de Mendonça Fernandes Glaucia Maria, Wang Wesley, Ahmadian Saman Seyed, Jones Daniel, Peng Jing, Giglio Pierre, Venere Monica, Otero José Javier
Departament of Cellular and Molecular Medicine, Florida International University Herbert Wertheim College of Medicine, Miami, FL, USA.
Department of Pathology, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
Acta Neuropathol Commun. 2025 Apr 11;13(1):74. doi: 10.1186/s40478-025-01966-5.
This study characterizes the glioblastoma (GB) epitranscriptomic landscape in patient who evolve to progressive disease (PD) or pseudo-progressive disease (psPD). Novel differences in N6-Methyladenosine (m6A) RNA methylation patterns between these groups are identified in the first biopsy. Retrospective data of patients that were eventually deemed to have progressive disease or pseudoprogressive disease was captured from the electronic health record, and RNA from the first resection specimen was utilized to evaluate N6-methyladenosine (m6A) biomarkers from FFPE samples. Molecular analysis of m6A methylation modified RNA employed ACA-based RNase MazF digestion. After Quantitative Normalization with ComBat to mitigate batch effects, we identifed differentially methylated transcripts and gene expression analyses, co-expression networks analyses with WGCNA, and subsequently performed gene set GO and KEGG enrichment analyses. Enrichments for metabolic biological processes and pathways were identified in our differential methylated transcripts and select module eigengene networks highlighted key co-expressed genes intricately tied to distinct phenotypes/traits in patients that would ultimately be deemed PD or psPD. Our study identified key genes and pathways modified by m6A RNA methylation associated with cell metabolism alterations, highlighting the importance of understanding m6A mechanisms leading to the oncometabolite accumulation governing PD versus psPD patients. Furthermore, these data indicate that epitranscriptomal differences between PD versus psPD are detected early in the disease course.
本研究对演变为进展性疾病(PD)或假性进展性疾病(psPD)的患者的胶质母细胞瘤(GB)表观转录组图谱进行了表征。在首次活检中发现了这些组之间N6-甲基腺苷(m6A)RNA甲基化模式的新差异。从电子健康记录中获取最终被判定为患有进展性疾病或假性进展性疾病的患者的回顾性数据,并利用首次切除标本中的RNA来评估来自福尔马林固定石蜡包埋(FFPE)样本的N6-甲基腺苷(m6A)生物标志物。对m6A甲基化修饰的RNA进行分子分析采用基于ACA的核糖核酸酶MazF消化。在用ComBat进行定量归一化以减轻批次效应后,我们鉴定了差异甲基化转录本并进行基因表达分析,用加权基因共表达网络分析(WGCNA)进行共表达网络分析,随后进行基因集GO和KEGG富集分析。在我们的差异甲基化转录本中鉴定出代谢生物学过程和途径的富集,选定模块特征基因网络突出了与最终被判定为PD或psPD的患者不同表型/特征紧密相关的关键共表达基因。我们的研究确定了由m6A RNA甲基化修饰的与细胞代谢改变相关的关键基因和途径,突出了理解导致控制PD与psPD患者的肿瘤代谢物积累的m6A机制的重要性。此外,这些数据表明,PD与psPD之间的表观转录组差异在疾病进程早期即可检测到。