Abstract
Objectives A growing body of evidence has shown that aberrant alternative splicing (AS) is closely related to the occurrence and development of cancer. However, prior studies mainly have concentrated on a few genes that exhibit aberrant AS. This study aimed to determine AS events through whole genome analysis and construct a prognostic model of endometrial cancer (EC). Methods We downloaded gene expression RNAseq data from UCSC Xena, and seven types of AS events from TCGA SpliceSeq. Univariate Cox regression was employed to analyze the prognostic-related alternative splicing events (PASEs) and splicing factors; multivariate Cox regression was conducted to analyze the effect of risk score (All) and clinicopathological parameters on EC prognosis. An underlying interaction network of PASEs of EC was constructed by Cytoscape Reactome FI, GO, and KEGG pathway enrichment was performed by DAVID. ROC curves and Kaplan-Meir analysis were used to assess the diagnostic value of prognostic model. The correlation between PASEs and splicing factors was analyzed by GraphPad Prism; then a network was constructed using Cytoscape. Results In total, 28,281 AS events in EC were identified, which consisted of 1166 PASEs. RNPS1, NEK2, and CTNNB1 were the hub genes in the network of the top 600 PASEs. The area under the curve (AUC) of risk score (All) reached 0.819. Risk score (All) together with FIGO stage, cancer status, and primary therapy outcome success was risk factors of the prognosis of EC patients. Splicing factors YBX1, HNRNPDL, and HNRNPA1 were significantly related to the overall survival (OS). The splicing network indicated that the expression of splicing factors was significantly correlated with percent-splice-in (PSI) value of PASEs. Conclusion We constructed a model for predicting the prognosis of EC patients based on PASEs using whole genome analysis of AS events and thereby provided a reliable theoretical basis for EC clinical prognosis evaluation.
Highlights
Alternative splicing (AS) is an important regulation mechanism in the process of mRNAs after transcription
It is worth noting that one gene can undergo multiple types AS events; UpSet picture was used to match the genes with AS events
The results showed that the most common event was exon skip (ES) followed by alternate terminator (AT) and alternate promoter (AP); mutually exclusive exons (ME) events occurred the least
Summary
Alternative splicing (AS) is an important regulation mechanism in the process of mRNAs after transcription. PremRNA produces different mRNAs through different splicing methods to translate into different proteins with versatile functions, which contributes to protein diversity [1]. Studies have shown that AS plays an important role in the occurrence and development of cancer, and AS participates in the process of proliferation, apoptosis, and metastasis of tumor cells [3, 4]. AS is mainly regulated by the spliceosome, which is the complex proteins composed of small nuclear ribonucleic acids (snRNA) and splicing factors [5]. A splicing factor is an important accessory protein that regulates pre-mRNA AS. Mutation and/or abnormal expression of splicing factors are closely related to the occurrence of abnormal AS [6]. There are seven types of AS events listed in the SpliceSeq database, i.e., alternate acceptor site (AA), alternate donor site (AD), alternate terminator (AT), alternate promoter (AP), exon skip (ES), mutually exclusive exons (ME), and retained intron (RI) [7]
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