Abstract
Background: This study was to explore differential RNA splicing patterns and elucidate the function of the splice variants served as prognostic biomarkers in colorectal cancer (CRC).Methods: Genome-wide profiling of prognostic alternative splicing (AS) events using RNA-seq data from The Cancer Genome Atlas (TCGA) program was conducted to evaluate the roles of seven AS patterns in 330 colorectal cancer cohort. The prognostic predictors models were assessed by integrated Cox proportional hazards regression. Based on the correlations between survival associated AS events and splicing factors, splicing networks were built.Results: A total of 2,158 survival associated AS events in CRC were identified. Interestingly, most of these top 20 survival associated AS events were adverse prognostic factors. The prognostic models were built by each type of splicing patterns, performing well for risk stratification in CRC patients. The area under curve (AUC) of receiver operating characteristic (ROC) for the combined prognostic predictors model could reach 0.963. Splicing network also suggested distinguished correlation between the expression of splicing factors and AS events in CRC patients.Conclusion: The ideal prognostic predictors model for risk stratification in CRC patients was constructed by differential splicing patterns of 13 genes. Our findings enriched knowledge about differential RNA splicing patterns and the regulation of splicing, providing generous biomarker candidates and potential targets for the treatment of CRC.
Highlights
Alternative splicing (AS) is an important post-transcriptional regulatory mechanism that regulates the translation of mRNA isoforms and generates protein diversity [1]
To explore the prognostic value of AS event in CancerColorectal cancer (CRC) patients, we used the Cox univariate analyses of overall survival to evaluate the prognostic impact of each AS event
2,158 AS signatures were found to be significantly associated with overall survival of CRC patients (p < 0.05) (Supplementary Table 1)
Summary
Alternative splicing (AS) is an important post-transcriptional regulatory mechanism that regulates the translation of mRNA isoforms and generates protein diversity [1]. Over 95% of human genes undergo alternative splicing and encode splice variants in the normal physiological processes [2]. Emerging data demonstrated that aberrant alternative splicing events were closely associated with cancer progression, metastasis, therapeutic resistance, and other oncogenic processes [3,4,5]. Growing evidence suggested the dysregulation of splicing events and cancer-specific spliced variants could serve as prognostic biomarkers and therapeutic targets for colorectal cancer [10, 11]. The scarcity of studies undertake a comprehensive examination of survival associated AS events in CRC. This study was to explore differential RNA splicing patterns and elucidate the function of the splice variants served as prognostic biomarkers in colorectal cancer (CRC)
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