Abstract
Growing evidence has revealed that abnormal alternative splicing (AS) events are closely related to carcinogenic processes. However, the comprehensive study on the prognostic value of splicing events involved in uveal melanoma (UM) is still lacking. Therefore, splicing data of 80 UM patients were obtained from the Cancer Genome Atlas (TCGA) SpliceSeq and RNA sequence data of UM and patient clinical features were downloaded from the Cancer Genome Atlas (TCGA) database to identify survival related splicing events in UM. As a result, a total of 37996 AS events of 17911 genes in UM were detected, among which 5299 AS events of 3529 genes were significantly associated with UM patients’ survival. Functional enrichment analysis revealed that this survival related splicing genes are corelated with mRNA catabolic process and ribosome pathway. Based on survival related splicing events, seven types of prognostic markers and the final overall prognostic signature could independently predict the overall survival of UM patients. Finally, an 11 spliced gene was identified in the final signature. On the basis of these 11 genes, we constructed a Support Vector Machine (SVM) classifier and evaluated it with leave-one-out cross-validation. The results showed that the 11 genes could determine short- and long-term survival with a predicted accuracy of 97.5%. Besides, the splicing factors and alternative splicing events correlation network was constructed to serve as therapeutic targets for UM treatment. Thus, our study depicts a comprehensive landscape of alternative splicing events in the prognosis of UM. The correlation network and associated pathways would provide additional potential targets for therapy and prognosis.
Highlights
Uveal melanoma (UM) is the most common type of malignant tumor in adult eyes, and 50% of UM patients will eventually die for their disease [1,2,3]
5599 Exon Skip (ES) in 14,019 genes, 1619 Retained Intron (RI) in 2388 genes, 2130 Alternate Acceptor site (AA) in 3022 genes, 1891 Alternate Donor site (AD) in 2705 genes, 3048 Alternate Promoter (AP) in 7565 genes, 3465 Alternate Terminator (AT) in 7938 genes, and 159 mutually exclusive exon (ME) in 159 genes (Figure 1B). These results revealed that one gene may have multiple types of alternative splicing events
Method was applied to annotate and the results showed that 21 pathways were significantly enriched in biological process terms including “protein targeting,” “protein targeting to membrane,” “mRNA
Summary
Uveal melanoma (UM) is the most common type of malignant tumor in adult eyes, and 50% of UM patients will eventually die for their disease [1,2,3]. It is important to explore the molecular mechanism underlying the survival events of UM and identify new prognostic factors and therapeutic targets [5]. There have some studies focusing on the prognostic gene signatures of UM, and protein-coding genes of tumor cells are very important in tumor progression [6]. Due to the limited number of mRNAs, it is difficult to illustrate the complicated function of protein molecular, especially for development and differentiation of tumors [7]. It is well known that alternative splicing (AS) is an important mechanism of post-transcriptional regulation that enables a single gene to produce multiple proteins, and most human protein-coding genes will undergo alternative splicing [8]. Growing evidence has revealed that abnormal splicing events are closely related to carcinogenic processes
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