Wu Song, Chen Jiahao, Dong Pei, Zhang Shiqiang, He Yingying, Sun Liang, Zhu Jialou, Cheng Yanbing, Li Xianxin, Tang Aifa, Huang Yi, Gui Yaoting, Liu Chunxiao, Yang Guosheng, Zhou Fangjian, Cai Zhiming, Wang Rongfu
Institute of Immunology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong 510060, China.
BMC Cancer. 2014 Nov 18;14:836. doi: 10.1186/1471-2407-14-836.
Current knowledge about the molecular properties and prognostic markers of upper tract urothelial carcinoma (UTUC) is sparse and often based on bladder urothelial carcinoma (UC), which is thought to share common risk factors with UTUC. However, studies have suggested that differences exist regarding tumor behavior and molecular biology of these cancers, comprehensive investigations are needed to guide the clinical management of UTUC. In recent years, massively parallel sequencing has allowed insights into the biology of many cancers, and molecular prognostic markers based on this approach are rapidly emerging. The goal of this study was to characterize the gene expression patterns of UTUC using massively parallel sequencing, and identify potential molecular markers for prognosis in patients with UTUC.
We compared the genome-wide mRNA expression profile of cancer and matched normal tissues from 10 patients with UTUC to identify significantly deregulated genes. We also examined the protein levels of prognostic marker candidates in 103 patients with UTUC, and tested the association of these markers with overall survival using Kaplan-Meier model and Cox regression.
Functional enrichment of significantly deregulated genes revealed that expression patterns of UTUC were characterized by disorders of cell proliferation and metabolism. And we also compared the expression profile of UTUC with that of bladder UC. Our results highlighted both shared (e.g. disorders of cell cycling and growth signal transduction) and tumor-specific (e.g. abnormal metabolism in UTUC and disruptions of adhesion pathways in bladder UC) features of these two cancers. Importantly, we identified that low protein expression of ALDH2 while high CCNE1 and SMAD3 were significantly associated with increased depth (*P <0.05) and lower overall survival (***P <0.0001) in an independent set of 103 patients. Multivariate Cox regression revealed that all these three genes were independent prognostic indicators in patients with UTUC (***P <0.001).
In conclusion, our study characterized the comprehensive expression profile of UTUC and highlighted both commons and differences in expression patterns between UTUC and bladder UC. And we, for the first time, revealed that ALDH2, CCNE1 and SMAD3 are associated with prognosis in patients with UTUC.
目前关于上尿路尿路上皮癌（UTUC）分子特性和预后标志物的知识较为匮乏，且常常基于膀胱尿路上皮癌（UC），人们认为二者具有共同的危险因素。然而，研究表明这些癌症在肿瘤行为和分子生物学方面存在差异，因此需要进行全面研究以指导UTUC的临床管理。近年来，大规模平行测序使人们能够深入了解多种癌症的生物学特性，基于此方法的分子预后标志物也迅速涌现。本研究的目的是利用大规模平行测序来描绘UTUC的基因表达模式，并识别UTUC患者潜在的预后分子标志物。
我们比较了10例UTUC患者癌组织与其匹配的正常组织的全基因组mRNA表达谱，以确定显著失调的基因。我们还检测了103例UTUC患者中预后标志物候选蛋白的水平，并使用Kaplan-Meier模型和Cox回归分析这些标志物与总生存期的相关性。
显著失调基因的功能富集分析显示，UTUC的表达模式以细胞增殖和代谢紊乱为特征。我们还比较了UTUC与膀胱UC的表达谱。我们的结果突出了这两种癌症的共同特征（如细胞周期和生长信号转导紊乱）以及肿瘤特异性特征（如UTUC中的异常代谢和膀胱UC中的黏附途径破坏）。重要的是，在一组独立的103例患者中，我们发现ALDH2蛋白低表达而CCNE1和SMAD3高表达与肿瘤深度增加（*P<0.05）和总生存期降低（***P<0.0001）显著相关。多变量Cox回归分析显示，这三个基因都是UTUC患者的独立预后指标（***P<0.001）。
总之，我们的研究描绘了UTUC的综合表达谱，突出了UTUC与膀胱UC在表达模式上的异同。并且我们首次揭示，ALDH2、CCNE1和SMAD3与UTUC患者的预后相关。
Zotero 插件