膀胱癌发病机制XYY概要课件

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,2016/7/13,#,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,Partial Molecular Pathogenesis in Bladder Carcinoma,夏阳阳,2016-7-13,Partial Molecular Pathogenesis,1,content,Epidemics,Grade and stage,Classification based on genetic characterics,Some pathways,Aristolochic Acid(AA),contentEpidemics,2,Lindsey A.Torre,MSPH;Freddie Bray,PhD,et al.Global cancer statistics,2012.,CA CANCER J CLIN 2015;65:87108,Estimated new cases,Estimated death,7,4,7,6,9,Lindsey A.Torre,MSPH;Freddi,3,Bladder Carcinoma,Transitional cell carcinoma,Non-Transitional cell carcinoma,Adeno-carcinoma,Squamous,Cell,carcinoma,mesenchymal,metastases,Inflatrating tumors,Of adjacent organs,Bladder CarcinomaTransitional,4,STAGE,Primary Tumor,T0 No evidence of tumor,Ta Noninvasive papillary urothelial carcinoma,Tis Urothelial carcinoma in situ,T1 Tumor invades lamina propria,T2 Tumor invades superficial(2a,inner half)or deep(2b,outer half)muscularis propria,T3 Tumor invades microscopically(3a)or macroscopically(3b)perivesical tissue,T4 Tumor invades adjacent organs(4a,prostatic stroma,seminal vesicles,uterus,vagina)or pelvic or abdominal wall(4b),Regional Lymph Nodes,N0 No lymph node metastasis,N1 Single lymph node metastasis in the true pelvis,N2 Multiple lymph node metastases in the true pelvis,N3 Lymph node metastasis to the common iliac lymph nodes,Distant Metastasis,M0 No distant metastasis,M1 Distant metastasis,Stage 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 Cancer Staging Manual.7th ed.New York,NY:Springer;2010:497505.,non-muscle invasive,bladder cancer(NMIBC),muscle invasive,bladder cancer(MIBC),Ta,Tis,T1,T2,T3,T4,STAGEPrimary TumorStage Groupi,5,GRADE,1973,cellular anaplasia,2004,architectural and cytological atypia,PUNLMP=papillary urothelial neoplasm of low malignant potential,Ashish M Kamat,Noah M Hahn,Jason A Efstathiou et al.Bladder cancer,，,2016.lancet,S0140-6736(16)30512-8.,GRADE 1973cellular anaplasia20,6,Classification Based on Genetic Characteristics,papillary,Non-papillary,Colin P.N.Dinney,Classification Based on Geneti,7,Dinney CP,McConkey DJ,Millikan RE,et al.Focus on bladder cancer.Cancer Cell 2004;6:11116,60%:alterationn involves exons 511 of p53 and the loss of RB gene function,20%:synchronous loss of the tandemly linked CDKN2a and ARF,20%:alterations of p53 in exons 14 followed by loss of CDKN2a and ARF function,Dinney CP,McConkey DJ,Millik,8,papillary,Activation of FGFR3,Chromatin-modifying enzyme,Non-,papillary,Inactivation of TP53 and RB Chromatin-modifying enzyme,H,istone acetyltransferases,histone methyltransferases,activating telomerase promoter mutations,inactivating 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;43:87578.46,2.Allory Y,Beukers W,Sagrera A,et al.Telomerase reverse transcriptase promoter mutations in bladder cancer:high frequency across stages,detection in urine,and lack of association with outcome.Eur Urol 2014;65:36066.44,3.Balbs-Martnez C,Sagrera A,Carrillo-de-Santa-Pau E,et al.Recurrent inactivation of STAG2 in bladder cancer is not associated with aneuploidy.Nat Genet 2013;45:146469.,papillaryActivation of FGFR3No,9,Basal-like and Luminal,Basal MIBCs shared biomarkers with basal,breast cancers and were characterized by,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.,Basal-like and LuminalBasal MI,10,a:Papillary histology,FGFR3 alterations,FGFR3 expression and reduced FGFR3-related miRNA expression are enriched in cluster I.,b:Expression of,epithelial lineage 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 and II.,Cancer Genome Atlas Research Network.Comprehensive molecular characterization of urothelial bladder carcinoma.Nature 2014;507:31522,a:Papillary histology,FGFR3 a,11,Cancer Genome Atlas Research Network.Comprehensive molecular characterization of urothelial bladder carcinoma.Nature 2014;507:31522,Cancer Genome Atlas Research N,12,膀胱癌发病机制XYY概要课件,13,1.Barski A,Cuddapah S,Cui K,Roh TY,Schones DE,Wang Z,Wei G,Chepelev I,Zhao K(May 2007).High-resolution profiling 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:10.1186/1471-2164-10-143.PMC2667539.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 modifications across 1%of the human genome in five human cell lines.Genome Research,17,(6):691707.doi:10.1101/gr.5704207.PMC1891331.PMID17567990.,1.Barski A,Cuddapah S,Cui K,14,Chromosomal 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 development,1,1.Ming Zhao,Xiang-Lei He,Xiao-Dong Teng,Understanding the molecular pathogenesis and prognostics of bladder cancer:an overview,Chromosomal AlterationsThe mos,15,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,17,Structural rearrangements and viral integration,The Cancer Genome Atlas Research Network,Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma,Some examples for chromosomal alterration,Structural rearrangements and,18,summary,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/RAS pathway,the TP53/RB1 pathway,In addition,TERT mutations are present in up to 79%of bladder neoplasms,but no relation with prognosis.,summaryThe pathogenesis of bla,19,膀胱癌发病机制XYY概要课件,20,Aristolochic Acid(AA):a carcinogen for UTUC,Overview:,Aristolochic acid(AA)is a nitrophenanthrene carboxylic acid found in all members of the genus Aristolochia,used for medical purposes for more than 2000 years,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,resulted 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 tract,Aristolochic Acid(AA):a carci,21,Aristolochic 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 disease 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.,Aristolochic Acid,implicated,22,Analysis of TP53 mutation reveals AA as a environmental carcinogen,Hollstein 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.,Analysis of TP53 mutation reve,23,Marie STIBOROV 1,Ji HUDEEK 1,Eva FREI 2 and Heinz H.SCHMEISER,Contribution of biotransformation enzymes to the development of renal injury and urothelial cancer caused by aristolochic acid:urgent questions,difficult answersMarie,Interdisc Toxicol.2008;Vol.1(1):812.,Marie STIBOROV 1,Ji HUDEE,24,END,END,25,