Nature2014-06-24 3:35 PM

与膀胱癌有关的频发突变 Comprehensive molecular characterization of urothelial bladder carcinoma

论文摘要 

对131个高等级肌肉入侵性尿路上皮膀胱癌所做的这项研究(“癌症基因组图集” (TCGA)项目的一部分),报告了32个基因的频发突变,其中包括那些在细胞周期调控、染色质调控和激酶信号作用通道中所涉及的基因。染色质调控基因在尿路上皮癌中发生突变的频率比在迄今所研究的任何常见癌症中都高。 “频发in-frame激发FGFR3–TACC3融合”以及与基因失活相关的病毒的表达或整合在这项研究中也被发现。重要的是,在69%的这些肿瘤中还发现了潜在的治疗目标。

Abstract 

Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities.

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