结构变异影响儿童高级别胶质瘤的驱动基因组合和预后。
Structural variants shape driver combinations and outcomes in pediatric high-grade glioma.
机构信息
Department of Cancer Biology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA.
Broad Institute of MIT and Harvard, Cambridge, MA, USA.
出版信息
Nat Cancer. 2022 Aug;3(8):994-1011. doi: 10.1038/s43018-022-00403-z. Epub 2022 Jul 4.
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 (TP53) 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 H3.3 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.
我们分析了 179 例儿童高级别胶质瘤 (pHGG) 中结构变异 (SV) 对胶质瘤发生的贡献。最常见的 SV 靶向 MYC 异构体和受体酪氨酸激酶 (RTKs)，包括在 12%弥漫性中线胶质瘤 (DMG) 中扩增 MYC 增强子的 SV，表明 MYC 在 pHGG 中具有被低估的作用。SV 特征分析显示，具有简单特征的肿瘤为 TP53 野生型 (TP53)，但在 TP53 通路成员 PPM1D 和 MDM4 中存在改变。复杂特征与 TP53、CDKN2A 和 RB1 的直接异常有关，这些异常发生在肿瘤进化的早期，与后来发生的染色体外扩增子有关。所有 pHGG 至少表现出一种简单-SV 特征，但复杂-SV 特征主要局限于 H3.3 DMG 和半球形 pHGG 亚组。重要的是，具有复杂-SV 特征的 DMG 与较短的总生存期相关，与组蛋白突变和 TP53 状态无关。这些数据提供了对 SV 对胶质瘤发生的影响以及形成它们的机制的深入了解。
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