Systematic Identification of Survival-Associated Alternative mRNA Splicing for Pancreatic Ductal Adenocarcinoma

Abstract

Background: Alternative splicing (AS) is deemed as a pivotal mechanism for post-transcriptional modification and protein diversity. Multiple studies have shown that cancer-specific AS alterations influence clinical outcome. We aimed to profile prognostic alternative mRNA splicing for pancreatic ductal adenocarcinoma (PDAC). Methods: RNA-sequencing data and clinical information of PDAC patients were downloaded from TCGA database, and the percent-spliced-in (PSI) data of AS was obtained from the SpliceSeq database. We selected overall survival (OS)-associated AS events using univariate Cox regression analysis. Gene functional enrichment analysis demonstrated the pathways enriched by survival-associated AS. Then, prognostic AS signatures were constructed for OS and chemoresistance prediction using the least absolute shrinkage and selection operator (LASSO) method. We also analyzed splicing factors (SFs) underlying regulation mechanisms by Pearson correlation and then built corresponding regulatory networks. Findings: After selection, 10354 AS events in 140 PDAC patients were profiled. We detected 677 OS-related AS events in 485 genes from Cox model. Computational algorithm results showed that RNA splicing-related pathways may be the potential mechanisms regulating poor prognosis. The AS signatures revealed high performance in predicting PDAC survival and gemcitabine chemoresistance. The area under of the ROC curve for AS-based predictor, constructed with significant survival-associated AS events, was 0.889 at 2000 days of OS. We identified prognostic SFs to build the AS regulatory network, which may be the underlying mechanism of AS events. Interpretation: Genome-wide prognostic AS signature was profiled in PDAC. We created AS-based models for OS and gemcitabine resistance, and revealed the regulatory splicing correlation networks. Funding Statement: This work was supported by grants from the Incubating Program for Clinical Research and Innovation of Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University (Grant No. PYMDT-001), Science and Technology Commission of Shanghai Municipality (Grant No. 16441906903), Three-year action plan for Shin Kang of Shanghai (16CR4005A). Declaration of Interests: The authors declare no potential conflicts of interest.