Novel insights into clear cell renal cell carcinoma prognosis by comprehensive characterization of aberrant alternative splicing signature: a study based on large-scale sequencing data

Abstract

ABSTRACT Clear cell renal cell carcinoma (ccRCC) is the most common type with poor prognosis in kidney tumor. Growing evidence has indicated that aberrant alternative splicing (AS) events are efficacious signatures for tumor prognosis prediction and therapeutic targets. However, the detailed roles of AS events in ccRCC are largely unknown. In our study, level 3 RNA-seq data was acquired from The Cancer Genome Atlas dataset and corresponding AS profiles were detected with the assistance of SpliceSeq software. A total of 2100 aberrant survival-associated AS events were identified via differential expression and univariate cox regression analysis. The final prognostic panel formed by 17 specific events was developed by stepwise least absolute shrinkage and selection operator (LASSO) penalty, with the area under curve (AUC) values of receiver operator characteristic (ROC) curves keeping above 0.7 spanning 1 year to 5 years. And the results from functional enrichment analyses are unanimous that autophagy could be a potential mechanism of splicing regulation in ccRCC. Furthermore, splicing regulatory network was constructed via Spearman correlation between splicing factors and AS events. Finally, unsupervised clustering analysis revealed three clusters with distinct survival patterns, and associated with specific clinicopathological phenotypes. In overall, we developed a robust and individualized predictive model based on large-scale sequencing data. The identified AS events and splicing network may be valuable in deciphering the crucial posttranscriptional mechanisms on tumorigenesis of ccRCC.