Identification of Prognostic Signatures of Alternative Splicing in Glioma
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Identification of Prognostic Signatures of Alternative Splicing in Glioma Yu Zeng 1,2 & Peidong Zhang 2,3 & Xizhao Wang 4 & Ke Wang 1 & Mingfeng Zhou 2 & Hao Long 2 & Jie Lin 2 & Zhiyong Wu 2 & Liang Gao 1 & Ye Song 2 Received: 1 January 2020 / Accepted: 13 May 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Alternative splicing . Low grade glioma . Glioblastoma . Prognostic signature . Grade . Molecular features
Introduction In the United States, the leading cause of cancer death among men aged 1) AS events in the GBM cohort; (b–h) Forest plots of HRs involving the top 20 most significantly OS-associated AS events regarding the AA (b), AD (c), AP (d), AT (e), ES (f), ME (g), and RI (h) splicing types in the
GBM cohort, respectively. P-values are indicated by the dot size on the side. HR = hazard ratio, OS = overall survival, AA = alternate acceptor site, AD = alternate donor site, AP = alternate promoter, AT = alternate terminator, ES = exon skip, ME = mutually exclusive exons, RI = retained intron
had only one AS event in the GBM cohort, and only three genes had up to three OS-associated AS events (Fig. 4b). On the other hand, single genes with multiple AS events were much more common in the LGG cohort, with up to four OS-associated AS events involving a single gene (Fig. 4a). Further attention is required to determine if those parent genes with multiple OS-associated AS events, such as NAP1L1, UBE2D3, and HOPX, play a more pivotal role in glioma progression than previously
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