Alternative Splicing Events as Indicators for the Prognosis of Uveal Melanoma

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.

Aberrant RNA Splicing Events Driven by Mutations of RNA-Binding Proteins as Indicators for Skin Cutaneous Melanoma Prognosis

“…Alternative splicing refers to a biological process that transforms a single pre-mRNA to multiple splice isoforms and finally leads to different or antagonistic functional as well as structural characteristics of protein products or results in different phenotypes due to alternating expression levels of the spliced genes ( 73 , 74 ). Currently, an increasing number of evidences have been proposed to regard the alternative splicing as an effective indicator of carcinogenic processes ( 9 , 29 , 39 , 75 – 79 ). Zhang et al revealed that U2AF2 can enhance melanoma migration and cancer aggressiveness by facilitating CD44v8-10 alternative splicing, an isoform switch required for tumor prognostic and metastases ( 80 ).…”

A Novel Nomogram Combining Alternative Splicing Events and Clinical Factors for Prognosis Prediction in Head and Neck Squamous Cell Carcinoma

“…For instance, Xie et al developed a splicing prognostic model using AS events, which showed satisfactory predictive efficacy for the GBM patients' survival, indicating the important clinical value of AS events for the developments of novel biomarkers [ 22 ]. In uveal melanoma, 1014 AS events were recognized as prognostic AS ones in total, and a robust prognostic prediction model containing seven AS events revealed a great promise for the prediction of overall survival of patients with uveal melanoma [ 23 ]. However, the related studies in HNSCC patients were rarely reported.…”

Transcriptomic Analysis Revealed an Emerging Role of Alternative Splicing in Embryonal Tumor with Multilayered Rosettes

“…Cancer cells are capable of dynamically changing gene expression and favoring the expression of aberrant oncogenic splice variants to overcome stresses within the tumor microenvironment [ 38 ]. Abnormal AS is now regarded as a valuable indicator of carcinogenic processes and prognosis, as well as a potential target of treatment in several types of cancer [ 39 , 40 , 41 , 42 , 43 , 44 ].Not only is it a valuable diagnostic marker of ETMRs [ 45 ], LIN28A overexpression can be functionally significant as well. LIN28A was reported as a regulator of self-renewal capacity in cancer stem cells, cellular metabolism, and the cell cycle through binding and repression of let-7 microRNAs [ 12 , 46 , 47 ].…”