Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes ‘pedGBM_MYCN’ (enriched for MYCN amplification), ‘pedGBM_RTK1’ (enriched for PDGFRA amplification) and ‘pedGBM_RTK2’ (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.

小儿胶质母细胞瘤（pedGBM）是一种极具侵略性的小儿脑肿瘤，约占儿童所有中枢神经系统肿瘤的6％。约有pedGBM的一半在组蛋白3变体或IDH1 / 2中很少出现复发性体细胞突变。pedGBM的其余子集是高度异质的，并显示出各种基因组和表观遗传学特征。在当前研究中，我们旨在进一步分层通过全基因组分子谱分析评估的H3- / IDH野生型（wt）pedGBM队列。结果，我们确定了这些肿瘤的三种分子亚型，它们的基因组和表观遗传学特征以及它们的临床行为不同。我们将这些亚型指定为“ pedGBM_MYCN”（丰富了MYCN扩增），“ pedGBM_RTK1”（丰富了PDGFRA扩增）和“ pedGBM_RTK2”（富含EGFR）放大）。这些分子亚型与显着不同的预后相关，即pedGBM_RTK2肿瘤显示明显更长的生存时间（中位OS为44个月），pedGBM_MYCN显示极差的预后（中位OS为14个月），并且pedGBM_RTK1肿瘤具有中等预后。此外，H3- / IDH-wt pedGBM的各种分子亚型与成年同龄动物明显不同，从而突显了它们的生物学独特性。总之，我们的研究表明H3- / IDH-wt pedGBM在DNA甲基化和细胞遗传学改变方面具有显着的分子异质性。H3- / IDH-wt pedGBM的三种分子亚型的识别进一步揭示了与生物学参数和临床结果的密切相关性，因此可以预测对标准治疗方案的反应，