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Prognostic alternative splicing signatures and underlying regulatory network in esophageal carcinoma.

ABSTRACT: Alternative splicing (AS) has been widely reported to play an important role in cancers, including esophageal carcinoma (ESCA). However, no study has comprehensively investigated the clinical use of combination of prognostic AS events and clinicopathological parameters. Therefore, we collected 165 ESCA patients including 83 esophageal adenocarcinoma (EAC) and 82 esophageal squamous cell carcinoma (ESCC) patients from The Cancer Genome Atlas to explore the survival rate associated with seven types of AS events. Prognostic predictors for the clinical outcomes of ESCA patients were built. Predictive prognosis models of the alternative acceptor site in ESCA (area under the curve [AUC] = 0.83), alternative donor site in EAC (AUC = 0.99), and alternative terminator site in ESCC (AUC = 0.974) showed the best predictive efficacy. A novel combined prognostic model of AS events and clinicopathological parameters in ESCA was also constructed. Combined prognostic models of ESCA all showed better predictive efficacy than independent AS models or clinicopathological parameters model. Through constructing splicing regulatory network, the expression of AS factor was found to be negatively correlated with the most favorable AS events. Moreover, gene amplification, mutation, and copy number variation of AS genes were commonly observed, which may indicate the molecular mechanism of how the AS events influence survival. Conclusively, the constructed prognostic models based on AS events, especially the combined prognostic models of AS signatures and clinicopathological parameters could be used to predict the outcome of ESCA patients. Moreover, the splicing regulatory network and genomic alteration in ESCA could be used for illuminating the potential molecular mechanism.

SUBMITTER: Xie ZC

PROVIDER: S-EPMC6684923 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Kidney renal clear cell carcinoma (KIRC) is the malignancy originated from the renal epithelium, with a high rate of distant metastasis. Aberrant alternative splicing (AS) of pre-mRNA are widely reported to be involved in the tumorigenesis and metastasis of multiple cancers. The aim of this study is to explore the mechanism of alternative splicing events (ASEs) underlying tumorigenesis and metastasis of KIRC. Methods: RNA-seq of 537 KIRC samples downloaded from the TCGA database and ASEs data from the TCGASpliceSeq database were used to identify ASEs in patients with KIRC. The univariate and Lasso regression analysis were used to screen the most significant overall survival-related ASEs (OS-SEs). Based on those, the OS-SEs model was proposed. The interaction network of OS-SEs and splicing factors (SFs) with absolute value of correlation coefficient value >0.750 was constructed by Pearson correlation analysis. The OS-SEs significantly related to distant metastasis and clinical stage were identified by non-parametric test, and those were also integrated into co-expression analysis with prognosis-related Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways identified by Gene Set Variation Analysis (GSVA). ASEs with significance were selected for multiple online database validation. Results: A total of prognostic 6,081 overall survival-related ASEs (OS-SEs) were identified by univariate Cox regression analysis and a prediction model was constructed based on 5 OS-SEs screened by Lasso regression with the Area Under Curve of 0.788. Its risk score was also illustrated to be an independent predictor, which the good reliability of the model. Among 390 identified candidate SFs, DExD-Box Helicase 39B (DDX39B) was significantly correlated with OS and metastasis. After external database validation, Retained Intron of Ras Homolog Family Member T2 (RHOT2) and T-Cell Immune Regulator 1 (TCIRG1) were identified. In the co-expression analysis, overlapped co-expression signal pathways for RHOT2 and TCIRG1 were sphingolipid metabolism and N-glycan biosynthesis. Conclusions: Based on the results of comprehensive bioinformatic analysis, we proposed that aberrant DDX39B regulated RHOT2-32938-RI and TCIRG1-17288-RI might be associated with the tumorigenesis, metastasis, and poor prognosis of KIRC via sphingolipid metabolism or N-glycan biosynthesis pathway.

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Prognostic alternative splicing signatures and underlying regulatory network in esophageal carcinoma.

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