文章：

独特的遗传和表观遗传机制驱动小儿弥漫性高级别胶质瘤

Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma

原文发布日期：2014-09-18

DOI: 10.1038/nrc3811

类型: Review Article

开放获取: 否

要点：

1. Diffuse high-grade gliomas (HGGs) carry a dismal prognosis in both children and adults; however, genome-wide molecular analyses have shown that the disease pathogenesis differs significantly between these age groups.
2. There are at least several distinct subgroups of paediatric diffuse HGG based on clinical features and recurrent mutations.
3. Diffuse intrinsic pontine gliomas (DIPGs) arise in the brainstem, occur almost exclusively in children and are incurable.
4. Aberrant epigenetic regulation has an important role in paediatric HGGs, with 'hotspot' K27M histone H3 mutations found in nearly 80% of DIPGs, and alternative G34R or G34V mutations found in paediatric HGGs of the cerebral hemispheres.
5. Recurrent mutations of the bone morphogenetic protein (BMP) receptor activin receptor type 1 (ACVR1; also known as ALK2) are restricted to the youngest patients with DIPG, highlighting crucial connections between development and gliomagenesis.
6. HGGs in children who are less than three years of age contain very few genomic abnormalities and recurrent gene fusions, and have a better outcome than HGGs in older children.
7. An improved understanding of the oncogenic mutations driving paediatric diffuse HGG has identified new potential therapeutic targets and shown that different strategies will be needed to combat this disease in children and adults.

要点翻译：

1. 弥漫性高级别胶质瘤在儿童和成人患者中均预后不良；然而全基因组分子分析显示，该疾病的发病机制在不同年龄群体中存在显著差异。
2. 基于临床特征和反复出现的基因突变，儿童弥漫性高级别胶质瘤至少存在数个明显亚群。
3. 弥漫内生型脑桥胶质瘤发生于脑干，几乎仅见于儿童群体且目前无法治愈。
4. 表观遗传调控异常在儿童高级别胶质瘤中起着重要作用——约80%的弥漫内生型脑桥胶质瘤存在K27M组蛋白H3"热点"突变，而大脑半球的儿童高级别胶质瘤则存在G34R或G34V替代突变。
5. 骨形态发生蛋白受体激活素受体1型（ACVR1，亦称ALK2）的反复突变仅见于最年幼的弥漫内生型脑桥胶质瘤患者，这揭示了发育过程与胶质瘤生成之间的关键联系。
6. 三岁以下婴幼儿的高级别胶质瘤基因组异常极少，且缺乏反复出现的基因融合，其预后较年长儿童患者更佳。
7. 通过对驱动儿童弥漫性高级别胶质瘤的致癌突变机制的深入理解，研究人员已识别出新的潜在治疗靶点，并表明需要采用不同于成人患者的治疗策略来对抗该疾病。

英文摘要：

Diffuse high-grade gliomas (HGGs) of childhood are a devastating spectrum of disease with no effective cures. The two-year survival for paediatric HGG ranges from 30%, for tumours arising in the cerebral cortex, to less than 10% for diffuse intrinsic pontine gliomas (DIPGs), which arise in the brainstem. Recent genome-wide studies provided abundant evidence that unique selective pressures drive HGG in children compared to adults, identifying novel oncogenic mutations connecting tumorigenesis and chromatin regulation, as well as developmental signalling pathways. These new genetic findings give insights into disease pathogenesis and the challenges and opportunities for improving patient survival in these mostly incurable childhood brain tumours.

摘要翻译： 

儿童弥漫性高级别胶质瘤（HGG）是一类预后极差的疾病，目前尚无有效治愈手段。其两年生存率：发生于大脑皮层的肿瘤约为30%，发生于脑干的弥漫性内生型脑桥胶质瘤（DIPG）则不足10%。近期全基因组研究提供了大量证据，表明儿童HGG与成人HGG受不同选择压力驱动，发现连接肿瘤发生与染色质调控以及发育信号通路的新型致癌突变。这些新遗传发现为理解疾病发病机制、改善这类基本无法治愈的儿童脑瘤患者生存带来了挑战与机遇。

原文链接：

Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma