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Genome-Wide Profiling of Prognostic Alternative Splicing Signature in Colorectal Cancer.

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.

SUBMITTER: Zong Z

PROVIDER: S-EPMC6262947 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Alternative splicing (AS) is a pervasive and vital mechanism involved in the progression of cancer by expanding genomic encoding capacity and increasing protein complexity. However, the systematic analysis of AS in hepatocellular carcinoma (HCC) is lacking and urgently required. In the present study, genome‑wide AS events with corresponding clinical information were profiled in 290 patients with HCC from the Cancer Genome Atlas and SpliceSeq software. Functional enrichment analyses revealed the pivotal biological process of AS regulation. Univariate Cox regression analyses were performed, followed by stepwise forward multivariate analysis to develop the prognostic signatures. Spearman's correlation analyses were also used to construct potential regulatory network between the AS events and aberrant splicing factors. A total of 34,163 AS events were detected, among which 1,805 AS events from 1,314 parent genes were significantly associated with the overall survival (OS) of patients with HCC, and their parent genes serve crucial roles in HCC‑related oncogenic processes, including the p53 signaling pathway, AMPK signaling pathway and HIF‑1 signaling pathway. A prognostic AS signature was established that was found to be an independent prognostic factor for OS in stratified cohorts, harboring a noteworthy ability to distinguish between the distinct prognoses of patients with HCC (high‑risk vs. low‑risk, 827 vs. 3,125 days, P<2e‑16). Time‑dependent receiver‑-operator characteristic curves confirmed its robustness and clinical efficacy, with the area under the curves maintained >0.9 for short‑term and long‑term prognosis prediction. The splicing correlation network suggested a trend in the interactions between splicing factors and prognostic AS events, further revealing the underlying mechanism of AS in the oncogenesis of HCC. In conclusion, the present study provides a comprehensive portrait of global splicing alterations involved in the progression and HCC in addition to valuable prognostic factors for patients, which may represent as underappreciated hallmark and provide novel clues of therapeutic targets in HCC.

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Genome-Wide Profiling of Prognostic Alternative Splicing Signature in Colorectal Cancer.

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