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.
Highlights
Medulloblastoma is the most common central nervous system (CNS) malignancy in children (Louis et al, 2016; Northcott et al, 2019)
We found that differentially expressed genes (DEGs) in module 1 were significantly enriched in pathways that were related to the development and function of CNS (Figure 7A and Supplementary Table 7), while those in module 2 were significantly enriched in pathways that were related to Validation set 1
We examined the association between our risk score model and immune checkpoint pathways, focusing on PD-L1 and cytotoxic T-lymphocyte associated protein 4 (CTLA4) since inhibitors targeting these checkpoints have been proposed to be effective in treating medulloblastoma animal models (Pham et al, 2016)
Summary
Medulloblastoma is the most common central nervous system (CNS) malignancy in children (Louis et al, 2016; Northcott et al, 2019). While the WNT and SHH subgroup can be clearly identified based on the WNT and SHH signaling pathway mutations, much less is known about Group 3 and Group 4 tumors, and these subgroups remain as non-SHH/non-WNT medulloblastomas in WHO’s 2016 classification for diagnostic considerations (Louis et al, 2016). Study from Cho et al (2011) demonstrated that Group 3β medulloblastomas have a clinical outcome similar to Group 4 tumors. A precise prognostic model with high efficacy and broad applicability would assist in prognostic prediction of the patients with medulloblastoma in addition to the molecular and histology characterization. Recent studies have identified several molecular subgroups of medulloblastoma associated with distinct clinical outcomes; 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
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