1 4951 105 PATHOGENESIS OF CHOLANGIOCARCINOMA: FROM GENETICS TO SIGNALLING PATHWAYS. CHOLANGIOCARCINOMA (CCA) IS A MALIGNANT TUMOUR OF BILE DUCT EPITHELIAL CELLS WITH DISMAL PROGNOSIS AND RISING INCIDENCE. CHRONIC INFLAMMATION RESULTING FROM LIVER FLUKE INFECTION, HEPATITIS AND OTHER INFLAMMATORY BOWEL DISEASES IS A MAJOR CONTRIBUTING FACTOR TO CHOLANGIOCARCINOGENESIS, LIKELY THROUGH ACCUMULATION OF SERIAL GENETIC AND EPIGENETIC ALTERATIONS RESULTING IN ABERRATION OF ONCOGENES AND TUMOUR SUPPRESSORS. RECENT STUDIES MAKING USE OF ADVANCES IN HIGH-THROUGHPUT GENOMICS HAVE REVEALED THE GENETIC LANDSCAPE OF CCA, GREATLY INCREASING OUR UNDERSTANDING OF ITS UNDERLYING BIOLOGY. A SERIES OF HIGHLY RECURRENT MUTATIONS IN GENES SUCH AS TP53, KRAS, SMAD4, BRAF, MLL3, ARID1A, PBRM1 AND BAP1, WHICH ARE KNOWN TO BE INVOLVED IN CELL CYCLE CONTROL, CELL SIGNALLING PATHWAYS AND CHROMATIN DYNAMICS, HAVE LED TO INVESTIGATIONS OF THEIR ROLES, THROUGH MOLECULAR TO MOUSE MODELLING STUDIES, IN CHOLANGIOCARCINOGENESIS. THIS REVIEW FOCUSES ON THE LANDSCAPE GENETIC ALTERATIONS IN CCA AND ITS FUNCTIONAL RELEVANCE TO THE FORMATION AND PROGRESSION OF CCA. 2015 2 1972 36 EPIGENETIC ALTERATIONS ASSOCIATED WITH CHOLANGIOCARCINOMA (REVIEW). CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION, AND HEPATOLITHIASIS, ARE CONSIDERED RISK FACTORS, BUT THE CAUSE IS STILL UNKNOWN IN MOST CASES. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS, INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION, IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. MORE RECENTLY, RESEARCH INTEREST HAS BEEN FOCUSING ON MICRORNA (MIR), A MAJOR SUBTYPE OF NON-CODING RNA. MIR IS HIGHLY CONSERVED AMONG SPECIES AND REGULATES THE EXPRESSION OF SPECIFIC TARGET GENES BY BINDING TO THE 3'-UNTRANSLATED REGIONS OF MESSENGER RNA. THE NUMBER OF STUDIES ON A POSSIBLE LINK BETWEEN MIR AND VARIOUS CANCERS IS GROWING. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES CURRENTLY KNOWN TO BE HYPERMETHYLATED IN CCA AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. THE EPIGENETIC ROLE OF MIR IN THE PATHOGENESIS OF CCA IS ALSO DISCUSSED. 2009 3 4472 46 MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA. BACKGROUND: CHOLANGIOCARCINOMAS ARE A HETEROGENEOUS GROUP OF MALIGNANCIES ARISING FROM A NUMBER OF CELLS OF ORIGIN ALONG THE BILIARY TREE. ALTHOUGH MOST CASES IN WESTERN COUNTRIES ARE SPORADIC, LARGE POPULATION-BASED STUDIES HAVE IDENTIFIED A NUMBER OF RISK FACTORS. THIS REVIEW SUMMARISES THE EVIDENCE BEHIND REPORTED RISK FACTORS AND CURRENT UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA, WITH A FOCUS ON INFLAMMATION AND CHOLESTASIS AS THE DRIVING FORCES IN CHOLANGIOCARCINOMA DEVELOPMENT. RISK FACTORS FOR CHOLANGIOCARCINOGENESIS: CHOLESTATIC LIVER DISEASES (E.G. PRIMARY SCLEROSING CHOLANGITIS AND FIBROPOLYCYSTIC LIVER DISEASES), LIVER CIRRHOSIS, AND BILIARY STONE DISEASE ALL INCREASE THE RISK OF CHOLANGIOCARCINOMA. CERTAIN BACTERIAL, VIRAL OR PARASITIC INFECTIONS SUCH AS HEPATITIS B AND C AND LIVER FLUKES ALSO INCREASE CHOLANGIOCARCINOMA RISK. OTHER RISK FACTORS INCLUDE INFLAMMATORY DISORDERS (SUCH AS INFLAMMATORY BOWEL DISEASE AND CHRONIC PANCREATITIS), TOXINS (E.G. ALCOHOL AND TOBACCO), METABOLIC CONDITIONS (DIABETES, OBESITY AND NON-ALCOHOLIC FATTY LIVER DISEASE) AND A NUMBER OF GENETIC DISORDERS. MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS CAUSE CHRONIC INFLAMMATION OR CHOLESTASIS. CHRONIC INFLAMMATION LEADS TO INCREASED EXPOSURE OF CHOLANGIOCYTES TO THE INFLAMMATORY MEDIATORS INTERLEUKIN-6, TUMOUR NECROSIS FACTOR-A, CYCLO-OXYGENASE-2 AND WNT, RESULTING IN PROGRESSIVE MUTATIONS IN TUMOUR SUPPRESSOR GENES, PROTO-ONCOGENES AND DNA MISMATCH-REPAIR GENES. ACCUMULATING BILE ACIDS FROM CHOLESTASIS LEAD TO REDUCED PH, INCREASED APOPTOSIS AND ACTIVATION OF ERK1/2, AKT AND NF-KAPPAB PATHWAYS THAT ENCOURAGE CELL PROLIFERATION, MIGRATION AND SURVIVAL. OTHER MEDIATORS UPREGULATED IN CHOLANGIOCARCINOMA INCLUDE TRANSFORMING GROWTH FACTOR-BETA, VASCULAR ENDOTHELIAL GROWTH FACTOR, HEPATOCYTE GROWTH FACTOR AND SEVERAL MICRORNAS. INCREASED EXPRESSION OF THE CELL SURFACE RECEPTOR C-MET, THE GLUCOSE TRANSPORTER GLUT-1 AND THE SODIUM IODIDE SYMPORTER LEAD TO TUMOUR GROWTH, ANGIOGENESIS AND CELL MIGRATION. STROMAL CHANGES ARE ALSO OBSERVED, RESULTING IN ALTERATIONS TO THE EXTRACELLULAR MATRIX COMPOSITION AND RECRUITMENT OF FIBROBLASTS AND MACROPHAGES THAT CREATE A MICROENVIRONMENT PROMOTING CELL SURVIVAL, INVASION AND METASTASIS. CONCLUSION: REGARDLESS OF AETIOLOGY, MOST RISK FACTORS FOR CHOLANGIOCARCINOMA CAUSE CHRONIC INFLAMMATION AND/OR CHOLESTASIS, LEADING TO THE ACTIVATION OF COMMON INTRACELLULAR PATHWAYS THAT RESULT IN REACTIVE CELL PROLIFERATION, GENETIC/EPIGENETIC MUTATIONS AND CHOLANGIOCARCINOGENESIS. AN UNDERSTANDING OF THE MOLECULAR PATHOGENESIS OF CHOLANGIOCARCINOMA IS VITAL WHEN DEVELOPING NEW DIAGNOSTIC BIOMARKERS AND TARGETED THERAPIES FOR THIS DISEASE. 2019 4 1978 35 EPIGENETIC ALTERATIONS IN CHOLANGIOCARCINOMA-SUSTAINED IL-6/STAT3 SIGNALING IN CHOLANGIO- CARCINOMA DUE TO SOCS3 EPIGENETIC SILENCING. CHOLANGIOCARCINOMA (CCA) IS A HIGHLY LETHAL MALIGNANT TUMOR ARISING FROM THE BILIARY TRACT EPITHELIUM, CHARACTERIZED BY ITS TYPICALLY LATE CLINICAL PRESENTATION AND LACK OF EFFECTIVE THERAPEUTIC MODALITIES. CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PRIMARY SCLEROSING CHOLANGITIS, LIVER FLUKE INFESTATION AND HEPATOLITHIASIS, ARE LISTED IN THE RISK FACTORS, BUT FOR MOST CASES OF CCA THE CAUSE IS UNKNOWN. RECENT ADVANCES IN MOLECULAR PATHOGENESIS HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC ALTERATIONS INCLUDING PROMOTER HYPERMETHYLATION AND HISTONE DEACETYLATION IN ADDITION TO GENETIC CHANGES IN THE PROCESS OF CHOLANGIOCARCINOGENESIS. THIS REVIEW PROVIDES A COMPREHENSIVE OVERVIEW OF THE GENES HYPERMETHYLATED IN CCA TO DATE AND THEIR PUTATIVE ROLES IN CHOLANGIOCARCINOGENESIS. AMONG GENES HYPERMETHYLATED, WE FOUND THE CPG ISLAND HYPERMETHYLATION IN SUPPRESSOR OF CYTOKINE SIGNALING 3 (SOCS3) GENE PROMOTER IN CCA. INTERLEUKIN-6 (IL-6)-MEDIATED SIGNAL TRANSDUCERS AND ACTIVATORS OF TRANSCRIPTION 3 (STAT3) ACTIVATION ARE ABERRANTLY SUSTAINED IN CCA CELLS, RESULTING IN RESISTANCE TO APOPTOSIS. SOCS3 CONTROLS THE IL-6/STAT3 SIGNALING PATHWAY BY A CLASSIC FEEDBACK LOOP. INDEED, SOCS3 EPIGENETIC SILENCING IS RESPONSIBLE FOR SUSTAINED IL-6/STAT3 SIGNALING IN CCA. THESE FINDINGS PROVIDE NEW PERSPECTIVES FOR EPIGENETIC THERAPY TO RESTORE SOCS3 IN THIS CANCER. 2009 5 2970 39 GENETIC AND EPIGENETIC SIGNATURES IN HUMAN HEPATOCELLULAR CARCINOMA: A SYSTEMATIC REVIEW. HEPATOCELLULAR CARCINOMA (HCC) IS THE THIRD MOST COMMON CAUSE OF CANCER DEATHS WORLDWIDE, AND THE INCIDENCE OF THIS FATAL DISEASE IS STILL ON RISE. THE MAJORITY OF HCCS EMERGE IN THE BACKGROUND OF A CHRONIC LIVER DISEASE, SUCH AS CHRONIC HEPATITIS AND LIVER CIRRHOSIS. THE CURRENT UNDERSTANDING IS THAT MAJORITY OF HCCS EVOLVE AS A CONSEQUENCE OF CHRONIC INFLAMMATION AND DUE TO THE PRESENCE OF INFECTION WITH HEPATITIS VIRUSES. THESE UNDERLYING PATHOGENIC STIMULI SUBSEQUENTLY INDUCE A SPECTRUM OF GENETIC AND EPIGENETIC ALTERATIONS IN SEVERAL CANCER-RELATED GENES, WHICH ARE INVOLVED IN CELL-CYCLE REGULATION, CELL GROWTH AND ADHESION. SUCH WIDESPREAD GENOMIC ALTERATIONS CAUSE DISRUPTION OF NORMAL CELLULAR SIGNALING AND FINALLY LEAD TO THE ACQUISITION OF A MALIGNANT PHENOTYPE IN HCC. IN GENERAL, THE TYPE OF GENE ALTERATIONS, SUCH AS POINT MUTATIONS, DELETION OF CHROMOSOMAL REGIONS AND ABNORMAL METHYLATION OF GENE PROMOTERS DIFFER ACCORDING TO THE INDIVIDUAL TARGETED GENE. IN HCC, INCIDENCE OF GENETIC ALTERATIONS IS RELATIVELY RARE AND IS LIMITED TO A SUBSET OF FEW CANCER-SPECIFIC GENES, SUCH AS THE TUMOR SUPPRESSOR P53, RB GENES AND ONCOGENES SUCH AS THE CTNNB1. IN CONTRAST, EPIGENETIC CHANGES THAT INVOLVE ABERRANT METHYLATION OF GENES AND OTHER POST-TRANSCRIPTIONAL HISTONE MODIFICATIONS OCCUR FAR MORE FREQUENTLY, AND SOME OF THESE EPIGENETIC ALTERATIONS ARE NOW BEING EXPLOITED FOR THE DEVELOPMENT OF MOLECULAR DIAGNOSTIC SIGNATURES FOR HCC. IN ADDITION, RECENT FINDINGS OF UNIQUE MICRORNA EXPRESSION PROFILES ALSO PROVIDE AN EVIDENCE FOR THE EXISTENCE OF NOVEL MECHANISMS FOR GENE EXPRESSION REGULATION IN HCC. IN THIS REVIEW ARTICLE, WE WILL REVIEW THE CURRENT STATE OF KNOWLEDGE ON THE ACTIVATION OF VARIOUS ONCOGENIC PATHWAYS AND THE INACTIVATION OF TUMOR SUPPRESSOR PATHWAYS IN HCC THAT RESULT IN THE DISRUPTION OF CANCER-RELATED GENE FUNCTION. IN ADDITION, WE WILL SPECIFICALLY EMPHASIZE THE CLINICAL IMPLICATION OF SOME OF THESE GENETIC AND EPIGENETIC ALTERATIONS IN THE MANAGEMENT OF HEPATOCARCINOGENESIS. 2011 6 2936 37 GENETIC AND EPIGENETIC ABNORMALITIES IN PRIMARY SCLEROSING CHOLANGITIS-ASSOCIATED CHOLANGIOCARCINOMA. PRIMARY SCLEROSING CHOLANGITIS (PSC) IS A CHOLESTATIC LIVER DISEASE OF UNKNOWN ETIOLOGY, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE BILIARY TREE WITH SUBSEQUENT FIBROSIS AND CIRRHOSIS OF THE LIVER. PATIENTS WITH PSC ARE AT INCREASED RISK FOR THE DEVELOPMENT OF CHOLANGIOCARCINOMA (CCA), A HIGHLY MALIGNANT EPITHELIAL TUMOR ARISING FROM THE INTRAHEPATIC AND EXTRAHEPATIC BILE DUCTS. CURRENTLY, ORTHOTOPIC LIVER TRANSPLANTATION IS THE ONLY CURATIVE TREATMENT. THE LACK OF EFFICIENT DIAGNOSTIC METHODS FOR EARLY DETECTION AND THE LIMITED THERAPEUTIC OPTIONS FOR CCA ARE MAJOR PROBLEMS AND ARE ASSOCIATED WITH POOR SURVIVAL. THE PATHOGENESIS OF PSC-ASSOCIATED CCA IS COMPLEX AND POORLY UNDERSTOOD. IT SEEMS THAT PRO-INFLAMMATORY CYTOKINES PLAY AN IMPORTANT ROLE IN GENETIC AND EPIGENETIC CHANGES THAT CONTRIBUTE TO THE CARCINOGENIC PROCESS. THE MAPPING OF GENETIC ALTERATIONS MAY ELUCIDATE MOLECULAR TARGETS THAT MAY BE APPLIED AS BIOMARKERS TO FACILITATE EARLY DIAGNOSIS OF MALIGNANT DEGENERATION TO IMPROVE PATIENT OUTCOME. IN THE LAST DECADE, THE INTRODUCTION OF SEVERAL NOVEL MOLECULAR TECHNIQUES AVAILABLE FOR GENOME-WIDE SCREENING HAS ADVANCED OUR KNOWLEDGE ON MANY OF THE GENETIC ABNORMALITIES THAT ARE PREVALENT IN CCA AND PSC-ASSOCIATED CCA. THIS REVIEW SUMMARIZES GENETIC AND EPIGENETIC ABNORMALITIES, WHICH HAVE IMPORTANT POTENTIAL FOR CLINICAL APPLICATION. 2013 7 4479 38 MOLECULAR PATHOGENESIS OF ORAL SQUAMOUS CELL CARCINOMA: IMPLICATIONS FOR THERAPY. THE DEVELOPMENT OF ORAL SQUAMOUS CELL CARCINOMA (OSCC) IS A MULTISTEP PROCESS REQUIRING THE ACCUMULATION OF MULTIPLE GENETIC ALTERATIONS, INFLUENCED BY A PATIENT'S GENETIC PREDISPOSITION AS WELL AS BY ENVIRONMENTAL INFLUENCES, INCLUDING TOBACCO, ALCOHOL, CHRONIC INFLAMMATION, AND VIRAL INFECTION. TUMORIGENIC GENETIC ALTERATIONS CONSIST OF TWO MAJOR TYPES: TUMOR SUPPRESSOR GENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN INACTIVATED; AND ONCOGENES, WHICH PROMOTE TUMOR DEVELOPMENT WHEN ACTIVATED. TUMOR SUPPRESSOR GENES CAN BE INACTIVATED THROUGH GENETIC EVENTS SUCH AS MUTATION, LOSS OF HETEROZYGOSITY, OR DELETION, OR BY EPIGENETIC MODIFICATIONS SUCH AS DNA METHYLATION OR CHROMATIN REMODELING. ONCOGENES CAN BE ACTIVATED THROUGH OVEREXPRESSION DUE TO GENE AMPLIFICATION, INCREASED TRANSCRIPTION, OR CHANGES IN STRUCTURE DUE TO MUTATIONS THAT LEAD TO INCREASED TRANSFORMING ACTIVITY. THIS REVIEW FOCUSES ON THE MOLECULAR MECHANISMS OF ORAL CARCINOGENESIS AND THE USE OF BIOLOGIC THERAPY TO SPECIFICALLY TARGET MOLECULES ALTERED IN OSCC. THE RAPID PROGRESS THAT HAS BEEN MADE IN OUR UNDERSTANDING OF THE MOLECULAR ALTERATIONS CONTRIBUTING TO THE DEVELOPMENT OF OSCC IS LEADING TO IMPROVEMENTS IN THE EARLY DIAGNOSIS OF TUMORS AND THE REFINEMENT OF BIOLOGIC TREATMENTS INDIVIDUALIZED TO THE SPECIFIC CHARACTERISTICS OF A PATIENT'S TUMOR. 2008 8 4539 29 MULTISTAGE CARCINOGENESIS IN MOUSE SKIN. THE MOUSE SKIN MODEL OF MULTISTAGE CARCINOGENESIS HAS FOR MANY YEARS PROVIDED A CONCEPTUAL FRAMEWORK FOR STUDYING CARCINOGENESIS MECHANISMS AND POTENTIAL MEANS FOR INHIBITING SPECIFIC STAGES OF CARCINOGENESIS. THE PROCESS OF SKIN CARCINOGENESIS INVOLVES THE STEPWISE ACCUMULATION OF GENETIC CHANGE ULTIMATELY LEADING TO MALIGNANCY. INITIATION, THE FIRST STEP IN MULTISTAGE SKIN CARCINOGENESIS INVOLVES CARCINOGEN-INDUCED GENETIC CHANGES. A TARGET GENE IDENTIFIED FOR SOME SKIN TUMOR INITIATORS IS C-HA-RAS. THE SECOND STEP, THE PROMOTION STAGE, INVOLVES PROCESSES WHEREBY INITIATED CELLS UNDERGO SELECTIVE CLONAL EXPANSION TO FORM VISIBLE PREMALIGNANT LESIONS TERMED PAPILLOMAS. THE PROCESS OF TUMOR PROMOTION INVOLVES THE PRODUCTION AND MAINTENANCE OF A SPECIFIC AND CHRONIC HYPERPLASIA CHARACTERIZED BY A SUSTAINED CELLULAR PROLIFERATION OF EPIDERMAL CELLS. THESE CHANGES ARE BELIEVED TO RESULT FROM EPIGENETIC MECHANISMS SUCH AS ACTIVATION OF THE CELLULAR RECEPTOR, PROTEIN KINASE C, BY SOME CLASSES OF TUMOR PROMOTERS. THE PROGRESSION STAGE INVOLVES THE CONVERSION OF PAPILLOMAS TO MALIGNANT TUMORS, SQUAMOUS CELL CARCINOMAS. THE ACCUMULATION OF ADDITIONAL GENETIC CHANGES IN CELLS COMPRISING PAPILLOMAS HAS BEEN CORRELATED WITH TUMOR PROGRESSION, INCLUDING TRISOMIES OF CHROMOSOMES 6 AND 7 AND LOSS OF HETEROZYGOSITY. THE CURRENT REVIEW FOCUSES ON THE MECHANISMS INVOLVED IN MULTISTAGE SKIN CARCINOGENESIS, A SUMMARY OF KNOWN INHIBITORS OF SPECIFIC STAGES AND THEIR PROPOSED MECHANISMS OF ACTION, AND THE RELEVANCE OF THIS MODEL SYSTEM TO HUMAN CANCER. 1992 9 4888 32 OXIDATIVE DAMAGE IN THE PROGRESSION OF CHRONIC LIVER DISEASE TO HEPATOCELLULAR CARCINOMA: AN INTRICATE PATHWAY. THE HISTO-PATHOLOGIC AND MOLECULAR MECHANISMS LEADING TO INITIATION AND PROGRESSION OF HEPATOCELLULAR CARCINOMA (HCC) ARE STILL ILL-DEFINED; HOWEVER, THERE IS INCREASING EVIDENCE THAT THE GRADUAL ACCUMULATION OF MUTATIONS, GENETIC AND EPIGENETIC CHANGES WHICH OCCUR IN PRENEOPLASTIC HEPATOCYTES RESULTS IN THE DEVELOPMENT OF DYSPLASTIC FOCI, NODULES, AND FINALLY, OVERT HCC. AS WELL AS MANY OTHER NEOPLASIAS, LIVER CANCER IS CONSIDERED AN "INFLAMMATORY CANCER", ARISING FROM A CONTEXT OF INFLAMMATION, AND CHARACTERIZED BY INFLAMMATION-RELATED MECHANISMS THAT FAVOR TUMOR CELL SURVIVAL, PROLIFERATION, AND INVASION. MOLECULAR MECHANISMS THAT LINK INFLAMMATION AND NEOPLASIA HAVE BEEN WIDELY INVESTIGATED, AND IT HAS BEEN WELL ESTABLISHED THAT INFLAMMATORY CELLS RECRUITED AT THESE SITES WITH ONGOING INFLAMMATORY ACTIVITY RELEASE CHEMOKINES THAT ENHANCE THE PRODUCTION OF REACTIVE OXYGEN SPECIES. THE LATTER, IN TURN, PROBABLY HAVE A MAJOR PATHOGENIC ROLE IN THE CONTINUUM STARTING FROM HEPATITIS FOLLOWED BY CHRONIC INFLAMMATION, AND ULTIMATELY LEADING TO CANCER. THE RELATIONSHIP AMONGST CHRONIC LIVER INJURY, FREE RADICAL PRODUCTION, AND DEVELOPMENT OF HCC IS EXPLORED IN THE PRESENT REVIEW, PARTICULARLY IN THE LIGHT OF THE COMPLEX NETWORK THAT INVOLVES OXIDATIVE DNA DAMAGE, CYTOKINE SYNTHESIS, TELOMERE DYSFUNCTION, AND MICRORNA REGULATION. 2014 10 4687 30 NEW TOOLS FOR MOLECULAR THERAPY OF HEPATOCELLULAR CARCINOMA. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER, ARISING FROM NEOPLASTIC TRANSFORMATION OF HEPATOCYTES OR LIVER PRECURSOR/STEM CELLS. HCC IS OFTEN ASSOCIATED WITH PRE-EXISTING CHRONIC LIVER PATHOLOGIES OF DIFFERENT ORIGIN (MAINLY SUBSEQUENT TO HBV AND HCV INFECTIONS), SUCH AS FIBROSIS OR CIRRHOSIS. CURRENT THERAPIES ARE ESSENTIALLY STILL INEFFECTIVE, DUE BOTH TO THE TUMOR HETEROGENEITY AND THE FREQUENT LATE DIAGNOSIS, MAKING NECESSARY THE CREATION OF NEW THERAPEUTIC STRATEGIES TO INHIBIT TUMOR ONSET AND PROGRESSION AND IMPROVE THE SURVIVAL OF PATIENTS. A PROMISING STRATEGY FOR TREATMENT OF HCC IS THE TARGETED MOLECULAR THERAPY BASED ON THE RESTORATION OF TUMOR SUPPRESSOR PROTEINS LOST DURING NEOPLASTIC TRANSFORMATION. IN PARTICULAR, THE DELIVERY OF MASTER GENES OF EPITHELIAL/HEPATOCYTE DIFFERENTIATION, ABLE TO TRIGGER AN EXTENSIVE REPROGRAMMING OF GENE EXPRESSION, COULD ALLOW THE INDUCTION OF AN EFFICIENT ANTITUMOR RESPONSE THROUGH THE SIMULTANEOUS ADJUSTMENT OF MULTIPLE GENETIC/EPIGENETIC ALTERATIONS CONTRIBUTING TO TUMOR DEVELOPMENT. HERE, WE REPORT RECENT LITERATURE DATA SUPPORTING THE USE OF MEMBERS OF THE LIVER ENRICHED TRANSCRIPTION FACTOR (LETF) FAMILY, IN PARTICULAR HNF4ALPHA, AS TOOLS FOR GENE THERAPY OF HCC. 2015 11 5291 33 PROSTATE CARCINOGENESIS: INSIGHTS IN RELATION TO EPIGENETICS AND INFLAMMATION. PROSTATE CANCER IS A MULTIFACTORIAL DISEASE THAT MAINLY OCCURS DUE TO THE ACCUMULATION OF SOMATIC, GENETIC, AND EPIGENETIC CHANGES, RESULTING IN THE INACTIVATION OF TUMOR-SUPPRESSOR GENES AND ACTIVATION OF ONCOGENES. MUTATIONS IN GENES, SPECIFICALLY THOSE THAT CONTROL CELL GROWTH AND DIVISION OR THE REPAIR OF DAMAGED DNA, MAKE THE CELLS GROW AND DIVIDE UNCONTROLLABLY TO FORM A TUMOR. THE RISK OF DEVELOPING PROSTATE CANCER DEPENDS UPON THE GENE THAT HAS UNDERGONE THE MUTATION. IDENTIFYING SUCH GENETIC RISK FACTORS FOR PROSTATE CANCER POSES A CHALLENGE FOR THE RESEARCHERS. BESIDES GENETIC MUTATIONS, MANY EPIGENETIC ALTERATIONS, INCLUDING DNA METHYLATION, HISTONE MODIFICATIONS (METHYLATION, ACETYLATION, UBIQUITYLATION, SUMOYLATION, AND PHOSPHORYLATION) NUCLEOSOMAL REMODELING, AND CHROMOSOMAL LOOPING, HAVE SIGNIFICANTLY CONTRIBUTED TO THE ONSET OF PROSTATE CANCER AS WELL AS THE PROGNOSIS, DIAGNOSIS, AND TREATMENT OF PROSTATE CANCER. CHRONIC INFLAMMATION ALSO PLAYS A MAJOR ROLE IN THE ONSET AND PROGRESSION OF HUMAN CANCER, VIA MODIFICATIONS IN THE TUMOR MICROENVIRONMENT BY INITIATING EPITHELIALMESENCHYMAL TRANSITION AND REMODELING THE EXTRACELLULAR MATRIX. IN THIS ARTICLE, THE AUTHORS PRESENT A BRIEF HISTORY OF THE MECHANISMS AND POTENTIAL LINKS BETWEEN THE GENETIC ABERRATIONS, EPIGENETIC CHANGES, INFLAMMATION, AND INFLAMMASOMES THAT ARE KNOWN TO CONTRIBUTE TO THE PROGNOSIS OF PROSTATE CANCER. FURTHERMORE, THE AUTHORS EXAMINE AND DISCUSS THE CLINICAL POTENTIAL OF PROSTATE CARCINOGENESIS IN RELATION TO EPIGENETICS AND INFLAMMATION FOR ITS DIAGNOSIS AND TREATMENT.. 2021 12 1232 31 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 13 3244 31 HEPATIC STELLATE CELLS AND EXTRACELLULAR MATRIX IN HEPATOCELLULAR CARCINOMA: MORE COMPLICATED THAN EVER. HEPATOCELLULAR CARCINOMA (HCC) IS THE FIFTH MOST COMMON CANCER WORLDWIDE AND THE THIRD LEADING CAUSE OF CANCER DEATH. RECENT EPIDEMIOLOGICAL DATA INDICATE THAT THE MORTALITY RATE OF HCC WILL DOUBLE OVER THE NEXT DECADES IN THE USA AND EUROPE. LIVER CANCER PROGRESSES IN A LARGE PERCENTAGE OF CASES DURING THE CLINICAL COURSE OF CHRONIC FIBRO-INFLAMMATORY LIVER DISEASES LEADING TO CIRRHOSIS. THEREFORE, HCC DEVELOPMENT IS REGARDED AS THE RESULT OF DIFFERENT ENVIRONMENTAL RISK FACTORS EACH INVOLVING DIFFERENT GENETIC, EPIGENETIC- AND CHROMOSOMAL ALTERATIONS AND GENE MUTATIONS. DURING TUMOUR PROGRESSION, THE MALIGNANT HEPATOCYTES AND THE ACTIVATED HEPATIC STELLATE CELLS ARE ACCOMPANIED BY CANCER-ASSOCIATED FIBROBLASTS, MYOFIBROBLASTS AND IMMUNE CELLS GENERALLY CALLED TUMOUR STROMAL CELLS. THIS NEW AND DYNAMIC MILIEU FURTHER ENHANCES THE RESPONSIVENESS OF TUMOUR CELLS TOWARDS SOLUBLE MEDIATORS SECRETED BY TUMOUR STROMAL CELLS, THUS DIRECTLY AFFECTING THE MALIGNANT HEPATOCYTES. THIS RESULTS IN ALTERED MOLECULAR PATHWAYS WITH CELL PROLIFERATION AS THE MOST IMPORTANT MECHANISM OF LIVER CANCER PROGRESSION. GIVEN THIS CONTEXTUAL COMPLEXITY, IT IS OF UTMOST IMPORTANCE TO CHARACTERIZE THE MOLECULAR PATHOGENESIS OF HCC, AND TO IDENTIFY THE DOMINANT PATHWAYS/DRIVERS AND ABERRANT SIGNALLING PATHWAYS. THIS WILL ALLOW AN EFFECTIVE THERAPY FOR HCC THAT SHOULD COMBINE STRATEGIES AFFECTING BOTH CANCER AND THE TUMOUR STROMAL CELLS. THIS REVIEW PROVIDES AN OVERVIEW OF THE RECENT CHALLENGES AND ISSUES REGARDING HEPATIC STELLATE CELLS, EXTRACELLULAR MATRIX DYNAMICS, LIVER FIBROSIS/CIRRHOSIS AND THERAPY, TUMOUR MICROENVIRONMENT AND HCC. 2014 14 5360 34 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 15 2166 33 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 16 4477 28 MOLECULAR PATHOGENESIS OF HUMAN HEPATOCELLULAR CARCINOMA. HEPATOCARCINOGENESIS IS A SLOW PROCESS DURING WHICH GENOMIC CHANGES PROGRESSIVELY ALTER THE HEPATOCELLULAR PHENOTYPE TO PRODUCE CELLULAR INTERMEDIATES THAT EVOLVE INTO HEPATOCELLULAR CARCINOMA. DURING THE LONG PRENEOPLASTIC STAGE, IN WHICH THE LIVER IS OFTEN THE SITE OF CHRONIC HEPATITIS, CIRRHOSIS, OR BOTH, HEPATOCYTE CYCLING IS ACCELERATED BY UPREGULATION OF MITOGENIC PATHWAYS, IN PART THROUGH EPIGENETIC MECHANISMS. THIS LEADS TO THE PRODUCTION OF MONOCLONAL POPULATIONS OF ABERRANT AND DYSPLASTIC HEPATOCYTES THAT HAVE TELOMERE EROSION AND TELOMERASE RE-EXPRESSION, SOMETIMES MICROSATELLITE INSTABILITY, AND OCCASIONALLY STRUCTURAL ABERRATIONS IN GENES AND CHROMOSOMES. DEVELOPMENT OF DYSPLASTIC HEPATOCYTES IN FOCI AND NODULES AND EMERGENCE OF HEPATOCELLULAR CARCINOMA ARE ASSOCIATED WITH THE ACCUMULATION OF IRREVERSIBLE STRUCTURAL ALTERATIONS IN GENES AND CHROMOSOMES, BUT THE GENOMIC BASIS OF THE MALIGNANT PHENOTYPE IS HETEROGENEOUS. THE MALIGNANT HEPATOCYTE PHENOTYPE MAY BE PRODUCED BY THE DISRUPTION OF A NUMBER OF GENES THAT FUNCTION IN DIFFERENT REGULATORY PATHWAYS, PRODUCING SEVERAL MOLECULAR VARIANTS OF HEPATOCELLULAR CARCINOMA. NEW STRATEGIES SHOULD ENABLE THESE VARIANTS TO BE CHARACTERIZED. 2002 17 4134 37 MECHANISMS OF HUMAN HEPATOCARCINOGENESIS. THE MAJOR RISK FACTORS AND ETIOLOGICAL AGENTS RESPONSIBLE FOR DEVELOPMENT OF HEPATOCELLULAR CARCINOMA IN HUMANS HAVE BEEN IDENTIFIED AND CHARACTERIZED. AMONG THESE ARE CHRONIC INFECTION WITH HEPATITIS B VIRUS OR HEPATITIS C VIRUS, EXPOSURE TO AFLATOXIN B1, AND CIRRHOSIS OF ANY ETIOLOGY (INCLUDING ALCOHOLIC CIRRHOSIS AND CIRRHOSIS ASSOCIATED WITH GENETIC LIVER DISEASES). BOTH CHRONIC HEPATITIS AND CIRRHOSIS REPRESENT MAJOR PRENEOPLASTIC CONDITIONS OF THE LIVER AS THE MAJORITY OF HEPATOCELLULAR CARCINOMAS ARISE IN THESE PATHOLOGICAL SETTINGS. HEPATOCARCINOGENESIS REPRESENTS A LINEAR AND PROGRESSIVE PROCESS IN WHICH SUCCESSIVELY MORE ABERRANT MONOCLONAL POPULATIONS OF HEPATOCYTES EVOLVE. REGENERATIVE HEPATOCYTES IN FOCAL LESIONS IN THE INFLAMED LIVER (CHRONIC HEPATITIS OR CIRRHOSIS) GIVE RISE TO HYPERPLASTIC HEPATOCYTE NODULES, AND THESE PROGRESS TO DYSPLASTIC NODULES, WHICH ARE THOUGHT TO BE THE DIRECT PRECURSOR OF HEPATOCELLULAR CARCINOMA. IN MOST CASES, THE NEOPLASTIC TRANSFORMATION OF HEPATOCYTES RESULTS FROM ACCUMULATION OF GENETIC DAMAGE DURING THE REPETITIVE CELLULAR PROLIFERATION THAT OCCURS IN THE INJURED LIVER IN RESPONSE TO PARACRINE GROWTH FACTOR AND CYTOKINE STIMULATION. HEPATOCELLULAR CARCINOMAS EXHIBIT NUMEROUS GENETIC ABNORMALITIES (INCLUDING CHROMOSOMAL DELETIONS, REARRANGEMENTS, ANEUPLOIDY, GENE AMPLIFICATIONS, AND MUTATIONS), AS WELL AS EPIGENETIC ALTERATIONS (INCLUDING MODULATION OF DNA METHYLATION). THESE GENETIC AND EPIGENETIC ALTERATIONS COMBINE TO ACTIVATE POSITIVE MEDIATORS OF CELLULAR PROLIFERATION (INCLUDING CELLULAR PROTO-ONCOGENES AND THEIR MITOGENIC SIGNALING PATHWAYS) AND INACTIVATE NEGATIVE MEDIATORS OF CELLULAR PROLIFERATION (INCLUDING TUMOR SUPPRESSOR GENES), RESULTING IN CELLS WITH AUTONOMOUS GROWTH POTENTIAL. HOWEVER, HEPATOCELLULAR CARCINOMAS EXHIBIT A HIGH DEGREE OF GENETIC HETEROGENEITY, SUGGESTING THAT MULTIPLE MOLECULAR PATHWAYS MAY BE INVOLVED IN THE GENESIS OF SUBSETS OF HEPATOCELLULAR NEOPLASMS. CONTINUED INVESTIGATION OF THE MECHANISMS OF HEPATOCARCINOGENESIS WILL REFINE OUR CURRENT UNDERSTANDING OF THE MOLECULAR AND CELLULAR BASIS FOR NEOPLASTIC TRANSFORMATION IN LIVER, ENABLING THE DEVELOPMENT OF EFFECTIVE STRATEGIES FOR PREVENTION AND/OR MORE EFFECTIVE TREATMENT OF HEPATOCELLULAR CARCINOMA. 2003 18 928 22 CHRONIC INFLAMMATION, THE TUMOR MICROENVIRONMENT AND CARCINOGENESIS. CHRONIC INFLAMMATION OFTEN PRECEDES OR ACCOMPANIES A SUBSTANTIAL NUMBER OF CANCERS. INDEED, ANTI-INFLAMMATORY THERAPIES HAVE SHOWN EFFICACY IN CANCER PREVENTION AND TREATMENT. THE EXACT MECHANISMS THAT TURN A WOUND HEALING PROCESS INTO A CANCER PRECURSOR ARE TOPICS OF INTENSE RESEARCH. A PATHOGENIC LINK HAS BEEN IDENTIFIED BETWEEN INFLAMMATORY MEDIATORS, INFLAMMATION RELATED GENE POLYMORPHISMS AND CARCINOGENESIS. ANIMAL MODELS OF CANCER HAVE BEEN INSTRUMENTAL IN DEMONSTRATING THE DIVERSITY OF MECHANISMS THROUGH WHICH EVERY TUMOR COMPARTMENT AND TUMOR STAGE MAY BE AFFECTED BY THE UNDERLYING INFLAMMATORY PROCESS. IN THIS REVIEW, WE FOCUS ON THE INTERACTION BETWEEN CHRONIC INFLAMMATION, TUMOR STEM CELLS AND THE TUMOR MICROENVIRONMENT. WE SUMMARIZE THE PROPOSED MECHANISMS THAT LEAD TO THE RECRUITMENT OF BONE MARROW DERIVED CELLS AND EXPLORE THE GENETIC AND EPIGENETIC ALTERATIONS THAT MAY OCCUR IN INFLAMMATION ASSOCIATED CANCERS. 2009 19 4733 27 NOVEL BIOMARKERS FOR THE IDENTIFICATION AND TARGETED THERAPY OF GASTRIC CANCER. GASTRIC CANCER DEVELOPMENT FOLLOWS THE PATHOLOGIC PATTERN SUCH THAT CHRONIC INFLAMMATION IN THE GASTRIC MUCOSA PROGRESSIVELY TRANSFORMS NORMAL MUCOSA INTO ATROPHY, INTESTINAL METAPLASIA, ADENOMA/DYSPLASIA AND EVENTUALLY INVASIVE AND METASTATIC TUMORS. THE ACCUMULATION OF MULTIPLE GENETIC AND EPIGENETIC ALTERATIONS LEADS TO THE DYSREGULATION OF ONCOGENES AND TUMOR SUPPRESSORS, WHICH WAS CONSIDERED AS THE DRIVER BEHIND EVENTS DURING THE TUMORIGENESIS. ALMOST ALL GASTRIC CANCERS ARE ADENOCARCINOMAS, WHICH SHARE CONSIDERABLE HETEROGENEITY WITH DISTINCT MORPHOLOGY, PATHOGENESIS AND CLINICAL BEHAVIOR. THEREFORE, IDENTIFYING SUBTYPES OF GASTRIC CANCERS WITH MOLECULAR AND GENETIC FEATURES WILL BE BENEFICIAL FOR THE EARLY IDENTIFICATION AND SELECTION OF NEW EFFECTIVE AGENTS FOR TARGETED TREATMENT. HIGH-THROUGHPUT SEQUENCING TECHNIQUES SUCH AS WHOLE GENOMIC, EPIGENOME AND TRANSCRIPTOME SEQUENCING AND PROTEOMICS PLATFORMS HAVE IDENTIFIED MAJOR GENOMIC CHARACTERISTICS THAT EXHIBIT IDENTIFICATION AND PROGNOSTIC IMPACTS AND DISTINCT RESPONSE PATTERNS. IN THIS ARTICLE, THE AUTHORS AIM TO SUMMARIZE THE INFORMATION REGARDING THE MOST PROMISING MOLECULES THAT MAY HAVE CLINICAL APPLICATION AS NON-INVASIVE BIOMARKERS AND THERAPY TARGETS. 2015 20 2538 27 EPIGENETICS IN HEPATOCELLULAR CARCINOMA: AN UPDATE AND FUTURE THERAPY PERSPECTIVES. HEPATOCELLULAR CARCINOMA (HCC), THE PREDOMINANT FORM OF ADULT LIVER MALIGNANCIES, IS A GLOBAL HEALTH CONCERN. ITS DISMAL PROGNOSIS HAS PROMPTED RECENT SIGNIFICANT ADVANCES IN THE UNDERSTANDING OF ITS ETIOLOGY AND PATHOGENESIS. THE DEREGULATION OF EPIGENETIC MECHANISMS, WHICH MAINTAIN HERITABLE GENE EXPRESSION CHANGES AND CHROMATIN ORGANIZATION, IS IMPLICATED IN THE DEVELOPMENT OF MULTIPLE CANCERS, INCLUDING HCC. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE OF EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF HCC, WITH AN EMPHASIS ON HCC MEDIATED BY CHRONIC HEPATITIS B VIRUS INFECTION. THIS REVIEW ALSO DISCUSSES THE ENCOURAGING OUTCOMES AND LESSONS LEARNT FROM EPIGENETIC THERAPIES FOR HEMATOLOGICAL AND OTHER SOLID CANCERS, AND HIGHLIGHTS THE FUTURE POTENTIAL OF SIMILAR THERAPIES IN THE TREATMENT OF HCC. 2014