Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq
Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be...
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2025-01-01
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| author | Christophe Desterke Yuanji Fu Jenny Bonifacio-Mundaca Claudia Monge Pascal Pineau Jorge Mata-Garrido Raquel Francés |
| author_facet | Christophe Desterke Yuanji Fu Jenny Bonifacio-Mundaca Claudia Monge Pascal Pineau Jorge Mata-Garrido Raquel Francés |
| author_sort | Christophe Desterke |
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| description | Medulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included <i>CCT3</i>, <i>SNX5</i>, <i>SQOR</i>, <i>G3BP1</i>, <i>CARS1</i>, <i>SLC39A14</i>, <i>FAM98A</i>, <i>FXR1</i>, <i>TFAP2C</i>, and <i>ATF4</i>. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; <i>p</i>-value = 1.04 × 10<sup>−9</sup>). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma. |
| format | Article |
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| institution | Kabale University |
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| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-c3c31f0feedf4a44b8adf2e208ef60132025-01-24T13:19:28ZengMDPI AGAntioxidants2076-39212025-01-011419610.3390/antiox14010096Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-SeqChristophe Desterke0Yuanji Fu1Jenny Bonifacio-Mundaca2Claudia Monge3Pascal Pineau4Jorge Mata-Garrido5Raquel Francés6INSERM UMRS-1310, Faculté de Médecine du Kremlin Bicêtre, Université Paris-Saclay, F-94270 Le Kremlin-Bicêtre, FranceINSERM, CNRS, Institut Necker Enfants Malades, Université Paris Cité, F-75015 Paris, FranceNational Tumor Bank, Department of Pathology, National Institute of Neoplastic Diseases, Surquillo 15038, PeruUnité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, INSERM U993, F-75015 Paris, FranceUnité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, INSERM U993, F-75015 Paris, FranceUnité Organisation Nucléaire et Oncogenèse, Institut Pasteur, Université Paris Cité, INSERM U993, F-75015 Paris, FranceEnergy & Memory, Brain Plasticity Unit, CNRS, ESPCI Paris, PSL Research University, F-75006 Paris, FranceMedulloblastoma (MB) is the most common malignant brain tumor in children, typically arising during infancy and childhood. Despite multimodal therapies achieving a response rate of 70% in children older than 3 years, treatment remains challenging. Ferroptosis, a form of regulated cell death, can be induced in medulloblastoma cells in vitro using erastin or RSL3. Using two independent medulloblastoma RNA-sequencing cohorts (MB-PBTA and MTAB-10767), we investigated the expression of ferroptosis-related molecules through multiple approaches, including Weighted Gene Co-Expression Network Analysis (WGCNA), molecular subtype stratification, protein–protein interaction (PPI) networks, and univariable and multivariable overall survival analyses. A prognostic expression score was computed based on a cross-validated ferroptosis signature. In training and validation cohorts, the regulation of the ferroptosis transcriptional program distinguished the four molecular subtypes of medulloblastoma. WGCNA identified nine gene modules in the MB tumor transcriptome; five correlated with molecular subtypes, implicating pathways related to oxidative stress, hypoxia, and trans-synaptic signaling. One module, associated with disease recurrence, included epigenetic regulators and nucleosome organizers. Univariable survival analyses identified a 45-gene ferroptosis prognostic signature associated with nutrient sensing, cysteine and methionine metabolism, and trans-sulfuration within a one-carbon metabolism. The top ten unfavorable ferroptosis genes included <i>CCT3</i>, <i>SNX5</i>, <i>SQOR</i>, <i>G3BP1</i>, <i>CARS1</i>, <i>SLC39A14</i>, <i>FAM98A</i>, <i>FXR1</i>, <i>TFAP2C</i>, and <i>ATF4</i>. Patients with a high ferroptosis score showed a worse prognosis, particularly in the G3 and SHH subtypes. The PPI network highlighted IL6 and CBS as unfavorable hub genes. In a multivariable overall survival model, which included gender, age, and the molecular subtype classification, the ferroptosis expression score was validated as an independent adverse prognostic marker (hazard ratio: 5.8; <i>p</i>-value = 1.04 × 10<sup>−9</sup>). This study demonstrates that the regulation of the ferroptosis transcriptional program is linked to medulloblastoma molecular subtypes and patient prognosis. A cross-validated ferroptosis signature was identified in two independent RNA-sequencing cohorts, and the ferroptosis score was confirmed as an independent and adverse prognostic factor in medulloblastoma.https://www.mdpi.com/2076-3921/14/1/96ferroptosisprognosismedulloblastomaRNA-sequencingresponse to oxidative stressmethionine–cysteine catabolism |
| spellingShingle | Christophe Desterke Yuanji Fu Jenny Bonifacio-Mundaca Claudia Monge Pascal Pineau Jorge Mata-Garrido Raquel Francés Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq Antioxidants ferroptosis prognosis medulloblastoma RNA-sequencing response to oxidative stress methionine–cysteine catabolism |
| title | Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq |
| title_full | Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq |
| title_fullStr | Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq |
| title_full_unstemmed | Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq |
| title_short | Ferroptosis Transcriptional Regulation and Prognostic Impact in Medulloblastoma Subtypes Revealed by RNA-Seq |
| title_sort | ferroptosis transcriptional regulation and prognostic impact in medulloblastoma subtypes revealed by rna seq |
| topic | ferroptosis prognosis medulloblastoma RNA-sequencing response to oxidative stress methionine–cysteine catabolism |
| url | https://www.mdpi.com/2076-3921/14/1/96 |
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