Role of alternative splicing signatures in the prognosis of glioblastoma

Abstract

Background: Increasing evidence has validated the crucial role of alternative splicing (AS) in tumors. However, comprehensive investigations on the entirety of AS and their clinical value in glioblastoma (GBM) are lacking.

Methods: The AS profiles and clinical survival data related to GBM were obtained from The Cancer Genome Atlas database. Univariate and multivariate Cox regression analyses were performed to identify survival-associated AS events. A risk score was calculated, and prognostic signatures were constructed using seven different types of independent prognostic AS events, respectively. The Kaplan-Meier estimator was used to display the survival of GBM patients. The receiver operating characteristic curve was applied to compare the predictive efficacy of each prognostic signature. Enrichment analysis and protein interactive networks were conducted using the gene symbols of the AS events to investigate important processes in GBM. A splicing network between splicing factors and AS events was constructed to display the potential regulatory mechanism in GBM.

Results: A total of 2355 survival-associated AS events were identified. The splicing prognostic model revealed that patients in the high-risk group have worse survival rates than those in the low-risk group. The predictive efficacy of each prognostic model showed satisfactory performance; among these, the Alternate Terminator (AT) model showed the best performance at an area under the curve (AUC) of 0.906. Enrichment analysis uncovered that autophagy was the most enriched process of prognostic AS gene symbols in GBM. The protein network revealed that UBC, VHL, KCTD7, FBXL19, RNF7, and UBE2N were the core genes in GBM. The splicing network showed complex regulatory correlations, among which ELAVL2 and SYNE1_AT_78181 were the most correlated (r = -.506).

Conclusions: Applying the prognostic signatures constructed by independent AS events shows promise for predicting the survival of GBM patients. A splicing regulatory network might be the potential splicing mechanism in GBM.

Keywords: TCGA; alternative splicing; glioblastoma; prognosis; prognostic signature.