Systematic Profiling of Alternative Splicing in Lower-Grade Diffuse Gliomas

Background: 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 has not been systematically addressed. Methods: AS data were obtained from the SpliceSeq database, and the clinical information of glioma patients was downloaded from The Cancer Genome Atlas (TCGA). Significance analysis of microarray (SAM) was performed to identify differential AS events among subgroups. Unsupervised consensus clustering was used for class discovery based on the comparison of AS events. Cox proportional hazards model was applied to develop an AS-related signature for prognostic prediction. Results: Totally, 48050 AS events of 10787 genes in lower-grade diffuse gliomas (n=515) were profiled. Subgroup-differential splicing analysis and functional annotation revealed that spliced genes were significantly enriched in numerous cancer-related biological phenotypes and signaling pathways. Consensus clustering of AS events identified three robust clusters of patients with distinguished molecular and prognostic features. Based on 445 AS events correlated with prognosis, an 18-AS event signature was built with Cox proportional hazards model. Kaplan-Meier analysis found that the acquired signature could differentiate the outcome of low and high-risk cases. Moreover, the signature, significantly associated with clinical and molecular features, could serve as an independent prognostic factor for lower-grade diffuse gliomas. Further analysis found that cases with high and low-risk scores showed distinct patterns of genomic alterations. Conclusion: Our results indicate that AS events are able to discriminate molecular subtypes and have prognostic impact in lower-grade diffuse gliomas. Funding Statement: This work was supported by National Natural Science Foundation of China (NSFC)/Research Grants Council (RGC) Joint Research Scheme (81761168038), the National Key Research and Development Plan (No. 2016YFC0902500) and National Natural Science Foundation of China (81672479, 81773208). Declaration of Interests: The authors have no conflicts of interest to declare. Ethics Approval Statement: All of these tissue samples and clinicopathologic information were collected with informed consent. The study was conducted in accordance with the Declaration of Helsinki. Study protocols were approved by the ethics committees of the participating institutions.