KEYGENETICALTERATIONSTelomereMaintananceGenes:TERTCumulativefrequency:20%-60%WNT/β-CateninGenes:CTNNB1,AXIN1/2,APCCumulativefrequency:2%-33%CellCycleGenes:TP53,CKN2A/B,CCND/E1,CDKs,RB1Cumulativefrequency:4%-35%ApoptosisGenes:TNFRSF10A/B,TRADD,CASP3/9,XIAPCumulativefrequency:8%-20%EpigeneticModifiersGenes:ARID1A,ARID2,MLLgenesCumulativefrequency:10%-24%ProliferationGenes:FGF19,RPS6KA,IRF2,KRASCumulativefrequency:2%-15%ImmuneResponseGenes:IL6R,IL20,IL6,JAK1Cumulativefrequency:2%-26%OxidativeStressRegulationGenes:NFEL2,KEAP1Cumulativefrequency:6%-8%CLINICALPROGRESSIONOFLIVERCANCERCELLTYPESOFORIGINFORHCCDifferentiationStemnessPROGNOSTICCLASSIFICATIONEMERGINGMOLECULARTARGETSBCLCSTAGING&THERAPYCHALLENGES&OUTLOOKPoorOutcomeHealthyliverChronicinjuryCirrhosisHCCStemcellCancerstemcellAggresivephenotypeIntermediatephenotypeBenignphenotypeBulktumorcellsBipotentialprogenitorHepatocyte/CholangiocyteClinical/MorphologicalfeaturesMolecularfeaturesFavorableOutcomeCurativetreatmentsHCCsuspectedPalliationEpigeneticsProliferationandSurvivalTivantinib,cixutumumab,erlotinib,everolimus,selumetinibControlofgeneexpression:ActivationoftumorsuppressorsRepressionofoncogenesResminostat,vorinostat,belinostat,zebularineStemnessDedifferentiation,progressionandmetastaticproperties12-AApeptide,resminostat,γ-secretaseinhibitorsAngiogenesisMedianOS:>60mo20mo11mo~3moSorafenib,brivanib,sunitinib,regorafenibECOG>2PoorliverfunctionPoordifferentiationCK19positiveLargertumorsVascularinvasionExtrahepaticspreadGenomicinstabilityTelomerasereactivationLossof8pGlobalhypomethylationLowmiR-122HighmiR-517aStemnessfeatures:EpCAM,SALL4HighNault5-genescoreAdversesubclass:G1-G3,S1-2,proliferation,HAsubtypeAdversemetabolicprofile:stearoyl-CoA-desaturaseactivity,palmitatesignalingAdversesignaling:HGF/MET,TGF-β,CK19,mTOR,IGF,MYC,AKT,WNT,lossofp53GenomicstabilityTelomeraserepressionCTNNB1mutationPolysomy7HighmiR-122LowmiR-517aExpressionofdifferentiationfactors:HNF4α,CYPsLowNault5-genescoreBeneficialsubclass:G4-G5,S3...
