Department of Neurology, Xiangya Hospital, Central South University, Changsha, China.
Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, China.
Cancer Med. 2023 Jan;12(1):760-788. doi: 10.1002/cam4.4913. Epub 2022 Jun 6.
Glioma is one of the most malignant brain tumors and diseases. N6-methyladenosine modification (m6A) is the most abundant and prevalent internal chemical modification of mRNA and long non-coding RNAs (lncRNAs) in eukaryotes. Nevertheless, the correlated pathways and clinical utilization of m6A-related lncRNAs have not been fully evaluated in glioma.
Public RNA-sequencing and clinical annotation data were retrieved from TCGA, CGGA and GEO database. Differential expression analysis and univariate Cox regression analysis were performed to identify the m6A-related and differentially expressed lncRNAs with prognostic function (m6A-DELPF). The consensus clustering was performed to identify the expression pattern of m6A-DELPF. LASSO Cox regression analysis was performed to construct the lncRNA-based signature. The CIBERSORT and ESTIMATE algorithms were performed to analyze immune infiltration and tumor microenvironment, respectively. Immunotherapy sensitivity analysis was performed using data from TCIA. The small molecule drugs prediction analysis was performed using The Connectivity Map (CMap) database and STITCH database. A competing endogenous RNAs (ceRNA) network was constructed based on miRcode, miRDB, miRTarBase, TargetScan database.
Two clusters (cluster1 and cluster2) were identified after unsupervised cluster analysis based on m6A-DELPF. Additionally, a 15-gene prognostic signature namely m6A-DELPFS was constructed. Analyses of epithelial-mesenchymal-transition score, tumor microenvironment, immune infiltration, clinical characterization analysis, and putative drug prediction were performed to confirm the clinical utility and efficacy of m6A-DELPFS. The potential mechanisms including tumor immune microenvironment of m6A-DELPF influence the initiation and progression of glioma. A clinically accessible nomogram was also constructed based on the m6A-DELPF and other survival-relevant clinical parameters. Two miRNAs and 114 mRNAs were identified as the downstream of seven m6A-related lncRNAs in a ceRNA network.
Our present research confirmed the clinical value of m6A related lncRNAs and their high correlation with tumor immunity, tumor microenvironment, tumor mutation burden and drug sensitivity in glioma.
神经胶质瘤是最恶性的脑肿瘤和疾病之一。N6-甲基腺苷修饰（m6A）是真核生物中 mRNA 和长链非编码 RNA（lncRNA）最丰富和普遍的内部化学修饰。然而，m6A 相关 lncRNA 的相关途径和临床应用尚未在神经胶质瘤中得到充分评估。
从 TCGA、CGGA 和 GEO 数据库中检索公共 RNA 测序和临床注释数据。进行差异表达分析和单变量 Cox 回归分析，以鉴定具有预后功能的 m6A 相关差异表达 lncRNA（m6A-DELPF）。进行共识聚类分析以鉴定 m6A-DELPF 的表达模式。进行 LASSO Cox 回归分析构建基于 lncRNA 的特征。使用 CIBERSORT 和 ESTIMATE 算法分别分析免疫浸润和肿瘤微环境。使用 TCIA 中的数据进行免疫治疗敏感性分析。使用 The Connectivity Map（CMap）数据库和 STITCH 数据库进行小分子药物预测分析。基于 miRcode、miRDB、miRTarBase、TargetScan 数据库构建竞争性内源 RNA（ceRNA）网络。
基于 m6A-DELPF 进行无监督聚类分析后，鉴定出两个聚类（cluster1 和 cluster2）。此外，构建了一个由 15 个基因组成的预后特征命名为 m6A-DELPFS。进行上皮-间充质转化评分、肿瘤微环境、免疫浸润、临床特征分析和潜在药物预测分析，以确认 m6A-DELPFS 的临床实用性和疗效。m6A-DELPF 影响肿瘤免疫微环境的潜在机制可能影响神经胶质瘤的发生和发展。还基于 m6A-DELPF 和其他与生存相关的临床参数构建了一个临床可访问的列线图。在 ceRNA 网络中，确定了七个 m6A 相关 lncRNA 的下游两个 miRNA 和 114 个 mRNA。
本研究证实了 m6A 相关 lncRNA 的临床价值及其与神经胶质瘤中的肿瘤免疫、肿瘤微环境、肿瘤突变负荷和药物敏感性的高度相关性。
