Genome-Wide Analysis of Prognostic Alternative Splicing Signature and Splicing Factors in Lung Adenocarcinoma

Abstract

Analysis of The Cancer Genome Atlas data revealed that alternative splicing (AS) events could serve as prognostic biomarkers in various cancer types. This study examined lung adenocarcinoma (LUAD) tissues for AS and assessed AS events as potential indicators of prognosis in our cohort. RNA sequencing and bioinformatics analysis were performed. We used SUPPA2 to analyze the AS profiles. Using univariate Cox regression analysis, overall survival (OS)-related AS events were identified. Genes relating to the OS-related AS events were imported into Cytoscape, and the CytoHubba application was run. OS-related splicing factors (SFs) were explored using the log-rank test. The relationship between the percent spliced-in value of the OS-related AS events and SF expression was identified by Spearman correlation analysis. We found 1957 OS-related AS events in 1151 genes, and most were protective factors. Alternative first exon splicing was the most frequent type of splicing event. The hub genes in the gene network of the OS-related AS events were FBXW11, FBXL5, KCTD7, UBB and CDC27. The area under the curve of the MIX prediction model was 0.847 for 5-year survival based on seven OS-related AS events. Overexpression of SFs CELF2 and SRSF5 was associated with better OS. We constructed a correlation network between SFs and OS-related AS events. In conclusion, we identified prognostic predictors using AS events that stratified LUAD patients into high- and low-risk groups. The discovery of the splicing networks in this study provides an insight into the underlying mechanisms.

Keywords

• lung adenocarcinoma
• RNA sequencing
• alternative splicing
• splicing factor