Abstract
Purpose: Alternative splicing (AS) was reported to play a vital role in development and progression of glioblastoma (GBM), the most common and fatal brain tumor. Systematic analysis of survival-associated AS event profiles and prognostic prediction model based on multiple AS events in GBM was needed.Methods: Genome-wide AS and RNA sequencing profiles were generated in 152 patients with GBM in the cancer genome atlas (TCGA). Prognosis-associated AS events were screened by integrated Cox regression analysis to construct the prognostic risk score model in the training cohort (n = 101). The AS-based signature and clinicopathologic parameters were applied to construct a prognostic nomogram for 0.5-, 1-, and 3-year OS prediction. Finally, the regulatory networks between prognostic AS events and splicing factors (SFs) were constructed.Results: A total of 1,598 prognosis-related AS events from 1,183 source genes were determined. Eight prognostic risk score model based on integrated AS events and 7 AS types were established, respectively. Concordance index (C-index) and receiver operating characteristic (ROC) curve analysis demonstrated powerful ability in distinguishing patients' outcomes. Only Alternate Donor site (AD) and Exon Skip (ES) signature out of the eight types of AS signature were identified as independent prognostic factors for GBM, which was validated in the internal validation cohort. The nomogram with age, new event, pharmaceutical therapy, radiation therapy, AD signature and ES signature were constructed, with C-index of 0.892 (95% CI, 0.853–0.931; P = 5.13 × 10−15). Calibration plots, ROC, and decision curve analysis suggested excellent predictive performance for the nomogram in both TCGA training cohort and validation cohort. Splicing network indicated distinguished correlations between prognostic AS events and SFs in GBM patients.Conclusions: AS-based prediction model could serve as a promising prognostic predictor and potential therapeutic target for GBM, facilitating better treatment strategies in clinical practice.
Highlights
Glioma is the most common primary tumor of the central nervous system, accounting for 40–50% of brain tumors in the United States from 2010 to 2014 [1]
Alternate Donor site (AD) and Exon Skip (ES) signature out of the eight types of Alternative splicing (AS) signature were identified as independent prognostic factors for GBM, which was validated in the internal validation cohort
The nomogram with age, new event, pharmaceutical therapy, radiation therapy, AD signature and ES signature were constructed, with Concordance index (C-index) of 0.892
Summary
Glioma is the most common primary tumor of the central nervous system, accounting for 40–50% of brain tumors in the United States from 2010 to 2014 [1]. Glioblastoma (GBM), corresponding to WHO grade IV, is the most commonly occurring and most lethal type of glioma, generally exhibiting a 5-year overall survival (OS) rate of ∼5% [1, 2]. Despite remarkable advances in the development of managements for GBM, including surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy, the optimal treatment strategy remains controversial [3]. It has been reported in the literature that age, extent of resection, and various molecular alterations can serve as prognostic factors for GBM [4,5,6]. Exploring the underlying molecular mechanisms and investigating prognostic biomarkers and predictors of therapeutic response are indispensable for the treatment of GBM patients
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