Comprehensive molecular characterization of urothelial bladder carcinoma.
Comprehensive molecular characterization of urothelial bladder carcinoma.
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膀胱尿路上皮癌是一种常见的恶性肿瘤，每年导致全球约15万人死亡。到目前为止，还没有分子靶向药物被批准用于治疗这种疾病。作为癌症基因组图谱项目的一部分，我们报告了对131例尿路上皮癌的综合分析，以提供一个全面的分子变化图景。有32个基因在统计学上有显著的反复突变，包括与细胞周期调节、染色质调节和激酶信号通路有关的多个基因，以及9个以前未报道的在任何癌症中显著突变的基因。RNA测序显示四种表达亚型，其中两种(乳头状和基底部/鳞片状)在microRNA测序和蛋白质数据中也明显存在。全基因组和RNA测序证实了反复的框内激活FGFR3-TACC3融合和几种与基因失活相关的病毒(包括HPV16)的表达或整合。我们的分析确定了69%的肿瘤具有潜在的治疗靶点，其中42%的靶点位于磷脂酰肌醇-3-羟基激酶/AKT/mTOR途径，45%的靶点(包括ERBB2)位于RTK/MAPK途径。与目前研究的其他常见癌症相比，尿路上皮癌中染色质调节基因的突变频率更高，这表明未来有可能对染色质异常进行靶向治疗。本文的在线版本(doi：10.1038/Nature12965)包含补充材料，授权用户可以使用。本文报道了作为癌症基因组图谱计划的一部分，对尿路上皮性膀胱癌进行的DNA、RNA和蛋白质水平的综合分子分析；在32个基因中发现了反复突变，包括那些与细胞周期调节、染色质调节和激酶信号通路有关的基因；在尿路上皮癌中，染色质调节基因的突变比迄今研究的任何其他常见癌症都要频繁。本文的在线版本(doi：10.1038/Nature12965)包含补充材料，授权用户可以使用。这项对131例高级别肌肉浸润性尿路上皮癌的研究，是癌症基因组图谱(TCGA)项目的一部分，报告了32个基因的反复突变，包括那些涉及细胞周期调节、染色质调节和激酶信号通路的基因。染色质调节基因在尿路上皮癌中的突变频率比迄今研究的任何常见癌症都要高。反复的框内激活FGFR3-TACC3融合和与基因失活相关的病毒的表达或整合也被发现。重要的是，在69%的肿瘤中确定了潜在的治疗靶点。本文的在线版本(doi：10.1038/Nature12965)包含补充材料，授权用户可以使用。
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. The online version of this article (doi:10.1038/nature12965) contains supplementary material, which is available to authorized users. This paper reports integrative molecular analyses of urothelial bladder carcinoma at the DNA, RNA, and protein levels performed as part of The Cancer Genome Atlas project; recurrent mutations were found in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways; chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far. The online version of this article (doi:10.1038/nature12965) contains supplementary material, which is available to authorized users. This study of 131 high-grade muscle-invasive urothelial bladder carcinomas, part of The Cancer Genome Atlas (TCGA) project, reports recurrent mutations in 32 genes, including those involved in cell-cycle regulation, chromatin regulation and kinase signalling pathways. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any common cancer studied to date. Recurrent in-frame activating FGFR3–TACC3 fusions and expression or integration of viruses associated with gene inactivation are also identified. Importantly, potential therapeutic targets are identified in 69% of the tumours. The online version of this article (doi:10.1038/nature12965) contains supplementary material, which is available to authorized users.
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DOI：
10.1126/science.1226344
发表时间：
2012-10-12
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Iyer G;Hanrahan AJ;Milowsky MI;Al-Ahmadie H;Scott SN;Janakiraman M;Pirun M;Sander C;Socci ND;Ostrovnaya I;Viale A;Heguy A;Peng L;Chan TA;Bochner B;Bajorin DF;Berger MF;Taylor BS;Solit DB
通讯作者：
Solit DB
DOI：
10.1093/bioinformatics/bts452
发表时间：
2012-09-15
期刊：
Bioinformatics (Oxford, England)
影响因子：
--
作者：
Ryan MC;Cleland J;Kim R;Wong WC;Weinstein JN
通讯作者：
Weinstein JN
选择性抑制BET溴结构域。
影响因子：
64.8
作者：
通讯作者：
--
DOI：
10.1038/nrurol.2012.142
发表时间：
2012-10
期刊：
Nature reviews. Urology
影响因子：
--
作者：
通讯作者：
--
影响因子：
28.2
作者：
Bose R;Kavuri SM;Searleman AC;Shen W;Shen D;Koboldt DC;Monsey J;Goel N;Aronson AB;Li S;Ma CX;Ding L;Mardis ER;Ellis MJ
通讯作者：
Ellis MJ