Prognostic value and potential function of splicing events in prostate adenocarcinoma

Abstract

Prostate adenocarcinoma (PRAD) is one of the most common types of malignancy in males and at present, effective prognostic indicators are limited. The development of PRAD has been associated with abnormalities in alternative splicing (AS), a requisite biological process of gene expression in eukaryotic cells; however, the prognostic value of AS products and splicing events remains to be elucidated. In the present study, the data of splicing events and the clinical information of PRAD patients were obtained from The Cancer Genome Atlas (TCGA)SpliceSeq and TCGA databases, respectively. A prognostic index (PI) was generated from disease-free survival-associated splicing events (DFS-SEs), which were identified by univariate/multivariate Cox regression analysis. A total of 6,909 DFS-SEs were identified in PRAD. The corresponding genes for the DFS-SEs were significantly enriched in mitochondria and their associated pathways according to Gene Ontology annotation and in the pathways of fatty acid metabolism, oxidative phosphorylation and Huntington's disease according to a Kyoto Encyclopedia of Genes and Genomes pathway analysis. The PI for mutually exclusive exons had the greatest ability to predict the probability of five-year disease-free survival of patients with PRAD, with an area under the time-dependent receiver-operating characteristic curve of 0.7606. Patients with PRAD, when divided into a 'low' and a 'high' group based on their median PI for exon skip values, exhibited a marked difference in disease-free survival (low vs. high, 3,588.45±250.51 vs. 1,531.08±136.50 days; P=7.43x10-9). A correlation network between DFS-SEs of splicing factors and non-splicing factors was constructed to determine the potential mechanisms in PRAD, which included the potential regulatory interaction between the splicing event of splicing factor RNA binding motif protein 5-alternate terminator (AT)-64957 and the splicing event of non-splicing factor heterochromatin protein 1 binding protein 3-AT-939. In conclusion, the PIs derived from DFS-SEs are valuable prognostic factors for patients with PRAD, and the function of splicing events in PRAD deserves further exploration.