嘌呤质性星形胶质瘤（PA）是最常见的儿童脑肿瘤，其由突变的丝裂原活化蛋白激酶信号传导所驱动，通常由BRAF基因融合或激活突变引起。尽管5年总体生存率超过95％，但未完全切除的肿瘤复发或进展是一个重大的临床挑战。本研究中，我们采用相似网络融合（SNF）分析结合RNA转录组和基于质谱的蛋白质组学方法，对62名患者的PA组织样本进行了分子特征化。从而，我们发现PA分为两个分子上有明显差异的组，即Group 1和Group 2，并在三个非重叠队列中进行了验证。与Group 2肿瘤的患者相比，Group 1肿瘤的患者年龄显著较小且无进展生存率较差。Ingenuity pathways分析（IPA）和基因集富集分析（GSEA）显示，Group 1肿瘤富集于免疫反应途径，如干扰素信号传导，而Group 2肿瘤则富集于动作电位和神经递质信号传导途径。免疫细胞相关基因签名分析显示Group 1相对于Group 2肿瘤中浸润的T细胞富集。综上所述，PA的多组学结合鉴定出具有生物学上明显差异和预后相关的肿瘤组，可能改善此种单一信号通路驱动的肿瘤类型的风险分层。 © 2023. The Author(s).

Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is driven by aberrant mitogen-activated protein kinase signaling most commonly caused by BRAF gene fusions or activating mutations. While 5-year overall survival rates exceed 95%, tumor recurrence or progression constitutes a major clinical challenge in incompletely resected tumors. Here, we used similarity network fusion (SNF) analysis in an integrative multi-omics approach employing RNA transcriptomic and mass spectrometry-based proteomic profiling to molecularly characterize PA tissue samples from 62 patients. Thereby, we uncovered that PAs segregated into two molecularly distinct groups, namely, Group 1 and Group 2, which were validated in three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and showed worse progression-free survival compared to patients with group 2 tumors. Ingenuity pathways analysis (IPA) and gene set enrichment analysis (GSEA) revealed that Group 1 tumors were enriched for immune response pathways, such as interferon signaling, while Group 2 tumors showed enrichment for action potential and neurotransmitter signaling pathways. Analysis of immune cell-related gene signatures showed an enrichment of infiltrating T Cells in Group 1 versus Group 2 tumors. Taken together, integrative multi-omics of PA identified biologically distinct and prognostically relevant tumor groups that may improve risk stratification of this single pathway driven tumor type.© 2023. The Author(s).