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Comprehensive molecular characterization of urothelial bladder carcinoma

机译：尿路上皮癌的综合分子表征

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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.%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。
机译：膀胱尿道上皮癌是一种常见的恶性肿瘤，每年在世界范围内导致约15万例死亡。迄今为止，还没有分子靶向药物被批准用于治疗该疾病。作为“癌症基因组图集”项目的一部分，我们在这里报告了131种尿路上皮癌的综合分析，以提供分子变化的全面概况。在32个基因中有统计学上显着的经常性突变，包括涉及细胞周期调控，染色质调控和激酶信号传导途径的多个基因，以及以前未报道在任何癌症中均显着突变的9个基因。 RNA测序揭示了四种表达亚型，其中两种（乳头状和基底/鳞状样）在microRNA测序和蛋白质数据中也很明显。全基因组和RNA测序鉴定了框内激活的FGFR3-TACC3融合复发以及与基因失活相关的几种病毒（包括HPV16）的表达或整合。我们的分析在69％的肿瘤中确定了潜在的治疗靶标，包括42％的磷脂酰肌醇3-OH激酶/ AKT / mTOR通路靶标和45％的RTK / MAPK通路靶标（包括ERBB2）。迄今为止，尿路上皮癌中的染色质调节基因发生突变的频率要高于其他任何普通癌症，这表明针对染色质异常进行靶向治疗的可能性更高。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变化，染色质替代和激酶信号作用通道中所涉及的基因。 “频发在帧内激发FGFR3-TACC3融合”以及与基因失活相关的病毒的表达或整合。在这个研究中也也被发现。重要的是，在69％的这些肿瘤中还发现了潜在的治疗目标。

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  • 来源
    《Nature》 |2014年第7492期|315-322b1|共9页
  • 作者

    John N. Weinstein; Rehan Akbani; Bradley M. Broom; Wenyi Wang; Roeland G. W. Verhaak; et al;

  • 作者单位

    Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA,Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

    Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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