Systemic characterization of alternative splicing related to prognosis, immune infiltration, and drug sensitivity analysis in ovarian cancer

Abstract

Background: Alternative splicing (AS) plays an essential role in tumorigenesis and progression. This study intended to construct an innovative prognostic model based on AS events to gain more precise survival prediction and search for potential therapeutic targets in ovarian cancer.Methods: Seven types of AS events in ovarian serous cystadenocarcinoma (OV) patients with RNA-seq were obtained using The Cancer Genome Atlas (TCGA) SpliceSeq tool and database. Cox and Kaplan-Meier curve analyses were employed to establish the prognostic models. Relying on drug sensitivity data from the CellMiner database, Genomics of Drug Sensitivity (GDS) was adopted to estimate the platinumsensitive analysis. Furthermore, a prognostic splicing factor (SF)-AS network was constructed using Cytoscape. Finally, in order to explore the influence of the tumor microenvironment on the prognosis of OV patients, we first combined a similar network fusion and consensus clustering (SNF-CC) algorithm to identify three OV subtypes based on survival-related AS events and then utilized single-sample Gene Set Enrichment Analysis (ssGSEA) method to perform immune cell infiltration analysis.Results: A total of 48,049 AS events and 21,841 related genes were selected from 318 OV samples, and 2,206 AS events associated with disease-free survival (DFS) were identified. Multivariate Cox and Kaplan-Meier curve analyses were then employed to establish the prognostic models. Receiver operating characteristic (ROC) analysis from 0.59 to 0.75 showed that these models were highly efficient in distinguishing patient survival. GDS was adopted with the CellMiner database to provide some insights for platinum-sensitive analysis of OV. Furthermore, a prognostic SF-AS network, which discovered a significant connection between SFs and prognostic AS genes, was constructed using Cytoscape. The combined SNF-CC algorithm revealed three distinct OV subtypes based on the prognostic AS events, and the associations between this novel molecular classification and immune cell infiltration were further explored. Conclusions:We developed a powerful prognostic AS signature for OV and provided a deeper understanding of SF-AS network regulatory mechanisms, as well as platinum-sensitive and cancer immune microenvironments. These results revealed various candidate biomarkers and potential targets for OV treatment strategies.