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<p>Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for approximately 20% of all childhood brain tumors. Despite recent advances, current treatments like surgery, radiation, and chemotherapy still lead to severe side effects and high morbidity. Limited knowledge exists regarding the regulatory mechanisms behind the MB transcriptional alterations in high-aggressive subgroups like Group 3 and Group 4, hindering the development of targeted therapies. Identifying key transcriptional regulators, known as master regulators (MRs), can elucidate the dysregulated pathways underlying MB progression and uncover potential treatment targets. In this study, we utilize primary MB gene expression samples to infer its regulatory network. Subsequently, we applied the Master Regulator Analysis identifying the transcription factors <i>BHLHE41</i>, <i>RFX4</i>, and <i>NPAS3</i> as its main transcriptional regulators, showing tumor suppressor features. We also identified eight risk MRs highly associated with patient outcome: four regulators (<i>MYC</i>, <i>REL</i>, <i>ZSCAN5 A</i>, and <i>ZFAT</i>) with activities associated with poor prognosis, and four (<i>PAX6</i>, <i>ARNT2</i>, <i>ZNF157</i>, and <i>HIVEP3</i>) acting antagonistically, being associated with good outcome. 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.</p>

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Medulloblastoma’s master regulators and their association with patients’ risk

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月10日

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  • Gustavo Lovatto Michaelsen,
  • Tayrone de Sousa Monteiro,
  • Danilo Oliveira Imparato,
  • João Vitor Almeida da Costa,
  • Daniel Rocha Silva,
  • Iara Dantas de Souza,
  • Marcel Câmara da Ribeiro-Dantas,
  • Otávio Cabral-Marques,
  • Marialva Sinigaglia,
  • Rodrigo Juliani Siqueira Dalmolin

摘要

Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for approximately 20% of all childhood brain tumors. Despite recent advances, current treatments like surgery, radiation, and chemotherapy still lead to severe side effects and high morbidity. Limited knowledge exists regarding the regulatory mechanisms behind the MB transcriptional alterations in high-aggressive subgroups like Group 3 and Group 4, hindering the development of targeted therapies. Identifying key transcriptional regulators, known as master regulators (MRs), can elucidate the dysregulated pathways underlying MB progression and uncover potential treatment targets. In this study, we utilize primary MB gene expression samples to infer its regulatory network. Subsequently, we applied the Master Regulator Analysis identifying the transcription factors BHLHE41, RFX4, and NPAS3 as its main transcriptional regulators, showing tumor suppressor features. We also identified eight risk MRs highly associated with patient outcome: four regulators (MYC, REL, ZSCAN5 A, and ZFAT) with activities associated with poor prognosis, and four (PAX6, ARNT2, ZNF157, and HIVEP3) acting antagonistically, being associated with good outcome. 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.