Frontiers in Genetics (May 2020)
Construction and Validation of a 13-Gene Signature for Prognosis Prediction in Medulloblastoma
Abstract
Background: Recent studies have identified several molecular subgroups of medulloblastoma associated with distinct clinical outcomes; however, no robust gene signature has been established for prognosis prediction. Our objective was to construct a robust gene signature-based model to predict the prognosis of patients with medulloblastoma.Methods: Expression data of medulloblastomas were acquired from the Gene Expression Omnibus (GSE85217, n = 763; GSE37418, n = 76). To identify genes associated with overall survival (OS), we performed univariate survival analysis and least absolute shrinkage and selection operator (LASSO) Cox regression. A risk score model was constructed based on selected genes and was validated using multiple datasets. Differentially expressed genes (DEGs) between the risk groups were identified. Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO), and protein–protein interaction (PPI) analyses were performed. Network modules and hub genes were identified using Cytoscape. Furthermore, tumor microenvironment (TME) was evaluated using ESTIMATE algorithm. Tumor-infiltrating immune cells (TIICs) were inferred using CIBERSORTx.Results: A 13-gene model was constructed and validated. Patients classified as high-risk group had significantly worse OS than those as low-risk group (Training set: p < 0.0001; Validation set 1: p < 0.0001; Validation set 2: p = 0.00052). The area under the curve (AUC) of the receiver operating characteristic (ROC) analysis indicated a good performance in predicting 1-, 3-, and 5-year OS in all datasets. Multivariate analysis integrating clinical factors demonstrated that the risk score was an independent predictor for the OS (validation set 1: p = 0.001, validation set 2: p = 0.004). We then identified 265 DEGs between risk groups and PPI analysis predicted modules that were highly related to central nervous system and embryonic development. The risk score was significantly correlated with programmed death-ligand 1 (PD-L1) expression (p < 0.001), as well as immune score (p = 0.035), stromal score (p = 0.010), and tumor purity (p = 0.010) in Group 4 medulloblastomas. Correlations between the 13-gene signature and the TIICs in Sonic hedgehog and Group 4 medulloblastomas were revealed.Conclusion: Our study constructed and validated a robust 13-gene signature model estimating the prognosis of medulloblastoma patients. We also revealed genes and pathways that may be related to the development and prognosis of medulloblastoma, which might provide candidate targets for future investigation.
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