Medulloblastomas (MBs) are malignant pediatric brain tumors that are molecularly and clinically heterogenous. The application of omics technologies—mainly studying nucleic acids—has significantly improved MB classification and stratification, but treatment options are still unsatisfactory. The proteome and their N-glycans hold the potential to discover clinically relevant phenotypes and targetable pathways. We compile a harmonized proteome dataset of 167 MBs and integrate findings with DNA methylome, transcriptome and N-glycome data. We show six proteome MB subtypes, that can be assigned to two main molecular programs: transcription/translation (pSHHt, pWNT and pG3myc), and synapses/immunological processes (pSHHs, pG3 and pG4). Multiomic analysis reveals different conservation levels of proteome features across MB subtypes at the DNA methylome level. Aggressive pGroup3myc MBs and favorable pWNT MBs are most similar in cluster hierarchies concerning overall proteome patterns but show different protein abundances of the vincristine resistance-associated multiprotein complex TriC/CCT and of N-glycan turnover-associated factors. The N-glycome reflects proteome subtypes and complex-bisecting N-glycans characterize pGroup3myc tumors. Our results shed light on targetable alterations in MB and set a foundation for potential immunotherapies targeting glycan structures.

髓母细胞瘤（MB）是一种在分子和临床上具有异质性的恶性儿童脑肿瘤。组学技术（主要是研究核酸）的应用显着改善了MB的分类和分层，但治疗方案仍然不能令人满意。蛋白质组及其 N-聚糖具有发现临床相关表型和可靶向途径的潜力。我们编译了 167 MB 的统一蛋白质组数据集，并将研究结果与 DNA 甲基化组、转录组和 N-糖组数据相整合。我们展示了六种蛋白质组 MB 亚型，它们可以分配给两个主要分子程序：转录/翻译（pSHHt、pWNT 和 pG3myc）和突触/免疫过程（pSHHs、pG3 和 pG4）。多组学分析揭示了在 DNA 甲基化水平上跨 MB 亚型的蛋白质组特征的不同保守水平。积极的 pGroup3myc MB 和有利的 pWNT MB 在总体蛋白质组模式的簇层次结构中最相似，但显示长春新碱抗性相关的多蛋白复合物 TriC/CCT 和 N-聚糖周转相关因子的不同蛋白质丰度。 N-糖组反映了蛋白质组亚型，复合二等分 N-聚糖表征了 pGroup3myc 肿瘤。我们的结果揭示了 MB 的可靶向改变，并为针对聚糖结构的潜在免疫疗法奠定了基础。