4级胶质瘤是目前最具侵袭性和不可治愈的脑肿瘤，在成年患者中的中位生存期为一年。阐明其侵袭性相关的新型转录组和表观遗传学改变，可能有助于改善临床预后。为了鉴定4级胶质瘤相关的5-羟甲基脱氧胞苷（5hmC）和转录组特征及其相互作用，我们对61例4级胶质瘤患者和9名正常对照者的组织样本进行了全基因组5hmC和转录组的分析，以进行差异和共调控/共修饰分析。我们采用机器学习算法基于转录组特征和基因区域上（启动子、基因本体）的5hmC修饰以及脑源性组蛋白标记开发了关于总体生存的预后模型。尽管全局降低，大部分差异5hmC特征在4级胶质瘤中的修饰水平比正常对照组更高。此外，在基因启动子区域或基因本体区域的5hmC修饰与基因表达之间的双向关联在4级胶质瘤中受到极大干扰，不考虑IDH1突变状态。表型相关的共调控5hmC-5hmC模块和5hmC-mRNA模块不仅富集于与4级胶质瘤发病机制相关的不同分子通路中，而且具有与IDH1突变状态相当的预后意义。最后，最佳的5hmC模型相对于常规预后因素IDH1（c-index = 57%）能够以更高的准确度（c-index = 74%）预测患者生存，捕捉与IDH1突变状态和基于基因表达的分子亚型无关的肿瘤分子特征。基于5hmC的预后模型可以为4级胶质瘤患者提供强有力的生存预测工具，可能优于目前的预后因素如IDH1突变。5hmC与基因表达之间的相互作用揭示了4级胶质瘤分子异质性的另一个复杂层面，为鉴定新的治疗目标提供了机会。© 2023. BioMed Central Ltd., Springer Nature 的一部分。

Grade 4 glioma is the most aggressive and currently incurable brain tumor with a median survival of one year in adult patients. Elucidating novel transcriptomic and epigenetic contributors to the molecular heterogeneity underlying its aggressiveness may lead to improved clinical outcomes.To identify grade 4 glioma -associated 5-hydroxymethylcytosine (5hmC) and transcriptomic features as well as their cross-talks, genome-wide 5hmC and transcriptomic profiles of tissue samples from 61 patients with grade 4 gliomas and 9 normal controls were obtained for differential and co-regulation/co-modification analyses. Prognostic models on overall survival based on transcriptomic features and the 5hmC modifications summarized over genic regions (promoters, gene bodies) and brain-derived histone marks were developed using machine learning algorithms.Despite global reduction, the majority of differential 5hmC features showed higher modification levels in grade 4 gliomas as compared to normal controls. In addition, the bi-directional correlations between 5hmC modifications over promoter regions or gene bodies and gene expression were greatly disturbed in grade 4 gliomas regardless of IDH1 mutation status. Phenotype-associated co-regulated 5hmC-5hmC modules and 5hmC-mRNA modules not only are enriched with different molecular pathways that are indicative of the pathogenesis of grade 4 gliomas, but also are of prognostic significance comparable to IDH1 mutation status. Lastly, the best-performing 5hmC model can predict patient survival at a much higher accuracy (c-index = 74%) when compared to conventional prognostic factor IDH1 (c-index = 57%), capturing the molecular characteristics of tumors that are independent of IDH1 mutation status and gene expression-based molecular subtypes.The 5hmC-based prognostic model could offer a robust tool to predict survival in patients with grade 4 gliomas, potentially outperforming existing prognostic factors such as IDH1 mutations. The crosstalk between 5hmC and gene expression revealed another layer of complexity underlying the molecular heterogeneity in grade 4 gliomas, offering opportunities for identifying novel therapeutic targets.© 2023. BioMed Central Ltd., part of Springer Nature.