Dados do Trabalho

Título

Reverse Engineering of Medulloblastoma Regulatory Network and Inference of Master Regulons

Introdução

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for approximately 20% of all childhood brain tumors. While recent advances have improved survival rates, current treatments like surgery, radiation, and chemotherapy lead to severe side effects and high morbidity, with around 30% of patients not achieving long-term survival. It is classified into four main molecular subgroups - WNT, SHH, Group 3, and Group 4 - each with distinct molecular characteristics and clinical features. The WNT and SHH subgroups are driven by mutations activating their respective signaling pathways. However, the highly aggressive Group 3 and Group 4 subgroups lack well-defined tumor drivers, hindering the development of targeted therapies

Objetivo

Identifying key transcriptional regulators, known as master regulators (MRs), can elucidate the dysregulated pathways underlying MB progression and uncover potential treatment targets.

Método

In this study, utilizing a dataset with 763 gene expression samples of primary MB, we inferred the MB regulatory network.

Resultados

Afterward, we applied the Master Regulator Analysis (MRA) identifying the transcription factors BHLHE41, RFX4, and NPAS3 among the most important regulators in the development of SHH, Group 3 and Group 4 MB subgroups. We also integrated the regulatory network with patient survival data. This analysis revealed eight MRs highly associated with patients' outcome, four regulators (MYC, REL, ZSCAN5A, and ZFAT) with activities associated with poor prognosis, and the remaining four (PAX6, ARNT2, ZNF157, and HIVEP3) acting antagonistically, being associated with good outcome.

Conclusão

Our results offer key insights into the molecular mechanisms driving these tumors and identify novel potential therapeutic targets, addressing the urgent need for more effective and less toxic treatments.