Diffuse midline gliomas (DMGs) are aggressive pediatric brain tumors with dismal prognosis due to therapy-resistant tumor growth and invasion. We performed the first integrated histologic/genomic/proteomic analysis of 21 foci from three pontine DMG cases with supratentorial dissemination. Histone H3.3-K27M was the driver mutation, usually at high variant allele fraction due to recurrent chromosome 1q copy number gain, in combination with germline variants in ATM, FANCM and MYCN genes. Both previously reported and novel recurrent copy number variations and somatic pathogenic mutations in chromatin remodeling, DNA damage response and PI3K/MAPK growth pathways were variably detected, either in multiple or isolated foci. Proteomic analysis showed global upregulation of histone H3, lack of H3-K27 trimethylation, and further impairment of polycomb repressive complex 2 by ASXL1 downregulation. Activation of oncogenic pathways resulted from combined upregulation of N-MYC, SOX2, p65/p50 NF-κB and STAT3 transcription factors, EGFR, FGFR2, PDGFRα/β receptor tyrosine kinases, and downregulation of PHLPP1/2, PTEN and p16/INK4A tumor suppressors. Upregulation of SMAD4, PAI-1, CD44, and c-SRC in multiple foci most likely contributed to invasiveness. This integrated comprehensive analysis revealed a complex spatiotemporal evolution in diffuse intrisic pontine glioma, recommending pontine and cerebellar biopsies for accurate populational genetic characterization, and delineated common signaling pathways and potential therapeutic targets. It also revealed an unsuspected activation of a multitude of oncogenic pathways, including cancer cell reprogramming, explaining the resistance of DMG to current therapies.

中文翻译：

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致癌途径的整体激活是弥漫性中线神经胶质瘤治疗抗性的基础。

弥漫性中线神经胶质瘤（DMG）是侵袭性的小儿脑肿瘤，由于对治疗有抗性的肿瘤生长和侵袭，预后不良。我们对3例脑桥DMG幕上播散的21个病灶进行了首次组织学/基因组/蛋白质组学综合分析。组蛋白H3.3-K27M是驱动突变，通常是由于复发性染色体1q拷贝数增加而导致的高等位基因等位基因突变，再加上ATM，FANCM和MYCN基因的种系变异。在多个或孤立的病灶中，均可变地检测到了先前报道的新的复发拷贝数变异和染色质重塑，DNA损伤反应和PI3K / MAPK生长途径中的体细胞致病突变。蛋白质组学分析显示，组蛋白H3整体上调，缺少H3-K27三甲基化，并通过ASXL1下调进一步损害多梳抑制复合物2。致癌途径的激活归因于N-MYC，SOX2，p65 / p50NF-κB和STAT3转录因子，EGFR，FGFR2，PDGFRα/β受体酪氨酸激酶的上调和PHLPP1 / 2，PTEN和p16 / INK4A肿瘤的下调抑制器。在多个病灶中SMAD4，PAI-1，CD44和c-SRC的上调最有可能导致侵袭性。这项综合的综合分析揭示了弥漫性固有性桥脑神经胶质瘤的复杂时空演变，建议对脑桥和小脑活检进行准确的群体遗传学表征，并勾画出常见的信号通路和潜在的治疗靶点。它还揭示了多种致癌途径的意外激活，包括癌细胞重编程，