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Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations

机译：髓母细胞瘤外显子组测序发现亚型特异性体细胞突变

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Medulloblastomas are the most common malignant brain tumours in children. Identifying and understanding the genetic events that drive these tumours is critical for the development of more effective diagnostic, prognostic and therapeutic strategies. Recently, our group and others described distinct molecular subtypes of medulloblastoma on the basis of transcriptional and copy number profiles. Here we use whole-exome hybrid capture and deep sequencing to identify somatic mutations across the coding regions of 92 primary medulloblastomaormal pairs. Overall, medulloblastomas have low mutation rates consistent with other paediatric tumours, with a median of 0.35 non-silent mutations per megabase. We identified twelve genes mutated at statistically significant frequencies, including previously known mutated genes in medulloblastoma such as CTNNB1, PTCH1, MLL2, SMARCA4 and TP53. Recurrent somatic mutations were newly identified in an RNA helicase gene, DDX3X, often concurrent with CTNNB1 mutations, and in the nuclear co-repressor (N-CoR) complex genes GPS2, BCOR and LDB1. We show that mutant DDX3X potentiates transactivation of a TCF promoter and enhances cell viability in combination with mutant, but not wild-type, β-catenin. Together, our study reveals the alteration of WNT, hedgehog, histone methyltransferase and now N-CoR pathways across medulloblastomas and within specific subtypes of this disease, and nominates the RNA helicase DDX3X as a component of pathogenic β-catenin signalling in medulloblastoma.
机译：髓母细胞瘤是儿童中最常见的恶性脑肿瘤。识别和理解驱动这些肿瘤的遗传事件对于开发更有效的诊断，预后和治疗策略至关重要。最近，我们的小组和其他小组根据转录和拷贝数概况描述了髓母细胞瘤的不同分子亚型。在这里，我们使用全外显子杂交捕获和深度测序来鉴定跨越92个原发性髓母细胞瘤/正常对的编码区的体细胞突变。总体而言，髓母细胞瘤具有与其他儿科肿瘤一致的低突变率，每兆碱基中位数为0.35个非沉默突变。我们鉴定了十二个以统计学上显着的频率突变的基因，包括髓母细胞瘤中先前已知的突变基因，例如CTNNB1，PTCH1，MLL2，SMARCA4和TP53。在RNA解旋酶基因DDX3X中经常与CTNNB1突变同时出现，在核共抑制基因（N-CoR）复杂基因GPS2，BCOR和LDB1中新发现了复发的体细胞突变。我们显示突变体DDX3X增强了TCF启动子的反式激活，并增强了与突变体（而非野生型）β-catenin结合的细胞活力。在一起，我们的研究揭示了跨髓母细胞瘤和该疾病特定亚型的WNT，刺猬，组蛋白甲基转移酶和现在的N-CoR途径的改变，并提名了RNA解旋酶DDX3X作为髓母细胞瘤中病原性β-catenin信号的组成部分。

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  • 来源
    《Nature》 |2012年第7409期|p.106-110|共5页
  • 作者

    Trevor J. Pugh; Shyamal Dilhan Weeraratne; Tenley C. Archer; Daniel A. Pomeranz Krummel; Daniel Auclair; et al;

  • 作者单位

    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA,Center for Cancer Genome Discovery, Departments of Medical Oncology and of Biological Chemistry and Molecular Pharmacology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA,Harvard Medical School, Boston, Massachusetts 02115, USA;

    Harvard Medical School, Boston, Massachusetts 02115, USA,Department of Neurology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Harvard Medical School, Boston, Massachusetts 02115, USA,Department of Neurology, Children's Hospital Boston, Boston, Massachusetts 02115, USA;

    Brandeis University. Waltham, Massachusetts 02453, USA;

    Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, 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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