A Functional Role of OLIG2 in Tumor Heterogeneity of MYC-amplified Medulloblastoma

The goal of this study was to compare gene expression profiles of MYC-amplified medulloblastoma tumors under three distinct conditions: primary tumors prior to radiation treatment, tumors derived from implanted radio-resistant tumor cells, and spontaneously recurring tumors several weeks post-irradiation. The purpose of this experiment was to identify the moleular pathways that are impacted during radiation and those which contribute to tumor recurrence. Unsupervised hierarchical cluster analysis revealed that the tumors which spontaneously recurred in vivo closely resembled the primary tumors. Tumors from implanted post-radiation neurospheres, however, had markedly different profiles. We identified 44 upregulated and 23 downregulated genes in the spontaneously recurred tumors compared to untreated primary tumors. Furthermore, we identified 817 upregulated and 509 downregulated genes in tumors derived from implanted post-radiation neurospheres compared to untreated primary tumors. Among these genes, 756 (57%) genes were also differentially expressed between tumors derived from implanted post-radiation neurospheres and spontaneously recurrent tumors. The downregulated pathways in tumors derived from implanted post-radiation neurospheres were associated with p53, cell cycle, DNA replication, and DNA damage, and the upregulated genes are involved in metabolic pathways. This study demonstrates that radiation resistant tumor cells exhibit differential gene expression post-irradiation and during tumor recurrence and provides a framework for the study of genetic pathways leading to tumor recurrence post-irradiation. Bulk RNA-seq and transcriptomic analysis of patient-derived MYC-amplified medulloblastoma tumors derived from radioresistant tumor cells post-transplantation, spontaneously relapsed tumors, and primary tumors