Comprehensive analysis of alternative splicing and transcriptome related to the prognosis of cervical squamous cell cancer

Abstract

Background: Cervical squamous cell cancer (CESC) is a common malignancy tumor with high incidence and mortality in women globally. Increasing studies have indicated that there was an indivisible association between alternative mRNA splicing (AS) and multiple types of cancer. However, comprehensive analysis of alternative mRNA splicing events is scarce in CESC. Methods: In this study, alternative mRNA splicing events data and clinical information of 216 CESC patients were downloaded from TCGA SpliceSeq database and TCGA website. We used identified survival-associated splicing events (SASEs) to construct prognostic signatures. Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curve were performed to evaluate the clinical value of prognostic signatures. A nomogram was carried out to quantitatively predict individuals’ survival probability. Regulatory network between splicing factors (SFs) and SASE was analyzed to explore the upstream regulators of a certain SASE. Additionally, we explored potential downstream pathways of a certain SASE. Results: A total of 41776 alternative splicing events in 9961 genes were collected. After sorting out SASEs, multivariable regression analysis was used to acquire 70 SASEs that could be independent prognostic factors for overall survival in CESC. Kaplan-Meier survival analyses showed that the difference was statistically significant (P＜0.01). The area under ROC curve (AUC) for all AS pattern was 0.932. A nomogram was constructed with a concordance index of 0.82 to predict individuals’ survival probability. EIF3A positively regulated SEC23A-27346-AP with highest correlation coefficient (P＜0.001, R=0.69). Besides, the most significant SASEs and KEGG pathways were SEC23A-27346-AP and adherens junction pathway (P=0.02, R=0.65). Conclusions: Prognostic signatures of survival-associated splicing events were independent prognostic factors for overall survival among CESC patients. A nomogram could quantitatively predict individuals’ survival probability. Moreover, we proposed that splicing factor EIF3A positively regulated SEC23A-27346-AP, and adherens junction pathway may be the downstream pathway of SEC23A-27346-AP. The aforementioned signaling pathway could play a crucial role in the development of CESC.