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Dissecting the genomic complexity underlying medulloblastoma

机译：剖析髓母细胞瘤的基因组复杂性

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摘要

Medulloblastoma is an aggressively growing tumour, arising in the cerebellum or medulla/brain stem. It is the most common malignant brain tumour in children, and shows tremendous biological and clinical heterogeneity. Despite recent treatment advances, approximately 40% of children experience tumour recurrence, and 30% will die from their disease. Those who survive often have a significantly reduced quality of life. Four tumour subgroups with distinct clinical, biological and genetic profiles are currently identified. WNT tumours, showing activated wingless pathway signalling, carry a favourable prognosis under current treatment regimens. SHH tumours show hedgehog pathway activation, and have an intermediate prognosis. Group and 4 tumours are molecularly less well characterized, and also present the greatest clinical challenges. The full repertoire of genetic events driving this distinction, however, remains unclear. Here we describe an integrative deep-sequencing analysis of 125 tumour-normal pairs, conducted as part of the International Cancer Genome Consortium (ICGC) PedBrain Tumor Project. Tetraploidy was identified as a frequent early event in Group 3 and 4 tumours, and a positive correlation between patient age and mutation rate was observed. Several recurrent mutations were identified, both in known medulloblastoma-related genes (CTNNB1, PTCH1, MLL2, SMARCA4) and in genes not previously linked to this tumour (DDX3X, CTDNEP1, KDM6A, TBR1), often in subgroup-specific patterns. RNA sequencing confirmed these alterations, and revealed the expression of what are, to our knowledge, the first medulloblastoma fusion genes identified. Chromatin modifiers were frequently altered across all subgroups. These findings enhance our understanding of the genomic complexity and heterogeneity underlying medulloblastoma, and provide several potential targets for new therapeutics, especially for Group 3 and 4 patients.
机译：髓母细胞瘤是一种侵袭性增长的肿瘤，起源于小脑或髓质/脑干。它是儿童中最常见的恶性脑肿瘤，并显示出巨大的生物学和临床异质性。尽管最近有新的治疗方法，约40％的儿童会复发肿瘤，而30％的儿童会死于疾病。那些生存的人往往生活质量大大降低。目前鉴定出具有不同临床，生物学和遗传特征的四个肿瘤亚组。 WNT肿瘤显示激活的无翼途径信号传导，在当前治疗方案下预后良好。 SHH肿瘤表现出刺猬通路激活，并具有中等预后。第4类和第4类肿瘤的分子特征欠佳，并且也带来了最大的临床挑战。然而，尚不清楚导致这种区分的遗传事件的全部内容。在这里，我们描述了作为国际癌症基因组协会（ICGC）PedBrain肿瘤项目的一部分而进行的125个正常肿瘤对的综合深度测序分析。四倍体被认为是3组和4组肿瘤中的常见早期事件，并且观察到患者年龄与突变率之间呈正相关。在已知的髓母细胞瘤相关基因（CTNNB1，PTCH1，MLL2，SMARCA4）和以前未与该肿瘤相关的基因（DDX3X，CTDNEP1，KDM6A，TBR1）中，通常以亚组特异性模式，鉴定出几种复发性突变。 RNA测序证实了这些改变，并揭示了据我们所知第一个已鉴定的髓母细胞瘤融合基因的表达。染色质修饰剂经常在所有亚组中改变。这些发现增强了我们对髓母细胞瘤的基因组复杂性和异质性的理解，并为新疗法提供了一些潜在的靶标，尤其是对于第3和第4组患者。

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  • 来源
    《Nature》 |2012年第7409期|p.100-105|共6页
  • 作者

    David T.W.Jones; Natal ieJager; Marcel Kool; Thomas Zichner; Barbara Hutter; et al;

  • 作者单位

    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany;

    Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany;

    Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany;

    European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, Heidelberg 69117, Germany;

    Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany;

  • 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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  • 正文语种 eng
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