Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer
Dysregulation of EMT Drives the Progression to Clinically Aggressive Sarcomatoid Bladder Cancer
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DOI：
10.1016/j.celrep.2019.04.048
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发表时间：
2019-05-07
期刊：
影响因子：
8.8
通讯作者：
Czerniak, Bogdan
中科院分区：
文献类型：
--
作者：
Guo, Charles C.;Majewski, Tadeusz;Czerniak, Bogdan
肉瘤样尿路上皮性膀胱癌（SARC）表现出高度的远处转移倾向，并且与短生存期相关。我们报告了28例SARC和84例常规尿路上皮癌（UC）的全面基因组分析，并以408例肌肉侵袭性膀胱癌的TCGA队列作为参考。SARCs表现出独特的突变景观，富集TP53、RB1和PIK3CA突变。它们与常规UCs的基础分子亚型有关，根据TP63及其靶基因表达水平可分为上皮基础亚型和更具临床侵袭性的间充质亚型。其他分析显示，SARCs是由同型粘附基因的下调和EMT网络的失调驱动的，近一半的SARCs表现出严重浸润的免疫表型。我们的观察结果对这种高致死率的膀胱癌变体的预后和开发更有效的治疗方法具有重要意义。
Sarcomatoid urothelial bladder cancer (SARC) displays a high propensity for distant metastasis and is associated with short survival. We report a comprehensive genomic analysis of 28 cases of SARC and 84 cases of conventional urothelial carcinoma (UC), with the TCGA cohort of 408 muscleinvasive bladder cancers serving as the reference. SARCs show a distinct mutational landscape, with enrichment of TP53, RB1, and PIK3CA mutations. They are related to the basal molecular subtype of conventional UCs and could be divided into epithelial-basal and more clinically aggressive mesenchymal subsets on the basis of TP63 and its target gene expression levels. Other analyses reveal that SARCs are driven by downregulation of homotypic adherence genes and dysregulation of the EMT network, and nearly half exhibit a heavily infiltrated immune phenotype. Our observations have important implications for prognostication and the development of more effective therapies for this highly lethal variant of bladder cancer.