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结构变异形成儿童高级别胶质瘤的驱动因子组合和结果

原文发布日期：2022-07-04

英文摘要：

摘要翻译：

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结构变异形成儿童高级别胶质瘤的驱动因子组合和结果

Structural variants shape driver combinations and outcomes in pediatric high-grade glioma

原文发布日期：2022-07-04

英文摘要：

We analyzed the contributions of structural variants (SVs) to gliomagenesis across 179 pediatric high-grade gliomas (pHGGs). The most recurrent SVs targeted MYC isoforms and receptor tyrosine kinases (RTKs), including an SV amplifying a MYC enhancer in 12% of diffuse midline gliomas (DMG), indicating an underappreciated role for MYC in pHGG. SV signature analysis revealed that tumors with simple signatures were TP53 wild type (TP53WT) but showed alterations in TP53 pathway members PPM1D and MDM4. Complex signatures were associated with direct aberrations in TP53, CDKN2A and RB1 early in tumor evolution and with later-occurring extrachromosomal amplicons. All pHGGs exhibited at least one simple-SV signature, but complex-SV signatures were primarily restricted to subsets of H3.3K27M DMGs and hemispheric pHGGs. Importantly, DMGs with complex-SV signatures were associated with shorter overall survival independent of histone mutation and TP53 status. These data provide insight into the impact of SVs on gliomagenesis and the mechanisms that shape them.

摘要翻译：

我们分析了179例儿童高级别胶质母细胞瘤（pHGGs）中结构变异（SVs）对胶质母细胞前体细胞生长（gliomagenesis）的贡献。发现突变频率最高的区域靶向MYC异构体和受体酪氨酸激酶（RTKs），其中12%的扩散性中间胶质母细胞瘤（DMG）具有增强MYC增强子的结构变异。结构变异签名分析显示，肿瘤样本中单一突变型谱对应于TP53野生型（TP53WT），但涉及PPM1D和MDM4的突变；复杂的突变型谱与肿瘤早期发生时TP53、CDKN2A和RB1的直接异常有关，并与跨染色体额外拷贝相关联。所有pHGG样本中至少有一个单一突变型谱，而复杂突变型谱主要限于H3.3K27M DMGs和半球性pHGGs的亚组。值得注意的是，具有复杂突变型谱的DMGs的总生存期较短，这一结果与表观遗传变异和TP53状态无关。这些数据为结构变异对胶质母细胞前体细胞生长的影响及影响其形成的机制提供了见解。