Research Paper Volume 11, Issue 13 pp 4720—4735

Alternative splicing events are prognostic in hepatocellular carcinoma

Qi-Feng Chen 1, 2, 3, *, , Wang Li 1, *, , Peihong Wu 1, , Lujun Shen 1, 2, 3, , Zi-Lin Huang 1, ,

  • 1 Department of Medical Imaging and Interventional Radiology, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong 510060, P.R. China
  • 2 State Key Laboratory of Oncology in South China, Guangzhou, Guangdong 510060, P.R. China
  • 3 Collaborative Innovation Center for Cancer Medicine, Guangzhou, Guangdong 510060, P.R. China
* Equal contribution

received: April 24, 2019 ; accepted: July 1, 2019 ; published: July 13, 2019 ;

https://doi.org/10.18632/aging.102085
How to Cite

Copyright: Chen et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Alternative splicing events (ASEs) play a role in cancer development and progression. We investigated whether ASEs are prognostic for overall survival (OS) in hepatocellular carcinoma (HCC). RNA sequencing data was obtained for 343 patients included in The Cancer Genome Atlas. Matched splicing event data for these patients was then obtained from the TCGASpliceSeq database, which includes data for seven types of ASEs. Univariate and multivariate Cox regression analysis demonstrated that 3,814 OS-associated splicing events (OS-SEs) were correlated with OS. Prognostic indices were developed based on the most significant OS-SEs. The prognostic index based on all seven types of ASEs (PI-ALL) demonstrated superior efficacy in predicting OS of HCC patients at 2,000 days compared to those based on single ASE types. Patients were stratified into two risk groups (high and low) based on the median prognostic index. Kaplan-Meier survival analysis demonstrated that PI-ALL had the greatest capacity to distinguish between patients with favorable vs. poor outcomes. Finally, univariate Cox regression analysis demonstrated that the expression of 23 splicing factors was correlated with OS-SEs in the HCC cohort. Our data indicate that a prognostic index based on ASEs is prognostic for OS in HCC.

Abbreviations

AS: alternative splicing; PI: prognostic index; HCC: hepatocellular carcinoma; SE: splicing events; OS: overall survival; SF: splicing factor; ASE: alternative splicing event; TCGA: The Cancer Genome Atlas; ES: exon skip; ME: mutually exclusive exons; RI: retained intron; AP: alternate promoter; AT: alternate terminator; AD: alternate donor site; AA: alternate acceptor site; PSI: Percent-Spliced-In; VEGF: vascular endothelial growth factor; ROC: receiver operating characteristic curve; HR: hazard ratio; CI: confidence interval; AUC: area under the ROC curve; GO: Gene Ontology; KEGG: Kyoto Encyclopedia of Genes and Genomes; KM: Kaplan–Meier; ANOVA: analysis of variance.