Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.
Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.
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DOI：
10.1007/s00401-015-1478-0
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发表时间：
2015-12
影响因子：
12.7
通讯作者：
Debily MA
中科院分区：
文献类型：
--
作者：
Castel D;Philippe C;Calmon R;Le Dret L;Truffaux N;Boddaert N;Pagès M;Taylor KR;Saulnier P;Lacroix L;Mackay A;Jones C;Sainte-Rose C;Blauwblomme T;Andreiuolo F;Puget S;Grill J;Varlet P;Debily MA
弥漫性桥脑胶质瘤（DIPG）是最严重的儿童实体瘤，在过去的50年里没有取得重大的治疗进展。最近的研究表明，弥漫性中线胶质瘤，H3-K27 M突变，可能包括一个以上的生物实体。该研究的目的是确定最影响其预后的临床和生物学变量。91例经典定义的DIPG患者接受了系统性立体定向活检，并被纳入这项观察性回顾性研究。组蛋白H3基因突变通过免疫化学和直接测序进行评估，而全球基因表达谱和染色体不平衡通过微阵列确定。在诊断和复发时的MRI结果的完整描述与分子分析数据和临床结果相结合。发现除了一个之外的所有DIPG都具有体细胞H3-K27 M突变和/或H3 K27三甲基化的丧失。我们还发现了HIST 2 H3C中的一个新的K27 M突变，以及H3 F3 A中的赖氨酸到异亮氨酸的取代（K27 I），也造成了三甲基化的损失。在H3.3（H3 F3 A）中携带K27 M突变的肿瘤患者对放疗也没有临床反应，复发明显早于H3.1（HIST 1H 3B/C），并且表现出更多的转移性复发。H3.3-K27 M突变的DIPG具有前神经/少突胶质细胞表型和具有PDGFRA激活的促转移基因表达特征，而H3.1-K27 M突变的肿瘤表现出间充质/星形胶质细胞表型和由表达谱和放射学发现支持的促血管生成/缺氧特征。H3 K27改变似乎是DIPG的基础事件，两种主要组蛋白H3变体的突变驱动了两种不同的致癌程序，具有潜在的特异性治疗靶点。本文的在线版本（doi：10.1007/s 00401 -015-1478-0）包含补充材料，可供授权用户使用。
Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study. Histone H3 genes mutations were assessed by immunochemistry and direct sequencing, whilst global gene expression profiling and chromosomal imbalances were determined by microarrays. A full description of the MRI findings at diagnosis and at relapse was integrated with the molecular profiling data and clinical outcome. All DIPG but one were found to harbour either a somatic H3-K27M mutation and/or loss of H3K27 trimethylation. We also discovered a novel K27M mutation in HIST2H3C, and a lysine-to-isoleucine substitution (K27I) in H3F3A, also creating a loss of trimethylation. Patients with tumours harbouring a K27M mutation in H3.3 (H3F3A) did not respond clinically to radiotherapy as well, relapsed significantly earlier and exhibited more metastatic recurrences than those in H3.1 (HIST1H3B/C). H3.3-K27M-mutated DIPG have a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature with PDGFRA activation, while H3.1-K27M-mutated tumours exhibit a mesenchymal/astrocytic phenotype and a pro-angiogenic/hypoxic signature supported by expression profiling and radiological findings. H3K27 alterations appear as the founding event in DIPG and the mutations in the two main histone H3 variants drive two distinct oncogenic programmes with potential specific therapeutic targets. The online version of this article (doi:10.1007/s00401-015-1478-0) contains supplementary material, which is available to authorized users.