRRHOTIC PATIENT AND THREE WITH CHRONIC HEPATITIS. CONCLUSION: THE HIGH PERCENTAGE OF SEQUENCE IDENTITY BETWEEN HBV ISOLATES IN OUR PATIENTS DEMONSTRATES THAT GENOMIC FACTORS, EXCEPT FOR GENOTYPE, ARE INVOLVED IN HEPATOCARCINOGENESIS. VARIATIONS IN GC CONTENT WHICH WERE CAUSED BY A DIFFERENT SPECTRUM OF MUTATIONS MAY AFFECT DNA COMPOSITIONAL ASYMMETRY AND EPIGENETIC MODIFICATION OF HBV DNA IN HCC.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                      
15 2902  34 GENDER DIFFERENCES IN THE LIVERS OF PATIENTS WITH HEPATOCELLULAR CARCINOMA AND CHRONIC HEPATITIS C INFECTION. OBJECTIVES: A UNIQUE CAUSATIVE ASPECT OF HEPATOCELLULAR CARCINOMA (HCC) IS A GENDER DIFFERENCE IN ITS INCIDENCE. TO DETERMINE THE SPECIFIC FACTORS THAT CONTRIBUTE TO A MALE PREDOMINANCE, WE ANALYZED THE CLINICOPATHOLOGICAL FACTORS, AND GENETIC AND EPIGENETIC ALTERATIONS OF HCCS IN MALE AND FEMALE PATIENTS. METHODS: WE RETROSPECTIVELY ANALYZED THREE COHORTS OF PATIENTS: THE FIRST COHORT CONSISTED OF 547 PATIENTS IDENTIFIED WITH THE FIRST EVENT OF HCC, THE SECOND COHORT INCLUDED 176 HCC PATIENTS, AND THE THIRD 127 PATIENTS WITH CHRONIC HEPATITIS C (CHC). RESULTS: MALE PATIENTS WERE FOUND TO HAVE HCC MORE FREQUENTLY THAN FEMALE PATIENTS IN CASES OF NON-CIRRHOTIC LIVER (P = 0.0030 BY THE CHI(2) TEST), ESPECIALLY IN HEPATITIS C-POSITIVE CASES. HOWEVER, THERE WERE NO GENDER-SPECIFIC DIFFERENCES IN THE GENETIC AND EPIGENETIC ALTERATIONS OF CANCER-RELATED GENES. DEPOSITION OF IRON WAS MORE SEVERE IN MALE CHC PATIENTS THAN IN FEMALE PATIENTS. CONCLUSIONS: MALE PATIENTS WITH CHC DEVELOP HCC MORE FREQUENTLY WHEN THEY HAVE A NON-CIRRHOTIC LIVER THAN DO FEMALE PATIENTS. THIS GENDER DIFFERENCE COULD BE, AT LEAST PARTIALLY, ATTRIBUTED TO A DIFFERENT DEGREE OF IRON DEPOSITION, WHICH CONTRIBUTES TO THE DEVELOPMENT OF HCC IN THE ABSENCE OF LIVER CIRRHOSIS IN MEN WITH CHC.	2012	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
16 6707  39 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                          
17  332  37 ALTERATION OF EPIGENETIC PROFILE IN HUMAN HEPATOCELLULAR CARCINOMA AND ITS CLINICAL IMPLICATIONS. HEPATOCELLULAR CARCINOMA (HCC) IS A COMMON CANCER WORLDWIDE AND DEVELOPS AGAINST A BACKGROUND OF CHRONIC LIVER DAMAGE. A VARIETY OF HCC-RELATED GENES ARE KNOWN TO BE ALTERED BY GENETIC AND EPIGENETIC MECHANISMS. THEREFORE, INFORMATION REGARDING ALTERATION OF THE GENETIC AND EPIGENETIC PROFILES IN HCC IS ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF THIS TYPE OF TUMOR. METHYLATION AT CPG SITES IN GENE PROMOTERS IS KNOWN TO AFFECT THE TRANSCRIPTION OF THE CORRESPONDING GENES. ABNORMAL REGIONAL HYPERMETHYLATION IS OBSERVED IN THE 5' REGION OF SEVERAL TUMOR SUPPRESSOR GENES (TSGS) IN HCC, AND THIS HYPERMETHYLATION MAY PROMOTE CARCINOGENESIS THROUGH THE TRANSCRIPTIONAL INACTIVATION OF DOWNSTREAM TSGS. THE DNA DAMAGE INDUCED BY OXIDATION IS A TRIGGER OF ABNORMAL DNA METHYLATION AND INACTIVATION OF TSGS THROUGH RECRUITMENT OF THE POLYCOMB REPRESSIVE COMPLEX TO THE PROMOTER SEQUENCE. THUS, OXIDATIVE STRESS MAY BE RESPONSIBLE FOR THE EMERGENCE OF HCC FROM CHRONIC HEPATITIS AND LIVER CIRRHOSIS THROUGH THE EPIGENETIC ALTERATION OF TSGS. THERE HAVE BEEN SEVERAL ATTEMPTS TO APPLY EPIGENETIC INFORMATION TO THE DIAGNOSIS AND TREATMENT OF HCC. THE PREDICTIVE VALUE OF SELECTED METHYLATION EVENTS ON SURVIVAL IN HCC PATIENTS HAS BEEN REPORTED, AND THE METHYLATION PROFILE OF BACKGROUND LIVER COULD BE ASSOCIATED WITH RECURRENCE-FREE SURVIVAL OF HCC PATIENTS WHO HAVE UNDERGONE HEPATECTOMY. ANOTHER STUDY DETECTED METHYLATED DNA FROM HCC CELLS IN SERUM, AND THE CIRCULATING TUMOR DNA WAS REGARDED AS A POTENTIAL TUMOR MARKER. IN ADDITION, SEVERAL TRIALS OF HCC THERAPY HAVE TARGETED THE EPIGENETIC MACHINERY AND WERE BASED UPON COMPREHENSIVE ANALYSES OF DNA METHYLATION OF THIS TYPE OF TUMOR. HERE, WE PRESENT AN OVERVIEW OF RESEARCH REGARDING DNA METHYLATION STATUS IN HUMAN HCC AND DESCRIBE THE CLINICAL APPLICATION OF EPIGENETIC INFORMATION TO HCC.	2014	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
18 5921  44 TARGETING CLINICAL EPIGENETIC REPROGRAMMING FOR CHEMOPREVENTION OF METABOLIC AND VIRAL HEPATOCELLULAR CARCINOMA. OBJECTIVE: HEPATOCELLULAR CARCINOMA (HCC) IS THE FASTEST-GROWING CAUSE OF CANCER-RELATED MORTALITY WITH CHRONIC VIRAL HEPATITIS AND NON-ALCOHOLIC STEATOHEPATITIS (NASH) AS MAJOR AETIOLOGIES. TREATMENT OPTIONS FOR HCC ARE UNSATISFACTORY AND CHEMOPREVENTIVE APPROACHES ARE ABSENT. CHRONIC HEPATITIS C (CHC) RESULTS IN EPIGENETIC ALTERATIONS DRIVING HCC RISK AND PERSISTING FOLLOWING CURE. HERE, WE AIMED TO INVESTIGATE EPIGENETIC MODIFICATIONS AS TARGETS FOR LIVER CANCER CHEMOPREVENTION. DESIGN: LIVER TISSUES FROM PATIENTS WITH NASH AND CHC WERE ANALYSED BY CHIP-SEQ (H3K27AC) AND RNA-SEQ. THE LIVER DISEASE-SPECIFIC EPIGENETIC AND TRANSCRIPTIONAL REPROGRAMMING IN PATIENTS WAS MODELLED IN A LIVER CELL CULTURE SYSTEM. PERTURBATION STUDIES COMBINED WITH A TARGETED SMALL MOLECULE SCREEN FOLLOWED BY IN VIVO AND EX VIVO VALIDATION WERE USED TO IDENTIFY CHROMATIN MODIFIERS AND READERS FOR HCC CHEMOPREVENTION. RESULTS: IN PATIENTS, CHC AND NASH SHARE SIMILAR EPIGENETIC AND TRANSCRIPTOMIC MODIFICATIONS DRIVING CANCER RISK. USING A CELL-BASED SYSTEM MODELLING EPIGENETIC MODIFICATIONS IN PATIENTS, WE IDENTIFIED CHROMATIN READERS AS TARGETS TO REVERT LIVER GENE TRANSCRIPTION DRIVING CLINICAL HCC RISK. PROOF-OF-CONCEPT STUDIES IN A NASH-HCC MOUSE MODEL SHOWED THAT THE PHARMACOLOGICAL INHIBITION OF CHROMATIN READER BROMODOMAIN 4 INHIBITED LIVER DISEASE PROGRESSION AND HEPATOCARCINOGENESIS BY RESTORING TRANSCRIPTIONAL REPROGRAMMING OF THE GENES THAT WERE EPIGENETICALLY ALTERED IN PATIENTS. CONCLUSION: OUR RESULTS UNRAVEL THE FUNCTIONAL RELEVANCE OF METABOLIC AND VIRUS-INDUCED EPIGENETIC ALTERATIONS FOR PATHOGENESIS OF HCC DEVELOPMENT AND IDENTIFY CHROMATIN READERS AS TARGETS FOR CHEMOPREVENTION IN PATIENTS WITH CHRONIC LIVER DISEASES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
19 3271  47 HEPATOCELLULAR CARCINOMA RISK AFTER VIRAL RESPONSE IN HEPATITIS C VIRUS-ADVANCED FIBROSIS: WHO TO SCREEN AND FOR HOW LONG? HEPATITIS C VIRUS (HCV) CHRONIC INFECTION IS ASSOCIATED WITH FIBROSIS PROGRESSION, END-STAGE LIVER COMPLICATIONS AND HCC. NOT SURPRISINGLY, HCV INFECTION IS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY WORLDWIDE. AFTER SUSTAINED VIROLOGICAL RESPONSE (SVR), THE RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA IS NOT COMPLETELY ELIMINATED IN PATIENTS WITH ESTABLISHED CIRRHOSIS OR WITH ADVANCED FIBROSIS. THEREFORE, LIFELONG SURVEILLANCE IS CURRENTLY RECOMMENDED. THIS STRATEGY IS LIKELY NOT UNIVERSALLY COST-EFFECTIVE AND HARMLESS, CONSIDERING THAT NOT ALL PATIENTS WITH ADVANCED FIBROSIS HAVE THE SAME RISK OF DEVELOPING HCC. FACTORS RELATED TO THE SEVERITY OF LIVER DISEASE AND ITS POTENTIAL TO IMPROVE AFTER SVR, THE MOLECULAR AND EPIGENETIC CHANGES THAT OCCUR DURING INFECTION AND OTHER ASSOCIATED COMORBIDITIES MIGHT ACCOUNT FOR DIFFERENT RISK LEVELS AND ARE LIKELY ESSENTIAL FOR IDENTIFYING PATIENTS WHO WOULD BENEFIT FROM SCREENING PROGRAMS AFTER SVR. EFFORTS TO DEVELOP PREDICTIVE MODELS AND RISK CALCULATORS, BIOMARKERS AND GENETIC PANELS AND EVEN DEEP LEARNING MODELS TO ESTIMATE THE INDIVIDUAL RISK OF HCC HAVE BEEN MADE IN THE DIRECT-ACTING ANTIVIRAL AGENTS ERA, WHEN THOUSANDS OF PATIENTS WITH ADVANCED FIBROSIS AND CIRRHOSIS HAVE REACHED SVR. THESE TOOLS COULD HELP TO IDENTIFY PATIENTS WITH VERY LOW HCC RISK IN WHOM SURVEILLANCE MIGHT NOT BE JUSTIFIED. IN THIS REVIEW, FACTORS AFFECTING THE PROBABILITY OF HCC DEVELOPMENT AFTER SVR, THE BENEFITS AND RISKS OF SURVEILLANCE, SUGGESTED STRATEGIES TO ESTIMATE INDIVIDUALIZED HCC RISK AND THE CURRENT EVIDENCE TO RECOMMEND LIFELONG SURVEILLANCE ARE DISCUSSED.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
20 4920  31 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