Department of Molecular Neuropathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China.
Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China.
J Cell Mol Med. 2020 Nov;24(22):13171-13180. doi: 10.1111/jcmm.15924. Epub 2020 Oct 2.
Alternative splicing (AS) is assumed to play important roles in the progression and prognosis of cancer. Currently, the comprehensive analysis and clinical relevance of AS in lower-grade diffuse gliomas have not been systematically addressed. Here, we gathered alternative splicing data of lower-grade diffuse gliomas from SpliceSeq. Based on the Percent Spliced In (PSI) values of 515 lower-grade diffuse glioma patients from the Cancer Genome Atlas (TCGA), we performed subtype-differential AS analysis and consensus clustering to determine robust clusters of patients. A total of 48 050 AS events in 10 787 genes in lower-grade diffuse gliomas were profiled. Subtype-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signalling pathways. Consensus clustering using AS events identified three robust clusters of patients with distinguished pathological and prognostic features. Moreover, each cluster was also associated with distinct genomic alterations. Finally, we developed and validated an AS-related signature with Cox proportional hazards model. The signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Thus, our results indicated that AS events could discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas.
选择性剪接（AS）被认为在癌症的发生和预后中起着重要作用。目前，尚未系统地研究低级别弥漫性神经胶质瘤中 AS 的综合分析和临床相关性。在这里，我们从 SpliceSeq 收集了低级别弥漫性神经胶质瘤的选择性剪接数据。基于癌症基因组图谱（TCGA）中 515 名低级别弥漫性神经胶质瘤患者的 Percent Spliced In（PSI）值，我们进行了亚型差异 AS 分析和共识聚类，以确定具有稳健特征的患者聚类。总共在 10,787 个基因中鉴定出了低级别弥漫性神经胶质瘤中的 48,050 个 AS 事件。亚型差异剪接分析和功能注释表明，剪接基因在许多与癌症相关的生物学表型和信号通路中显著富集。使用 AS 事件进行的共识聚类确定了具有明显病理和预后特征的三个稳健的患者聚类。此外，每个聚类还与不同的基因组改变相关。最后，我们使用 Cox 比例风险模型开发并验证了一个与 AS 相关的特征。该特征与临床和分子特征显著相关，可作为低级别弥漫性神经胶质瘤的独立预后因素。因此，我们的研究结果表明，AS 事件可以区分分子亚型，并对低级别弥漫性神经胶质瘤具有预后影响。
