Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma
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DOI：
10.1007/s13311-012-0137-6
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发表时间：
2012-02-09
期刊：
影响因子：
64.8
通讯作者：
Jabado, Nada
中科院分区：
文献类型：
--
作者：
Schwartzentruber, Jeremy;Korshunov, Andrey;Jabado, Nada
多形性胶质母细胞瘤(GBM)是一种成人和儿童的致命性脑瘤。然而，DNA拷贝数和基因表达特征表明成人和儿童病例之间存在差异(1-4)。为了探索这种差异背后的遗传事件，我们对48个儿科GBM样本的外显子进行了测序。在44%的肿瘤中发现了H3.3-ATRX-DAXX染色质重塑途径的体细胞突变(21/48)。H3F3A编码不依赖复制的组蛋白3变异体H3.3，在31%的肿瘤中观察到反复突变，并导致组蛋白尾部(K27M，G34R/G34V)中两个关键位置的氨基酸替换，涉及关键的调控翻译后修饰。ATRX(α-地中海贫血症/智力低下综合征X连锁)(5)和DAXX(死亡结构域相关蛋白)编码H3.3在着丝点周围异染色质和端粒(6，7)掺入所需的染色质重塑复合体的两个亚单位的突变，在总共31%的样本中被发现，在100%的肿瘤中发现G34R或G34V H3.3突变。在所有病例中，54%的病例发现了体细胞TP53突变，而在H3F3A和/或ATRX突变的样本中，发现了86%的突变。对一大群不同级别和组织学的胶质瘤(n=784)的筛查显示，H3F3A突变是GBM特有的，在儿童和年轻人中高度流行。此外，H3F3A/ATRX-DAXX/TP53突变的存在与端粒的交替延长和特定的基因表达谱密切相关。据我们所知，这是第一份强调人类调节性组蛋白反复突变的报告，我们的数据表明染色质结构缺陷是儿科和年轻人GBM发病的基础。
Glioblastoma multiforme (GBM) is a lethal brain tumour in adults and children. However, DNA copy number and gene expression signatures indicate differences between adult and paediatric cases(1-4). To explore the genetic events underlying this distinction, we sequenced the exomes of 48 paediatric GBM samples. Somatic mutations in the H3.3-ATRX-DAXX chromatin remodelling pathway were identified in 44% of tumours (21/48). Recurrent mutations in H3F3A, which encodes the replication-independent histone 3 variant H3.3, were observed in 31% of tumours, and led to amino acid substitutions at two critical positions within the histone tail (K27M, G34R/G34V) involved in key regulatory post-translational modifications. Mutations in ATRX (alpha-thalassaemia/mental retardation syndrome X-linked)(5) and DAXX (death-domain associated protein), encoding two subunits of a chromatin remodelling complex required for H3.3 incorporation at pericentric heterochromatin and telomeres(6,7), were identified in 31% of samples overall, and in 100% of tumours harbouring a G34R or G34V H3.3 mutation. Somatic TP53 mutations were identified in 54% of all cases, and in 86% of samples with H3F3A and/or ATRX mutations. Screening of a large cohort of gliomas of various grades and histologies (n = 784) showed H3F3A mutations to be specific to GBM and highly prevalent in children and young adults. Furthermore, the presence of H3F3A/ATRX-DAXX/TP53 mutations was strongly associated with alternative lengthening of telomeres and specific gene expression profiles. This is, to our knowledge, the first report to highlight recurrent mutations in a regulatory histone in humans, and our data suggest that defects of the chromatin architecture underlie paediatric and young adult GBM pathogenesis.