1 5521 136 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 2 3271 48 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 3 3260 53 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 4 6640 49 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 5 1042 34 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 6 2172 43 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 7 5622 44 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 8 5770 41 SPECIFIC MOLECULAR SIGNATURES OF NON-TUMOR LIVER TISSUE MAY PREDICT A RISK OF HEPATOCARCINOGENESIS. HEPATOCELLULAR CARCINOMA (HCC) IS ONE OF THE MOST COMMON HUMAN CANCERS AND A MAJOR CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE BLEAK OUTCOMES OF HCC PATIENTS EVEN AFTER CURATIVE TREATMENT HAVE BEEN, AT LEAST PARTIALLY, ATTRIBUTED TO ITS MULTICENTRIC ORIGIN. THEREFORE, IT IS NECESSARY TO EXAMINE NOT ONLY TUMOR TISSUE BUT ALSO NON-TUMOR LIVER TISSUE TO INVESTIGATE THE MOLECULAR MECHANISMS OPERATING DURING HEPATOCARCINOGENESIS BASED ON THE CONCEPT OF "FIELD CANCERIZATION". SEVERAL STUDIES PREVIOUSLY INVESTIGATED THE ASSOCIATION OF MOLECULAR ALTERATIONS IN NON-TUMOR LIVER TISSUE WITH CLINICAL FEATURES AND PROGNOSIS IN HCC PATIENTS ON A GENOME-WIDE SCALE. IN PARTICULAR, SPECIFIC ALTERATIONS OF DNA METHYLATION PROFILES HAVE BEEN CONFIRMED IN NON-TUMOR LIVER TISSUE. THIS REVIEW FOCUSES ON THE POSSIBLE CLINICAL VALUE OF ARRAY-BASED COMPREHENSIVE ANALYSES OF MOLECULAR ALTERATIONS, ESPECIALLY ABERRANT DNA METHYLATION, IN NON-TUMOR LIVER TISSUE TO CLARIFY THE RISK OF HEPATOCARCINOGENESIS. CARCINOGENETIC RISK ESTIMATION BASED ON SPECIFIC METHYLATION SIGNATURES MAY BE ADVANTAGEOUS FOR CLOSE FOLLOW-UP OF PATIENTS WHO ARE AT HIGH RISK OF HCC DEVELOPMENT. FURTHERMORE, EPIGENETIC THERAPIES FOR PATIENTS WITH CHRONIC LIVER DISEASES MAY BE HELPFUL TO REDUCE THE RISK OF HCC DEVELOPMENT BECAUSE EPIGENETIC ALTERATIONS ARE POTENTIALLY REVERSIBLE, AND THUS PROVIDE PROMISING MOLECULAR TARGETS FOR THERAPEUTIC INTERVENTION. 2014 9 3567 40 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 10 3928 31 LIVER CELL CIRCUITS AND THERAPEUTIC DISCOVERY FOR ADVANCED LIVER DISEASE AND CANCER. HEPATOCELLULAR CARCINOMA (HCC) IS A MAJOR GLOBAL HEALTH CHALLENGE WITH RISING INCIDENCE. DESPITE THE PREVIOUS APPROVAL OF SEVERAL NOVEL THERAPEUTIC APPROACHES, HCC REMAINS THE SECOND COMMON CAUSE OF CANCER-RELATED DEATH WORLDWIDE. THE VAST MAJORITY OF HCCS ARISES IN THE CONTEXT OF CHRONIC FIBROTIC LIVER DISEASES CAUSED BY VIRAL OR METABOLIC ETIOLOGIES. IN PATIENTS WITH ADVANCED LIVER DISEASE THE RISK OF HCC PERSISTS EVEN AFTER VIRAL CURE OR CONTROL OF INFECTION. MOREOVER, GIVEN THE CHANGE IN THE LIFESTYLE AND INCREASE OF OBESITY AND METABOLIC DISORDERS, HCC INCIDENCE IS PREDICTED TO DRASTICALLY AUGMENT IN THE NEXT DECADE. EARLY DETECTION, IMPROVEMENT OF THE SCREENING METHOD IN PATIENT AT-RISK AND DEVELOPMENT OF CHEMOPREVENTIVE STRATEGIES ARE THEREFORE URGENTLY NEEDED TO REDUCE HCC RISK. THIS REVIEW SUMMARIZES THE MAJOR CHALLENGES IN THE IDENTIFICATION OF PATIENT AT RISK FOR HCC AND THE EMERGENT STRATEGIES FOR HCC PREVENTION TO IMPROVE PATIENTS' OUTCOME. 2021 11 3927 41 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 12 2166 52 EPIGENETIC MECHANISMS IN HEPATOCELLULAR CARCINOMA: HOW ENVIRONMENTAL FACTORS INFLUENCE THE EPIGENOME. EPIGENETIC MECHANISMS MAINTAIN HERITABLE CHANGES IN GENE EXPRESSION AND CHROMATIN ORGANIZATION OVER MANY CELL GENERATIONS. IMPORTANTLY, DEREGULATED EPIGENETIC MECHANISMS PLAY A KEY ROLE IN A WIDE RANGE OF HUMAN MALIGNANCIES, INCLUDING LIVER CANCER. HEPATOCELLULAR CARCINOMA (HCC), WHICH ORIGINATES FROM THE HEPATOCYTES, IS BY FAR THE MOST COMMON LIVER CANCER, WITH RATES AND AETIOLOGY THAT SHOW CONSIDERABLE GEOGRAPHIC VARIATION. VARIOUS ENVIRONMENTAL AGENTS AND LIFESTYLES KNOWN TO BE RISK FACTORS FOR HCC (SUCH AS INFECTION BY HEPATITIS B VIRUS (HBV) AND HEPATITIS C VIRUS (HCV), CHRONIC ALCOHOL INTAKE, AND AFLATOXINS) ARE SUSPECTED TO PROMOTE ITS DEVELOPMENT BY ELICITING EPIGENETIC CHANGES, HOWEVER THE PRECISE GENE TARGETS AND UNDERLYING MECHANISMS HAVE NOT BEEN ELUCIDATED. MANY RECENT STUDIES HAVE EXPLOITED CONCEPTUAL AND TECHNOLOGICAL ADVANCES IN EPIGENETICS AND EPIGENOMICS TO INVESTIGATE THE ROLE OF EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN HCC TUMORS AND NON-TUMOR PRECANCEROUS (CIRRHOTIC) LESIONS. THESE STUDIES HAVE IDENTIFIED A LARGE NUMBER OF GENES AND PATHWAYS THAT ARE TARGETED BY EPIGENETIC DEREGULATION (CHANGES IN DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-MEDIATED GENE SILENCING) DURING THE DEVELOPMENT AND PROGRESSION OF HCC. FREQUENT IDENTIFICATION OF ABERRANT EPIGENETIC CHANGES IN SPECIFIC GENES IN CIRRHOTIC TISSUE IS CONSISTENT WITH THE NOTION THAT EPIGENETIC DEREGULATION OF SELECTED GENES IN PRE-MALIGNANT LESIONS PRECEDES AND PROMOTES THE DEVELOPMENT OF HCC. IN ADDITION, SEVERAL LINES OF EVIDENCE ARGUE THAT SOME ENVIRONMENTAL FACTORS (SUCH AS HBV VIRUS) MAY ABROGATE CELLULAR DEFENSE SYSTEMS, INDUCE SILENCING OF HOST GENES AND PROMOTE HCC DEVELOPMENT VIA AN "EPIGENETIC STRATEGY". FINALLY, PROFILING STUDIES REVEAL THAT HCC TUMORS AND PRE-CANCEROUS LESIONS MAY EXHIBIT EPIGENETIC SIGNATURES ASSOCIATED WITH SPECIFIC RISK FACTORS AND TUMOR PROGRESSION STAGE. TOGETHER, RECENT EVIDENCE UNDERSCORES THE IMPORTANCE OF ABERRANT EPIGENETIC EVENTS INDUCED BY ENVIRONMENTAL FACTORS IN LIVER CANCER AND HIGHLIGHTS POTENTIAL TARGETS FOR BIOMARKER DISCOVERY AND FUTURE PREVENTIVE AND THERAPEUTIC STRATEGIES. 2011 13 5360 37 RECENT ADVANCEMENTS IN COMPREHENSIVE GENETIC ANALYSES FOR HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) TYPICALLY DEVELOPS IN THE LIVER WITH CHRONIC HEPATITIS AND CIRRHOSIS, AND ACTIVATION OF ONCOGENES AND INACTIVATION OF TUMOR SUPPRESSOR GENES OCCURS DURING CARCINOGENESIS VIA GENETIC AND EPIGENETIC MECHANISMS. RECENT ADVANCEMENTS IN THE DEVELOPMENT OF ANALYSES FOR EXAMINING THE CANCER GENOME HAVE REVEALED INFORMATION REGARDING GENETIC ALTERATIONS IN HCC TISSUES. ACCORDING TO PREVIOUS STUDIES, THE INCIDENCE OF RECURRENT GENETIC ALTERATIONS IN INDIVIDUAL GENES WAS THOUGHT TO BE RELATIVELY RARE AND LIMITED TO A SUBSET OF A FEW CANCER-SPECIFIC GENES SUCH AS TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS CTNNB1. HOWEVER, RECENT WHOLE-GENOME ANALYSES AND EXOME SEQUENCING OF TUMOR DNA HAVE REVEALED NUMEROUS NOVEL ALTERATIONS OF CANCER-RELATED GENES AND PATHWAYS CRITICAL FOR HCC DEVELOPMENT. IN ADDITION, VARIOUS RISK FACTORS FOR HCC, SUCH AS THE PRESENCE OR ABSENCE OF HEPATITIS B AND C VIRUS, MAY AFFECT THE MUTATION PROFILE OF THE CORRESPONDING CANCER GENOME. ON THE OTHER HAND, GENOME-WIDE ASSOCIATION STUDIES HAVE ALSO IDENTIFIED IMPORTANT SINGLE-NUCLEOTIDE POLYMORPHISMS INVOLVED IN HCC DEVELOPMENT, WHICH MAY ALLOW DETECTION OF A GROUP AT HIGH RISK OF HCC EMERGENCE. SUCH ANALYSES WILL CLARIFY HOW THIS MALIGNANCY CAN BE TREATED, DIAGNOSED AND PREVENTED MORE EFFECTIVELY. 2013 14 4920 28 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 15 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 16 5233 38 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 17 4461 31 MOLECULAR MECHANISMS OF GENDER DISPARITY IN HEPATITIS B VIRUS-ASSOCIATED HEPATOCELLULAR CARCINOMA. CHRONIC HEPATITIS B VIRUS (HBV) INFECTION IS ONE OF THE MOST COMMON CAUSES OF HEPATOCELLULAR CARCINOMA (HCC), A MALIGNANT TUMOR WITH HIGH MORTALITY WORLDWIDE. ONE REMARKABLE CLINICAL FEATURE OF HBV-RELATED HCC IS THAT ITS INCIDENCE IS HIGHER IN MALES AND POSTMENOPAUSAL FEMALES COMPARED TO OTHER FEMALES. INCREASING EVIDENCE INDICATES THAT HBV-ASSOCIATED HCC MAY INVOLVE GENDER DISPARITY AND THAT IT MAY BE A TYPE OF HORMONE-RESPONSIVE MALIGNANT TUMOR. SEX HORMONES, SUCH AS ANDROGEN AND ESTROGEN, HAVE BEEN SHOWN TO PLAY VERY DIFFERENT ROLES IN THE PROGRESSION OF AN HBV INFECTION AND IN THE DEVELOPMENT OF HBV-RELATED HCC. THROUGH BINDING TO THEIR SPECIFIC CELLULAR RECEPTORS AND AFFECTING THE CORRESPONDING SIGNALING PATHWAYS, SEX HORMONES CAN REGULATE THE TRANSACTIVATION OF HBX, CAUSE THE CHRONIC RELEASE OF INFLAMMATORY CYTOKINES IN THE HEPATOCELLULAR MICROENVIRONMENT, AND PARTICIPATE IN EPIGENETIC AND GENETIC ALTERNATIONS IN HEPATOCYTES. ALL OF THESE FUNCTIONS MAY BE RELATED TO THE INITIATION AND PROGRESSION OF HBV-ASSOCIATED HCC. A THOROUGH INVESTIGATION OF THE MOLECULAR MECHANISMS UNDERLYING THE GENDER-RELATED DISPARITY IN HBV-RELATED HCC SHOULD PROVIDE A NEW PERSPECTIVE FOR BETTER UNDERSTANDING ITS PATHOGENESIS AND EXPLORING MORE EFFECTIVE METHODS FOR THE PREVENTION AND TREATMENT OF THIS DISEASE. 2014 18 4133 27 MECHANISMS OF HEPATITIS B VIRUS-INDUCED HEPATOCARCINOGENESIS. HEPATITIS B VIRUS (HBV) IS A MAJOR CAUSE OF HEPATOCELLULAR CARCINOMA (HCC). THERE ARE APPROXIMATELY 250 MILLION PEOPLE IN THE WORLD THAT ARE CHRONICALLY INFECTED BY THIS VIRUS, RESULTING IN NEARLY 1 MILLION DEATHS EVERY YEAR. MANY OF THESE PATIENTS DIE FROM SEVERE LIVER DISEASES, INCLUDING HCC. HBV MAY INDUCE HCC THROUGH THE INDUCTION OF CHRONIC LIVER INFLAMMATION, WHICH CAN CAUSE OXIDATIVE STRESS AND DNA DAMAGE. HOWEVER, MANY STUDIES ALSO INDICATED THAT HBV COULD INDUCE HCC VIA THE ALTERATION OF HEPATOCELLULAR PHYSIOLOGY THAT MAY INVOLVE GENETIC AND EPIGENETIC CHANGES OF THE HOST DNA, THE ALTERATION OF CELLULAR SIGNALING PATHWAYS, AND THE INHIBITION OF DNA REPAIR MECHANISMS. THIS ALTERATION OF CELLULAR PHYSIOLOGY CAN LEAD TO THE ACCUMULATION OF DNA DAMAGES AND THE PROMOTION OF CELL CYCLES AND PREDISPOSE HEPATOCYTES TO ONCOGENIC TRANSFORMATION. 2021 19 3250 38 HEPATITIS B VIRUS INFECTION, MICRORNAS AND LIVER DISEASE. HEPATITIS B VIRUS (HBV) ATTACKS THE LIVER AND CAN CAUSE BOTH ACUTE AS WELL AS CHRONIC LIVER DISEASES WHICH MIGHT LEAD TO LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. REGARDLESS OF THE AVAILABILITY OF A VACCINE AND NUMEROUS TREATMENT OPTIONS, HBV IS A MAJOR CAUSE OF MORBIDITY AND MORTALITY ACROSS THE WORLD. RECENTLY,MICRORNAS (MIRNAS) HAVE EMERGED AS IMPORTANT MODULATORS OF GENE FUNCTION. STUDIES ON THE ROLE OF MIRNA IN THE REGULATION OF HEPATITIS B VIRUS GENE EXPRESSION HAVE BEEN THE FOCUS OF MODERN ANTIVIRAL RESEARCH. MIRNAS CAN REGULATE VIRAL REPLICATION AND PATHOGENESIS IN A NUMBER OF DIFFERENT WAYS, WHICH INCLUDEFACILITATION, DIRECT OR INDIRECT INHIBITION, ACTIVATION OF IMMUNE RESPONSE, EPIGENETIC MODULATION, ETC. NEVERTHELESS, THESE MECHANISMS CAN APPROPRIATELY BE USED WITH A DIAGNOSTICAND/OR THERAPEUTIC APPROACH. THE PRESENT REVIEW IS AN ATTEMPT TO CLASSIFY SPECIFIC MIRNAS THAT ARE REPORTED TO BE ASSOCIATED WITH VARIOUS ASPECTS OF HEPATITIS B BIOLOGY, IN ORDER TO PRECISELY PRESENT THE PARTICIPATION OF INDIVIDUAL MIRNAS IN MULTIPLE ASPECTS RELATING TO HBV. 2015 20 3190 50 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