Abstract
The Group 3 Medulloblastoma (Grp3-MB) is an aggressive molecular subtype with a high incidence of metastasis and deaths. In this study, were used an RNA sequencing data (RNA-Seq) from a Brazilian cohort of MBs to identify hub genes associated with the metastatic risk. Data validation were performed by using multiple large datasets from MBs (GSE85217, GSE37418, and EGAS00001001953). DESeq2 package in R software was used to identify the differentially expressed genes (DEGs) in our RNA-Seq data. The DEGs data were accessed to construct the modules/graphs of co-expression and to identify hub genes through Cytoscape platform. The coregulated genes were enriched by the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and the protein-protein interaction (PPI) network was visualized by Cytoscape. The Kaplan-Meier plotter and ROC curves were used to validate the diagnostic and prognostic values of specific biomarkers identified through this model. We identified that inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) as a downregulated hub gene, with a high diagnostic accuracy to Grp3-MBs and associated with tumor metastasis. In addition, we identified genes significantly correlated with ITPR1 that were associated with metastasis in Grp3-MB (ATP1A2, MTTL7A, and RGL1) and worst overall survival in MBs (ANTXR1 and RGL1). Our findings suggest that the ITPR1 hub gene is potentially involved in the metastatic process for Grp3-MB. Our data also provide evidence of targets that may serve as prognostic predictors and/or regulators for the metastatic process that maybe explored for further research of individualized therapy to Grp3-MBs.
Highlights
Medulloblastoma (MB) is the most common malignant embryonal brain tumor in the pediatric population (Northcott et al 2019)
We identified genes significantly correlated with ITPR1 that were associated with metastasis in Grp3-MB ( ATP1A2, MTTL7A and RGL1), and worst overall survival in MBs ( ANTXR1 and RGL1 )
We identified 17 genes significantly coregulated with ITPR1, highlighting the ATP1A2, MTTL7A and RGL1 which demonstrated association with metastasis in Grp3-MB, and ANTXR1 and RGL1 correlated to worse overall survival (OS) in MBs
Summary
Medulloblastoma (MB) is the most common malignant embryonal brain tumor in the pediatric population (Northcott et al 2019). Integrative genomic studies have clarified several mechanisms on MBs tumorigenesis, (Juraschka and Taylor 2019; Menyhárt and Győrffy 2019) it is of note the paucity of genes with clinical relevance that could be used as metastastatic biomarkers and predictors for prognostication, improving therapeutic strategies for Grp3-MB. The low expression of ITPR1 was associated with the presence of metastasis in MBs. In addition, we identified 17 genes significantly coregulated with ITPR1, highlighting the ATP1A2, MTTL7A and RGL1 which demonstrated association with metastasis in Grp3-MB, and ANTXR1 and RGL1 correlated to worse overall survival (OS) in MBs. Our study provides for the first-time insights about the association of ITPR1 as a prognostic biomarker and a potential therapeutic target to Grp3-MBs
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