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1、Partial Molecular Pathogenesis inPartial Molecular Pathogenesis in Bladder Carcinoma Bladder Carcinoma夏阳阳夏阳阳2016-7-13contentcontentEpidemicsGradeandstageClassificationbasedongeneticcharactericsSomepathwaysAristolochicAcid(AA)LindseyA.Torre,MSPH;FreddieBray,PhD,etal.Globalcancerstatistics,2012.CACANC
2、ERJCLIN2015;65:87108EstimatednewcasesEstimateddeath74769Bladder CarcinomaTransitional cell carcinomaNon-Transitional cell carcinomaAdeno-carcinomaSquamous Cell carcinomamesenchymalmetastasesInflatrating tumorsOf adjacent organsSTAGEPrimaryTumorT0NoevidenceoftumorTaNoninvasivepapillaryurothelialcarci
3、nomaTisUrothelialcarcinomainsituT1TumorinvadeslaminapropriaT2Tumorinvadessuperficial(2a,innerhalf)ordeep(2b,outerhalf)muscularispropriaT3Tumorinvadesmicroscopically(3a)ormacroscopically(3b)perivesicaltissueT4Tumorinvadesadjacentorgans(4a,prostaticstroma,seminalvesicles,uterus,vagina)orpelvicorabdomi
4、nalwall(4b)RegionalLymphNodesN0NolymphnodemetastasisN1SinglelymphnodemetastasisinthetruepelvisN2MultiplelymphnodemetastasesinthetruepelvisN3LymphnodemetastasistothecommoniliaclymphnodesDistantMetastasisM0NodistantmetastasisM1DistantmetastasisStageGroupingsStage0TaN0M0orTisN0M0StageIT1N0M0StageIIT2N0
5、M0StageIIIT3N0M0orT4aN0M0StageIVT4bN0M0AnyT,N1-3,AnyMAnyT,AnyN,M1EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA.Urinarybladder.In:EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA,eds.AJCCCancerStagingManual.7thed.NewYork,NY:Springer;2010:497505.non-muscleinvasivebladdercancer(NMIBC)muscleinvasiveb
6、laddercancer(MIBC)TaTisT1T2T3T4GRADE 1973cellularanaplasia2004architecturalandcytologicalatypiaPUNLMP=papillaryurothelialneoplasmoflowmalignantpotentialAshishMKamat,NoahMHahn,JasonAEfstathiouetal.Bladdercancer，2016.lancetS0140-6736(16)30512-8.Classification Based on Genetic CharacteristicspapillaryN
7、on-papillaryColinP.N.Dinney,DinneyCP,McConkeyDJ,MillikanRE,etal.Focusonbladdercancer.CancerCell2004;6:1111660%:alterationninvolvesexons511ofp53andthelossofRBgenefunction 20%:synchronouslossofthetandemlylinkedCDKN2aandARF 20%:alterationsofp53inexons14followedbylossofCDKN2aandARFfunctionpapillaryActiv
8、ationofFGFR3ActivationofFGFR3Chromatin-modifyingenzymeChromatin-modifyingenzymeNon-papillaryInactivationofTP53andRBInactivationofTP53andRBChromatin-modifyingenzymeChromatin-modifyingenzymeHistone acetyltransferases histone methyltransferasesactivating telomerase promoter mutationsinactivating STAG2
9、mutations 1.GuiY,GuoG,HuangY,etal.Frequentmutationsofchromatinremodelinggenesintransitionalcellcarcinomaofthebladder.NatGenet2011;43:87578.462.AlloryY,BeukersW,SagreraA,etal.Telomerasereversetranscriptasepromotermutationsinbladdercancer:highfrequencyacrossstages,detectioninurine,andlackofassociation
10、withoutcome.EurUrol2014;65:36066.443.Balbs-MartnezC,SagreraA,Carrillo-de-Santa-PauE,etal.RecurrentinactivationofSTAG2inbladdercancerisnotassociatedwithaneuploidy.NatGenet2013;45:146469.Basal-like and LuminalBasalMIBCssharedbiomarkerswithbasalbreastcancersandwerecharacterizedbyp53activation,squamousd
11、ifferentiation,andmoreaggressivediseaseatpresentation.LuminalMIBCscontainedfeaturesofactivePPARandestrogenreceptor(ER)transcriptionandwereenrichedwithactivatingFGFR3mutationsandpotentiallyFGFRinhibitorsensitivity.a:Papillaryhistology,FGFR3alterations,FGFR3expressionandreducedFGFR3-relatedmiRNAexpres
12、sionareenrichedinclusterI.b:Expressionofepitheliallineagegenesandstem/progenitorcytokeratinsaregenerallyhighinclusterIII,someofwhichexpressvariantsquamoushistology.c:LuminalbreastandurothelialdifferentiationfactorsareenrichedinclustersIandII.d:ERBB2mutationandestrogenreceptorbeta(ESR2)expressionaree
13、nrichedinclustersIandII.CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:31522CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:315221.BarskiA,CuddapahS,CuiK,RohTY,Schon
14、esDE,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-genicportionsofthehumangenom
15、e.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).Thelandscapeofhistonemodificati
16、onsacross1%ofthehumangenomeinfivehumancelllines.GenomeResearch 17(6):691707.doi:10.1101/gr.5704207.PMC1891331.PMID17567990.Chromosomal AlterationsThemostfrequentobservedcopynumberaberrationsinUCareonchromosomes1,8,9,10,11,13,and14.Chromosome9alterationsaretheearliestgeneticalterationsinbothofthedesc
17、ribeddivergentpathwaysofBCdevelopment11.MingZhao,Xiang-LeiHe,Xiao-DongTeng,Understandingthemolecularpathogenesisandprognosticsofbladdercancer:anoverviewStructuralrearrangementsandviralintegrationTheCancerGenomeAtlasResearchNetwork,ComprehensiveMolecularCharacterizationofUrothelialBladderCarcinomaSom
18、eexamplesforchromosomalalterrationsummaryThepathogenesisofbladdercancerisacomplicatedcourse,withmanygenesandchromosomesinvolved.Themostfrequentlyalteredpathwaysinbladdercancerinclude:thePI3K/AKT/mammalianpathwaytheFGFR3/RAF/RASpathwaytheTP53/RB1pathwayInaddition,TERTmutationsarepresentinupto79%ofbla
19、dderneoplasms,butnorelationwithprognosis.Aristolochic Acid(AA):a carcinogen for UTUCOverview:1.Aristolochicacid(AA)isanitrophenanthrenecarboxylicacidfoundinallmembersofthegenusAristolochia2.usedformedicalpurposesformorethan2000years3.nephrotoxicityandcarcinogenicityassociatedwiththeuseoftheseplantsc
20、ametolightwhenAristolochiafangchi,administeredto1800healthyBelgianwomenaspartofaweightreductionregimen,resultedinmorethan100casesofchronictubulointerstitialdiseaseprogressingtoend-stagerenalfailure.ManyoftheaffectedwomendevelopedneoplasticchangesintheupperurinarytractAristolochic Acid,implicated as
21、an environmental carcinogenBalkanendemicnephropathy(BEN),adevastatingkidneydiseaseassociatedwithurothelialcarcinomaoftheupperurinarytract.AAwasshowntobethecausativeagentofthisdiseaseInthesestudies,AL-DNAadductsandtheTP53mutationalspectrumofUTUC.Between1997and2003,aboutone-thirdoftheTaiwanesepopulati
22、onhadbeenprescribedremediescontainingAristolochiaherbs.Moreover,theincidenceofUTUCinTaiwanisthehighestintheworld.Analysis of TP53 mutation reveals AA as a environmental carcinogen48%52%humanTP53geneknock-inmousewithA:T-to-T:AmutationswithoutA:T-to-T:Amutations6%94%IARCTP53databasewithAAareA:T-to-T:A
23、mutationswithoutAAareA:T-to-T:AmutationsHollsteinM,MoriyaM,GrollmanAP,OlivierM.AnalysisofTP53mutationspectrarevealsthefingerprintofthepotentenvironmentalcarcinogen,aristolochicacid.MutatRes.201310.1016/j.mrrev.2013.02.00319.MarieSTIBOROV1,JiHUDEEK1,EvaFREI2andHeinzH.SCHMEISER,Contributionofbiotransformationenzymestothedevelopmentofrenalinjuryandurothelialcancercausedbyaristolochicacid:urgentquestions,difficultanswersMarie,InterdiscToxicol.2008;Vol.1(1):812.END
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