Zeng Yu, Zhang Peidong, Wang Xizhao, Wang Ke, Zhou Mingfeng, Long Hao, Lin Jie, Wu Zhiyong, Gao Liang, Song Ye
Department of Neurosurgery, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, People's Republic of China.
Department of Neurosurgery, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong Province, People's Republic of China.
J Mol Neurosci. 2020 Oct;70(10):1484-1492. doi: 10.1007/s12031-020-01581-0. Epub 2020 Jun 29.
Alternative splicing (AS) is a ubiquitous mechanism in which pre-mRNA can be spliced into divergent variants and involved in carcinogenesis and progression in several cancers. In the present study, we systematically profiled prognostic AS signatures involving both low grade glioma (LGG) and glioblastoma (GBM) and investigated the association of AS signatures with tumor grade and IDH1 status in glioma. Percent spliced in (PSI) values and corresponding clinical data were obtained from TCGA SpliceSeq and TCGA data portal, respectively. Prognostic AS signatures were identified using univariate and stepwise multivariate Cox regression. Heatmap analysis was performed based on prognostic AS signatures. A prognostic signature was established with 69 and 88 AS events, including specific splicing events of MUTYH, STEAP3, and CTNNB1, in LGG and GBM cohorts, respectively. The area under the curve (AUC) of the prediction model was 0.968 at 2000 days of overall survival (OS) in the LGG cohort and 0.966 at 450 days of OS in the GBM cohort. In addition, these prognostic AS signatures could complement current molecular classification, such as IDH1 mutation, 1p/19q codeletion, and ATRX loss, of glioma and further identify potential subgroups of glioma with the same molecular features. In conclusion, our study systematically profiled prognostic AS events involving both low grade glioma and glioblastoma for the first time, which also shed light on the crosstalk between AS signatures and molecular features of glioma.
可变剪接（AS）是一种普遍存在的机制，通过该机制前体mRNA可以剪接成不同的变体，并参与多种癌症的发生和进展。在本研究中，我们系统地分析了涉及低级别胶质瘤（LGG）和胶质母细胞瘤（GBM）的预后AS特征，并研究了AS特征与胶质瘤肿瘤分级和异柠檬酸脱氢酶1（IDH1）状态的关联。分别从TCGA SpliceSeq和TCGA数据门户获得剪接百分率（PSI）值和相应的临床数据。使用单变量和逐步多变量Cox回归确定预后AS特征。基于预后AS特征进行热图分析。在LGG和GBM队列中分别建立了包含69个和88个AS事件的预后特征，包括MUTYH、STEAP3和CTNNB1的特定剪接事件。在LGG队列中，预测模型在总生存期（OS）2000天时的曲线下面积（AUC）为0.968，在GBM队列中，OS 450天时的AUC为0.966。此外，这些预后AS特征可以补充当前胶质瘤的分子分类，如IDH1突变、1p/19q共缺失和ATRX缺失，并进一步识别具有相同分子特征的潜在胶质瘤亚组。总之，我们的研究首次系统地分析了涉及低级别胶质瘤和胶质母细胞瘤的预后AS事件，这也为AS特征与胶质瘤分子特征之间的相互作用提供了线索。
