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Dynamic prognostic model for kidney renal clear cell carcinoma (KIRC) patients by combining clinical and genetic information.

ABSTRACT: We aim to construct more accurate prognostic model for KIRC patients by combining the clinical and genetic information and monitor the disease progression in dynamically updated manner. By obtaining cross-validated prognostic indices from clinical and genetic model, we combine the two sources information into the Super learner model, and then introduce the time-varying effect into the combined model using the landmark method for real-time dynamic prediction. The Super learner model has better prognostic performance since it can not only employ the preferable clinical prognostic model constructed by oneself or reported in the current literature, but also incorporate genome level information to strengthen effectiveness. Apart from this, four representative patients' mortality curves are drawn in the dynamically updated manner based on the Super learner model. It is found that effectively reducing the two prognostic indices value through suitable treatments might achieve the purpose of controlling the mortality of patients. Combining clinical and genetic information in the Super learner model would enhance the prognostic performance and yield more accurate results for dynamic predictions. Doctors could give patients more personalized treatment with dynamically updated monitoring of disease status, as well as some candidate prognostic factors for future research.

SUBMITTER: Zhao H

PROVIDER: S-EPMC6279814 | biostudies-other | 2018 Dec

REPOSITORIES: biostudies-other

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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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Dynamic prognostic model for kidney renal clear cell carcinoma (KIRC) patients by combining clinical and genetic information.

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