膀胱癌發(fā)病機制ppt課件

1、Partial Molecular Pathogenesis in Bladder Carcinoma,夏陽陽 2016-7-13,1,.,content,Epidemics Grade and stage Classification based on genetic characterics Some pathways Aristolochic Acid (AA),2,.,Lindsey A. Torre, MSPH; Freddie Bray, PhD, et al. Global cancer statistics, 2012. CA CANCER J CLIN 2015;65:871

2、08,7,3,.,Bladder Carcinoma,Transitional cell carcinoma,Non-Transitional cell carcinoma,Adeno-carcinoma,Squamous Cell carcinoma,mesenchymal,metastases,Inflatrating tumors Of adjacent organs,4,.,STAGE,Primary Tumor T0 No evidence of tumor Ta Noninvasive papillary urothelial carcinoma Tis Urothelial ca

3、rcinoma 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,

4、 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 D

5、istant 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

6、 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 T4,5,.,GRADE,PUNLMP=papillary urothelial neoplasm of low malignant potential,Ashish M Kamat, Noah M Hahn, Jaso

7、n A Efstathiou et al. Bladder cancer， 2016.lancet S0140-6736(16)30512-8.,6,.,Classification Based on Genetic Characteristics,papillary,Non-papillary,Colin P.N. Dinney,7,.,Dinney CP, McConkey DJ, Millikan RE, et al. Focus on bladder cancer. Cancer Cell 2004; 6: 11116,60% :alterationn involves exons 5

8、11 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,8,.,papillary,Activation of FGFR3 Chromatin-modifying enzyme,Non- papillary,Inactivation of TP53 and RB Chromatin-modi

9、fying enzyme,Histone 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.Allo

10、ry 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 inact

11、ivation of STAG2 in bladder cancer is not associated with aneuploidy. Nat Genet 2013; 45: 146469.,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.,Lumina

12、l MIBCs contained features of active PPAR and estrogen receptor (ER) transcription and were enriched with activating FGFR3 mutations and potentially FGFR inhibitor sensitivity.,10,.,a:Papillary histology, FGFR3 alterations, FGFR3 expression and reduced FGFR3-related miRNA expression are enriched in

13、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 recep

14、tor 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: 31522,11,.,Cancer Genome Atlas Research Network. Comprehensive molecular characterization of urothelial blad

15、der carcinoma. Nature 2014; 507: 31522,12,.,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,

16、 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 Genomics10: 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, Bear

17、e 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 Research17(6): 691707.doi:10.1101/gr.

18、5704207.PMC1891331.PMID17567990.,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 development1,1.Ming Z

19、hao , Xiang-Lei He, Xiao-Dong Teng, Understanding the molecular pathogenesis and prognostics of bladder cancer: an overview,15,.,16,.,17,.,Structural rearrangements and viral integration,The Cancer Genome Atlas Research Network,Comprehensive Molecular Characterization of Urothelial Bladder Carcinoma

20、,Some examples for chromosomal alterration,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

21、In addition, TERT mutations are present in up to 79% of bladder neoplasms,but no relation with prognosis.,19,.,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 pur

22、poses 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 p

23、rogressing to end-stage renal failure.Many of the affected women developed neoplastic changes in the upper urinary tract,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-thi