膀胱癌发病机制ppt课件.pptx

PartialMolecularPathogenesisinBladderCarcinoma,夏阳阳2016-7-13,content,EpidemicsGradeandstageClassificationbasedongeneticcharactericsSomepathwaysAristolochicAcid(AA),LindseyA.Torre,MSPH;FreddieBray,PhD,etal.Globalcancerstatistics,2012.CACANCERJCLIN2015;65:87108,7,BladderCarcinoma,Transitionalcellcarcinoma,Non-Transitionalcellcarcinoma,Adeno-carcinoma,SquamousCellcarcinoma,mesenchymal,metastases,InflatratingtumorsOfadjacentorgans,STAGE,PrimaryTumorT0NoevidenceoftumorTaNoninvasivepapillaryurothelialcarcinomaTisUrothelialcarcinomainsituT1TumorinvadeslaminapropriaT2Tumorinvadessuperficial(2a,innerhalf)ordeep(2b,outerhalf)muscularispropriaT3Tumorinvadesmicroscopically(3a)ormacroscopically(3b)perivesicaltissueT4Tumorinvadesadjacentorgans(4a,prostaticstroma,seminalvesicles,uterus,vagina)orpelvicorabdominalwall(4b)RegionalLymphNodesN0NolymphnodemetastasisN1SinglelymphnodemetastasisinthetruepelvisN2MultiplelymphnodemetastasesinthetruepelvisN3LymphnodemetastasistothecommoniliaclymphnodesDistantMetastasisM0NodistantmetastasisM1Distantmetastasis,StageGroupingsStage0TaN0M0orTisN0M0StageIT1N0M0StageIIT2N0M0StageIIIT3N0M0orT4aN0M0StageIVT4bN0M0AnyT,N1-3,AnyMAnyT,AnyN,M1,EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA.Urinarybladder.In:EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA,eds.AJCCCancerStagingManual.7thed.NewYork,NY:Springer;2010:497505.,non-muscleinvasivebladdercancer(NMIBC),muscleinvasivebladdercancer(MIBC),TaTisT1,T2T3T4,GRADE,PUNLMP=papillaryurothelialneoplasmoflowmalignantpotential,AshishMKamat,NoahMHahn,JasonAEfstathiouetal.Bladdercancer，2016.lancetS0140-6736(16)30512-8.,ClassificationBasedonGeneticCharacteristics,papillary,Non-papillary,ColinP.N.Dinney,DinneyCP,McConkeyDJ,MillikanRE,etal.Focusonbladdercancer.CancerCell2004;6:11116,60%:alterationninvolvesexons511ofp53andthelossofRBgenefunction,20%:synchronouslossofthetandemlylinkedCDKN2aandARF,20%:alterationsofp53inexons14followedbylossofCDKN2aandARFfunction,papillary,ActivationofFGFR3Chromatin-modifyingenzyme,Non-papillary,InactivationofTP53andRBChromatin-modifyingenzyme,Histoneacetyltransferases,histonemethyltransferasesactivatingtelomerasepromotermutationsinactivatingSTAG2mutations,1.GuiY,GuoG,HuangY,etal.Frequentmutationsofchromatinremodelinggenesintransitionalcellcarcinomaofthebladder.NatGenet2011;43:87578.462.AlloryY,BeukersW,SagreraA,etal.Telomerasereversetranscriptasepromotermutationsinbladdercancer:highfrequencyacrossstages,detectioninurine,andlackofassociationwithoutcome.EurUrol2014;65:36066.443.Balbs-MartnezC,SagreraA,Carrillo-de-Santa-PauE,etal.RecurrentinactivationofSTAG2inbladdercancerisnotassociatedwithaneuploidy.NatGenet2013;45:146469.,Basal-likeandLuminal,BasalMIBCssharedbiomarkerswithbasalbreastcancersandwerecharacterizedbyp53activation,squamousdifferentiation,andmoreaggressivediseaseatpresentation.,LuminalMIBCscontainedfeaturesofactivePPARandestrogenreceptor(ER)transcriptionandwereenrichedwithactivatingFGFR3mutationsandpotentiallyFGFRinhibitorsensitivity.,a:Papillaryhistology,FGFR3alterations,FGFR3expressionandreducedFGFR3-relatedmiRNAexpressionareenrichedinclusterI.b:Expressionofepitheliallineagegenesandstem/progenitorcytokeratinsaregenerallyhighinclusterIII,someofwhichexpressvariantsquamoushistology.c:LuminalbreastandurothelialdifferentiationfactorsareenrichedinclustersIandII.d:ERBB2mutationandestrogenreceptorbeta(ESR2)expressionareenrichedinclustersIandII.,CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:31522,CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:31522,1.BarskiA,CuddapahS,CuiK,RohTY,SchonesDE,WangZ,WeiG,ChepelevI,ZhaoK(May2007).High-resolutionprofilingofhistonemethylationsinthehumangenome.Cell129(4):82337.doi:10.1016/j.cell.2007.05.009.PMID17512414.2.RosenfeldJA,WangZ,SchonesDE,ZhaoK,DeSalleR,ZhangMQ(2009).Determinationofenrichedhistonemodificationsinnon-genicportionsofthehumangenome.BMCGenomics10:143.doi:10.1186/1471-2164-10-143.PMC2667539.PMID193358993.KochCM,AndrewsRM,FlicekP,DillonSC,KarazU,ClellandGK,WilcoxS,BeareDM,FowlerJC,CouttetP,JamesKD,LefebvreGC,BruceAW,DoveyOM,EllisPD,DhamiP,LangfordCF,WengZ,BirneyE,CarterNP,VetrieD,DunhamI(Jun2007).Thelandscapeofhistonemodificationsacross1%ofthehumangenomeinfivehumancelllines.GenomeResearch17(6):691707.doi:10.1101/gr.5704207.PMC1891331.PMID17567990.,ChromosomalAlterations,ThemostfrequentobservedcopynumberaberrationsinUCareonchromosomes1,8,9,10,11,13,and14.Chromosome9alterationsaretheearliestgeneticalterationsinbothofthedescribeddivergentpathwaysofBCdevelopment1,1.MingZhao,Xiang-LeiHe,Xiao-DongTeng,Understandingthemolecularpathogenesisandprognosticsofbladdercancer:anoverview,Structuralrearrangementsandviralintegration,TheCancerGenomeAtlasResearchNetwork,ComprehensiveMolecularCharacterizationofUrothelialBladderCarcinoma,Someexamplesforchromosomalalterration,summary,Thepathogenesisofbladdercancerisacomplicatedcourse,withmanygenesandchromosomesinvolved.Themostfrequentlyalteredpathwaysinbladdercancerinclude:thePI3K/AKT/mammalianpathwaytheFGFR3/RAF/RASpathwaytheTP53/RB1pathwayInaddition,TERTmutationsarepresentinupto79%ofbladderneoplasms,butnorelationwithprognosis.,AristolochicAcid(AA):acarcinogenforUTUC,Overview:Aristolochicacid(AA)isanitrophenanthrenecarboxylicacidfoundinallmembersofthegenusAristolochiausedformedicalpurposesformorethan2000yearsnephrotoxicityandcarcinogenicityassociatedwiththeuseoftheseplantscametolightwhenAristolochiafangchi,administeredto1800healthyBelgianwomenaspartofaweightreductionregimen,resultedinmorethan100casesofchronictubulointerstitialdiseaseprogressingtoend-stagerenalfailure.Manyoftheaffectedwomendevelopedneoplasticchangesintheupperurinarytract,AristolochicAcid,implicatedasanenvironmentalcarcinogen,Balkanendemicnephropathy(BEN),adevastatingkidneydiseaseassociatedwithurothelialcarcinomaoftheupperurinarytract.AAwasshowntobethecausativeagentofthisdiseaseInthesestudies,AL-DNAadductsandtheTP53mutationalspectrumofUTUC.Between1997and2003,aboutone