膀胱癌发病机制XYY概要课件.pptx

1、With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyPartial Molecular Pathogenesis inPartial Molecular Pathogenesis in Bladder Carcinoma Bladder Carcinoma夏阳阳夏阳阳2016-7-13With the

2、 improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societycontentcontentEpidemicsGrade and stage Classification based on genetic charactericsSome pathwaysAristolochic Acid(AA)With the improvi

3、ng quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyLindsey A.Torre,MSPH;Freddie Bray,PhD,et al.Global cancer statistics,2012.CA CANCER J CLIN 2015;65:87108Estimated new casesEstimated deathWit

4、h the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyBladder CarcinomaTransitional cell carcinomaNon-Transitional cell carcinomaAdeno-carcinomaSquamous Cell carcinomamesenchymalmeta

5、stasesInflatrating tumorsOf adjacent organsWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societySTAGEPrimary TumorT0 No evidence of tumorTa Noninvasive papillary urothelial carci

6、nomaTis Urothelial carcinoma in situT1 Tumor invades lamina propriaT2 Tumor invades superficial(2a,inner half)or deep(2b,outer half)muscularis propriaT3 Tumor invades microscopically(3a)or macroscopically(3b)perivesical tissueT4 Tumor invades adjacent organs(4a,prostatic stroma,seminal vesicles,uter

7、us,vagina)or pelvic or abdominal wall(4b)Regional Lymph NodesN0 No lymph node metastasisN1 Single lymph node metastasis in the true pelvisN2 Multiple lymph node metastases in the true pelvis N3 Lymph node metastasis to the common iliac lymph nodesDistant MetastasisM0 No distant metastasisM1 Distant

8、metastasisStage Groupings Stage 0 TaN0M0 or TisN0M0 Stage I T1N0M0 Stage II T2N0M0 Stage III T3N0M0 or T4aN0M0 Stage IV T4bN0M0 Any T,N1-3,Any M Any T,Any N,M1 Edge SB,Byrd DR,Compton CC,Fritz AG,Greene FL,Trotti A.Urinary bladder.In:Edge SB,Byrd DR,Compton CC,Fritz AG,Greene FL,Trotti A,eds.AJCC Ca

9、ncer Staging Manual.7th ed.New York,NY:Springer;2010:497505.non-muscle invasive bladder cancer(NMIBC)muscle invasive bladder cancer(MIBC)TaTisT1T2T3T4With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to

10、meet the needs of societyGRADE 1973cellular anaplasia2004architectural and cytological atypiaPUNLMP=papillary urothelial neoplasm of low malignant potentialAshish M Kamat,Noah M Hahn,Jason A Efstathiou et al.Bladder cancer，2016.lancet S0140-6736(16)30512-8.With the improving quality of life as well

11、as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyClassification Based on Genetic CharacteristicspapillaryNon-papillaryColin P.N.Dinney,With the improving quality of life as well as the ever-accelerating pace of life,t

12、he quality of peoples food needs and rate also changing.In order to meet the needs of societyDinney CP,McConkey DJ,Millikan RE,et al.Focus on bladder cancer.Cancer Cell 2004;6:1111660%:alterationn involves exons 511 of p53 and the loss of RB gene function 20%:synchronous loss of the tandemly linked

13、CDKN2a and ARF 20%:alterations of p53 in exons 14 followed by loss of CDKN2a and ARF functionWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyHistone acetyltransferases histo

14、ne methyltransferasesactivating telomerase promoter mutationsinactivating STAG2 mutations 1.Gui Y,Guo G,Huang Y,et al.Frequent mutations of chromatin remodeling genes in transitional cell carcinoma of the bladder.Nat Genet 2011;43:87578.462.Allory Y,Beukers W,Sagrera A,et al.Telomerase reverse trans

15、criptase promoter mutations in bladder cancer:high frequency across stages,detection in urine,and lack of association with outcome.Eur Urol 2014;65:36066.443.Balbs-Martnez C,Sagrera A,Carrillo-de-Santa-Pau E,et al.Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.Na

16、t Genet 2013;45:146469.With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyBasal-like and LuminalBasal MIBCs shared biomarkers with basal breast cancers and were characterized b

17、y p53 activation,squamous differentiation,and more aggressive disease at presentation.Luminal MIBCs contained features of active PPAR and estrogen receptor(ER)transcription and were enriched with activating FGFR3 mutations and potentially FGFR inhibitor sensitivity.With the improving quality of life

18、 as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societya:Papillary histology,FGFR3 alterations,FGFR3 expression and reduced FGFR3-related miRNA expression are enriched in cluster I.b:Expression of epithelial lineag

19、e genes and stem/progenitor cytokeratins are generally high in cluster III,some of which express variant squamous histology.c:Luminal breast and urothelial differentiation factors are enriched in clusters I and II.d:ERBB2 mutation and estrogen receptor beta(ESR2)expression are enriched in clusters I

20、 and II.Cancer Genome Atlas Research Network.Comprehensive molecular characterization of urothelial bladder carcinoma.Nature 2014;507:31522With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the ne

21、eds of societyCancer Genome Atlas Research Network.Comprehensive molecular characterization of urothelial bladder carcinoma.Nature 2014;507:31522With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet

22、the needs of societyWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of society1.Barski A,Cuddapah S,Cui K,Roh TY,Schones DE,Wang Z,Wei G,Chepelev I,Zhao K(May 2007).High-resolution pr

23、ofiling of histone methylations in the human genome.Cell 129(4):82337.doi:10.1016/j.cell.2007.05.009.PMID 17512414.2.Rosenfeld JA,Wang Z,Schones DE,Zhao K,DeSalle R,Zhang MQ(2009).Determination of enriched histone modifications in non-genic portions of the human genome.BMC Genomics 10:143.doi:10.118

24、6/1471-2164-10-143.PMC 2667539.PMID 19335899 3.Koch CM,Andrews RM,Flicek P,Dillon SC,Karaz U,Clelland GK,Wilcox S,Beare DM,Fowler JC,Couttet P,James KD,Lefebvre GC,Bruce AW,Dovey OM,Ellis PD,Dhami P,Langford CF,Weng Z,Birney E,Carter NP,Vetrie D,Dunham I(Jun 2007).The landscape of histone modificati

25、ons across 1%of the human genome in five human cell lines.Genome Research 17(6):691707.doi:10.1101/gr.5704207.PMC 1891331.PMID 17567990.With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs

26、 of societyChromosomal Alterations The most frequent observed copy number aberrations in UC are on chromosomes 1,8,9,10,11,13,and 14.Chromosome 9 alterations are the earliest genetic alterations in both of the described divergent pathways of BC development11.Ming Zhao,Xiang-Lei He,Xiao-Dong Teng,Und

27、erstanding the molecular pathogenesis and prognostics of bladder cancer:an overviewWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyWith the improving quality of life as well

28、 as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of

29、 societyStructural rearrangements and viral integrationThe Cancer Genome Atlas Research Network,Comprehensive Molecular Characterization of Urothelial Bladder CarcinomaSome examples for chromosomal alterrationWith the improving quality of life as well as the ever-accelerating pace of life,the qualit

30、y of peoples food needs and rate also changing.In order to meet the needs of societysummary The pathogenesis of bladder cancer is a complicated course,with many genes and chromosomes involved.The most frequently altered pathways in bladder cancer include:the PI3K/AKT/mammalian pathway the FGFR3/RAF/

31、RAS pathway the TP53/RB1 pathwayIn addition,TERT mutations are present in up to 79%of bladder neoplasms,but no relation with prognosis.With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs

32、of societyWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyAristolochic Acid(AA):a carcinogen for UTUC Overview:1.Aristolochic acid(AA)is a nitrophenanthrene carboxylic acid

33、found in all members of the genus Aristolochia2.used for medical purposes for more than 2000 years3.nephrotoxicity and carcinogenicity associated with the use of these plants came to light when Aristolochia fangchi,administered to 1800 healthy Belgian women as part of a weight reduction regimen,resu

34、lted in more than 100 cases of chronic tubulointerstitial disease progressing to end-stage renal failure.Many of the affected women developed neoplastic changes in the upper urinary tractWith the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food need

35、s and rate also changing.In order to meet the needs of societyAristolochic Acid,implicated as an environmental carcinogen Balkan endemic nephropathy(BEN),a devastating kidney disease associated with urothelial carcinoma of the upper urinary tract.AA was shown to be the causative agent of this diseas

36、e In these studies,AL-DNA adducts and the TP53 mutational spectrum of UTUC.Between 1997 and 2003,about one-third of the Taiwanese population had been prescribed remedies containing Aristolochia herbs.Moreover,the incidence of UTUC in Taiwan is the highest in the world.With the improving quality of l

37、ife as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyAnalysis of TP53 mutation reveals AA as a environmental carcinogen48%52%human TP53 gene knock-in mousewith A:T-to-T:A mutations without A:T-to-T:A mutations

38、 6%94%IARC TP53 databasewith AA are A:T-to-T:A mutationswithout AA are A:T-to-T:A mutationsHollstein M,Moriya M,Grollman AP,Olivier M.Analysis of TP53 mutation spectra reveals the fingerprint of the potent environmental carcinogen,aristolochic acid.Mutat Res.201310.1016/j.mrrev.2013.02.00319.With th

39、e improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of societyMarie STIBOROV 1,Ji HUDEEK 1,Eva FREI 2 and Heinz H.SCHMEISER,Contribution of biotransformation enzymes to the development of renal

40、injury and urothelial cancer caused by aristolochic acid:urgent questions,difficult answersMarie,Interdisc Toxicol.2008;Vol.1(1):812.With the improving quality of life as well as the ever-accelerating pace of life,the quality of peoples food needs and rate also changing.In order to meet the needs of society