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PartialMolecularPathogenesisin

BladderCarcinoma夏阳阳2016-7-13PartialMolecularPathogenesis1contentEpidemicsGradeandstageClassificationbasedongeneticcharactericsSomepathwaysAristolochicAcid(AA)contentEpidemics2LindseyA.Torre,MSPH;FreddieBray,PhD,etal.Globalcancerstatistics,2012.CACANCERJCLIN2015;65:87–108EstimatednewcasesEstimateddeath74769LindseyA.Torre,MSPH;Freddi3BladderCarcinomaTransitionalcellcarcinomaNon-TransitionalcellcarcinomaAdeno-carcinomaSquamousCellcarcinomamesenchymalmetastasesInflatratingtumorsOfadjacentorgansBladderCarcinomaTransitional4STAGEPrimaryTumorT0NoevidenceoftumorTaNoninvasivepapillaryurothelialcarcinomaTisUrothelialcarcinomainsituT1TumorinvadeslaminapropriaT2Tumorinvadessuperficial(2a,innerhalf)ordeep(2b,outerhalf)muscularispropriaT3Tumorinvadesmicroscopically(3a)ormacroscopically(3b)perivesicaltissueT4Tumorinvadesadjacentorgans(4a,prostaticstroma,seminalvesicles,uterus,vagina)orpelvicorabdominalwall(4b)RegionalLymphNodesN0NolymphnodemetastasisN1SinglelymphnodemetastasisinthetruepelvisN2MultiplelymphnodemetastasesinthetruepelvisN3LymphnodemetastasistothecommoniliaclymphnodesDistantMetastasisM0NodistantmetastasisM1DistantmetastasisStageGroupingsStage0TaN0M0orTisN0M0StageIT1N0M0StageIIT2N0M0StageIIIT3N0M0orT4aN0M0StageIVT4bN0M0AnyT,N1-3,AnyMAnyT,AnyN,M1EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA.Urinarybladder.In:EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA,eds.AJCCCancerStagingManual.7thed.NewYork,NY:Springer;2010:497–505.non-muscleinvasivebladdercancer(NMIBC)muscleinvasivebladdercancer(MIBC)TaTisT1T2T3T4STAGEPrimaryTumorStageGroupi5GRADE1973cellularanaplasia2004architecturalandcytologicalatypiaPUNLMP=papillaryurothelialneoplasmoflowmalignantpotentialAshishMKamat,NoahMHahn,JasonAEfstathiouetal.Bladdercancer，2016.lancetS0140-6736(16)30512-8

.GRADE1973cellularanaplasia206ClassificationBasedonGeneticCharacteristicspapillaryNon-papillaryColinP.N.Dinney,ClassificationBasedonGeneti7DinneyCP,McConkeyDJ,MillikanRE,etal.Focusonbladdercancer.CancerCell2004;6:111–1660%:alterationninvolvesexons5–11ofp53andthelossofRBgenefunction

20%:synchronouslossofthetandemlylinkedCDKN2aandARF

20%:alterationsofp53inexons1–4followedbylossofCDKN2aandARFfunctionDinneyCP,McConkeyDJ,Millik8papillaryActivationofFGFR3Chromatin-modifyingenzymeNon-papillaryInactivationofTP53andRBChromatin-modifyingenzymeHistoneacetyltransferaseshistonemethyltransferasesactivatingtelomerasepromotermutationsinactivatingSTAG2mutations

1.GuiY,GuoG,HuangY,etal.Frequentmutationsofchromatinremodelinggenesintransitionalcellcarcinomaofthebladder.NatGenet2011;43:875–78.462.AlloryY,BeukersW,SagreraA,etal.Telomerasereversetranscriptasepromotermutationsinbladdercancer:highfrequencyacrossstages,detectioninurine,andlackofassociationwithoutcome.EurUrol2014;65:360–66.443.Balbás-MartínezC,SagreraA,Carrillo-de-Santa-PauE,etal.RecurrentinactivationofSTAG2inbladdercancerisnotassociatedwithaneuploidy.NatGenet2013;45:1464–69.papillaryActivationofFGFR3No9Basal-likeandLuminalBasalMIBCssharedbiomarkerswithbasalbreastcancersandwerecharacterizedbyp53activation,squamousdifferentiation,andmoreaggressivediseaseatpresentation.LuminalMIBCscontainedfeaturesofactivePPARγandestrogenreceptor(ER)transcriptionandwereenrichedwithactivatingFGFR3mutationsandpotentiallyFGFRinhibitorsensitivity.Basal-likeandLuminalBasalMI10a:Papillaryhistology,FGFR3alterations,FGFR3expressionandreducedFGFR3-relatedmiRNAexpressionareenrichedinclusterI.b:Expressionofepitheliallineagegenesandstem/progenitorcytokeratinsaregenerallyhighinclusterIII,someofwhichexpressvariantsquamoushistology.c:LuminalbreastandurothelialdifferentiationfactorsareenrichedinclustersIandII.d:ERBB2mutationandestrogenreceptorbeta(ESR2)expressionareenrichedinclustersIandII.CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:315–22a:Papillaryhistology,FGFR3a11CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:315–22CancerGenomeAtlasResearchN12膀胱癌发病机制XYY概要课件131.BarskiA,CuddapahS,CuiK,RohTY,SchonesDE,WangZ,WeiG,ChepelevI,ZhaoK(May2007)."High-resolutionprofilingofhistonemethylationsinthehumangenome".Cell129(4):823–37.doi:10.1016/j.cell.2007.05.009.PMID17512414.

2.RosenfeldJA,WangZ,SchonesDE,ZhaoK,DeSalleR,ZhangMQ(2009).

"Determinationofenrichedhistonemodificationsinnon-genicportionsofthehumangenome".

BMCGenomics

10:143.doi:10.1186/1471-2164-10-143.

PMC

2667539.

PMID19335899

3.KochCM,AndrewsRM,FlicekP,DillonSC,KaraözU,ClellandGK,WilcoxS,BeareDM,FowlerJC,CouttetP,JamesKD,LefebvreGC,BruceAW,DoveyOM,EllisPD,DhamiP,LangfordCF,WengZ,BirneyE,CarterNP,VetrieD,DunhamI(Jun2007).

"Thelandscapeofhistonemodificationsacross1%ofthehumangenomeinfivehumancelllines".

GenomeResearch

17

(6):691–707.

doi:10.1101/gr.5704207.PMC

1891331.

PMID

17567990.1.BarskiA,CuddapahS,CuiK,14ChromosomalAlterationsThemostfrequentobservedcopynumberaberrationsinUCareonchromosomes1,8,9,10,11,13,and14.Chromosome9alterationsaretheearliestgeneticalterationsinbothofthedescribeddivergentpathwaysofBCdevelopment[1]1.MingZhao,Xiang-LeiHe,Xiao-DongTeng,Understandingthemolecularpathogenesisandprognosticsofbladdercancer:anoverviewChromosomalAlterationsThemos15膀胱癌发病机制XYY概要课件16膀胱癌发病机制XYY概要课件17StructuralrearrangementsandviralintegrationTheCancerGenomeAtlasResearchNetwork,ComprehensiveMolecularCharacterizationofUrothelialBladderCarcinomaSomeexamplesforchromosomalalterrationStructuralrearrangementsand18summaryThepathogenesisofbladdercancerisacomplicatedcourse,withmanygenesandchromosomesinvolved.Themostfrequentlyalteredpathwaysinbladdercancerinclude:thePI3K/AKT/mammalianpathwaytheFGFR3/RAF/RASpathwaytheTP53/RB1pathwayInaddition,TERTmutationsarepresentinupto79%ofbladderneoplasms,butnorelationwithprognosis.summaryThepathogenesisofbla19膀胱癌发病机制XYY概要课件20AristolochicAcid(AA):acarcinogenforUTUCOverview:Aristolochicacid(AA)isanitrophenanthrenecarboxylicacidfoundinallmembersofthegenusAristolochiausedformedicalpurposesformorethan2000yearsnephrotoxicityandcarcinogenicityassociatedwiththeuseoftheseplantscametolightwhenAristolochiafangchi,administeredto1800healthyBelgianwomenaspartofaweightreductionregimen,resultedinmorethan100casesofchronictubulointerstitialdiseaseprogressingtoend-stagerenalfailure.ManyoftheaffectedwomendevelopedneoplasticchangesintheupperurinarytractAristolochicAcid(AA):acarci21AristolochicAcid,implicatedasanenvironmentalcarcinogenBalkanendemicnephropathy(BEN),adevastatingkidneydiseaseassociatedwithurothelialcarcinomaoftheupperurinarytract.AAwasshowntobethecausativeagentofthisdiseaseInthesestudies,AL-DNAadductsandtheTP53mutationalspectrumofUTUC.Between1997and2003,aboutone-thirdoftheTaiwanesepopulationhadbeenprescribedremediescontainingAristolochiaherbs.Moreover,theincidenceofUTUCinTaiwanisthehighestintheworld.AristolochicAcid,implicated22AnalysisofTP53mutationrevealsAAasaenvironmentalcarcinogenHollsteinM,MoriyaM,GrollmanAP,OlivierM.AnalysisofTP53mutationspectrarevealsthefingerprintofthepotentenvironmentalcarcinogen,aristolochicacid.MutatRes.201310.1016/j.mrrev.2013.02.00319.AnalysisofTP53mutationreve23MarieSTIBOROVÁ1,JiříHUDEČEK1,EvaFREI2andHeinzH.SCHMEISER,Contributionofbiotransformationenzymestothedevelopmentofrenalinjuryandurothelialcancercausedbyaristolochicacid:urgentquestions,difficultanswersMarie,InterdiscToxicol.2008;Vol.1(1):8–12.MarieSTIBOROVÁ1,JiříHUDEČE24ENDEND25PartialMolecularPathogenesisin

BladderCarcinoma夏阳阳2016-7-13PartialMolecularPathogenesis26contentEpidemicsGradeandstageClassificationbasedongeneticcharactericsSomepathwaysAristolochicAcid(AA)contentEpidemics27LindseyA.Torre,MSPH;FreddieBray,PhD,etal.Globalcancerstatistics,2012.CACANCERJCLIN2015;65:87–108EstimatednewcasesEstimateddeath74769LindseyA.Torre,MSPH;Freddi28BladderCarcinomaTransitionalcellcarcinomaNon-TransitionalcellcarcinomaAdeno-carcinomaSquamousCellcarcinomamesenchymalmetastasesInflatratingtumorsOfadjacentorgansBladderCarcinomaTransitional29STAGEPrimaryTumorT0NoevidenceoftumorTaNoninvasivepapillaryurothelialcarcinomaTisUrothelialcarcinomainsituT1TumorinvadeslaminapropriaT2Tumorinvadessuperficial(2a,innerhalf)ordeep(2b,outerhalf)muscularispropriaT3Tumorinvadesmicroscopically(3a)ormacroscopically(3b)perivesicaltissueT4Tumorinvadesadjacentorgans(4a,prostaticstroma,seminalvesicles,uterus,vagina)orpelvicorabdominalwall(4b)RegionalLymphNodesN0NolymphnodemetastasisN1SinglelymphnodemetastasisinthetruepelvisN2MultiplelymphnodemetastasesinthetruepelvisN3LymphnodemetastasistothecommoniliaclymphnodesDistantMetastasisM0NodistantmetastasisM1DistantmetastasisStageGroupingsStage0TaN0M0orTisN0M0StageIT1N0M0StageIIT2N0M0StageIIIT3N0M0orT4aN0M0StageIVT4bN0M0AnyT,N1-3,AnyMAnyT,AnyN,M1EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA.Urinarybladder.In:EdgeSB,ByrdDR,ComptonCC,FritzAG,GreeneFL,TrottiA,eds.AJCCCancerStagingManual.7thed.NewYork,NY:Springer;2010:497–505.non-muscleinvasivebladdercancer(NMIBC)muscleinvasivebladdercancer(MIBC)TaTisT1T2T3T4STAGEPrimaryTumorStageGroupi30GRADE1973cellularanaplasia2004architecturalandcytologicalatypiaPUNLMP=papillaryurothelialneoplasmoflowmalignantpotentialAshishMKamat,NoahMHahn,JasonAEfstathiouetal.Bladdercancer，2016.lancetS0140-6736(16)30512-8

.GRADE1973cellularanaplasia2031ClassificationBasedonGeneticCharacteristicspapillaryNon-papillaryColinP.N.Dinney,ClassificationBasedonGeneti32DinneyCP,McConkeyDJ,MillikanRE,etal.Focusonbladdercancer.CancerCell2004;6:111–1660%:alterationninvolvesexons5–11ofp53andthelossofRBgenefunction

20%:synchronouslossofthetandemlylinkedCDKN2aandARF

20%:alterationsofp53inexons1–4followedbylossofCDKN2aandARFfunctionDinneyCP,McConkeyDJ,Millik33papillaryActivationofFGFR3Chromatin-modifyingenzymeNon-papillaryInactivationofTP53andRBChromatin-modifyingenzymeHistoneacetyltransferaseshistonemethyltransferasesactivatingtelomerasepromotermutationsinactivatingSTAG2mutations

1.GuiY,GuoG,HuangY,etal.Frequentmutationsofchromatinremodelinggenesintransitionalcellcarcinomaofthebladder.NatGenet2011;43:875–78.462.AlloryY,BeukersW,SagreraA,etal.Telomerasereversetranscriptasepromotermutationsinbladdercancer:highfrequencyacrossstages,detectioninurine,andlackofassociationwithoutcome.EurUrol2014;65:360–66.443.Balbás-MartínezC,SagreraA,Carrillo-de-Santa-PauE,etal.RecurrentinactivationofSTAG2inbladdercancerisnotassociatedwithaneuploidy.NatGenet2013;45:1464–69.papillaryActivationofFGFR3No34Basal-likeandLuminalBasalMIBCssharedbiomarkerswithbasalbreastcancersandwerecharacterizedbyp53activation,squamousdifferentiation,andmoreaggressivediseaseatpresentation.LuminalMIBCscontainedfeaturesofactivePPARγandestrogenreceptor(ER)transcriptionandwereenrichedwithactivatingFGFR3mutationsandpotentiallyFGFRinhibitorsensitivity.Basal-likeandLuminalBasalMI35a:Papillaryhistology,FGFR3alterations,FGFR3expressionandreducedFGFR3-relatedmiRNAexpressionareenrichedinclusterI.b:Expressionofepitheliallineagegenesandstem/progenitorcytokeratinsaregenerallyhighinclusterIII,someofwhichexpressvariantsquamoushistology.c:LuminalbreastandurothelialdifferentiationfactorsareenrichedinclustersIandII.d:ERBB2mutationandestrogenreceptorbeta(ESR2)expressionareenrichedinclustersIandII.CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:315–22a:Papillaryhistology,FGFR3a36CancerGenomeAtlasResearchNetwork.Comprehensivemolecularcharacterizationofurothelialbladdercarcinoma.Nature2014;507:315–22CancerGenomeAtlasResearchN37膀胱癌发病机制XYY概要课件381.BarskiA,CuddapahS,CuiK,RohTY,SchonesDE,WangZ,WeiG,ChepelevI,ZhaoK(May2007)."High-resolutionprofilingofhistonemethylationsinthehumangenome".Cell129(4):823–37.doi:10.1016/j.cell.2007.05.009.PMID17512414.

2.RosenfeldJA,WangZ,SchonesDE,ZhaoK,DeSalleR,ZhangMQ(2009).

"Determinationofenrichedhistonemodificationsinnon-genicportionsofthehumangenome".

BMCGenomics

10:143.doi:10.1186/1471-2164-10-143.

PMC

2667539.

PMID19335899

3.KochCM,AndrewsRM,FlicekP,DillonSC,KaraözU,ClellandGK,WilcoxS,BeareDM,FowlerJC,CouttetP,JamesKD,LefebvreGC,BruceAW,DoveyOM,EllisPD,DhamiP,LangfordCF,WengZ,BirneyE,CarterNP,VetrieD,DunhamI(Jun2007).

"Thelandscapeofhistonemodificationsacross1%ofthehumangenomeinfivehumancelllines".

GenomeResearch

17

(6):691–707.

doi:10.1101/gr.5704207.PMC

1891331.

PMID

17567990.1.BarskiA,CuddapahS,CuiK,39ChromosomalAlterationsThemostfrequentobservedcopynumberaberrationsinUCareonchromosomes1,8,9,10,11,13,and14.Chromosome9alterationsaretheearliestgeneticalterationsinbothofthedescribeddivergentpathwaysofBCdevelopment[1]1.MingZhao,Xiang-LeiHe,Xiao-DongTeng,Understandingthemolecularpathogenesisandprognosticsofbladdercancer:anoverviewChromosomalAlterationsThemos40膀胱癌发病机制XYY概要课件41膀胱癌发病机制XYY概要课件42StructuralrearrangementsandviralintegrationTheCancerGenomeAtlasResearchNetwork,ComprehensiveMolecularCharacterizationofUrothelialBladderCarcinomaSomeexamplesforchromosomalalterrationStructuralrearrangementsand43summaryThepathogenesisofbladdercancerisacomplicatedcourse,withmanygenesandchromosomesinvolved.Themostfrequentlyalteredpathwaysinbladdercancerinclude:thePI3K/AKT/mammalianpathwaytheFGFR3/RAF/RASpathwaytheTP53/RB1pathwayInaddition,TERTmutationsarepresentinupto79%ofbladderneoplasms,butnorelationwithprognosis.summaryThepathogenesisofbla44膀胱癌发病机制XYY概要课件45AristolochicAcid(AA):acarcinogenforUTUCOverview:Aristoloch

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