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Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas

SIMPLE SUMMARY: Approximately 50% of high-grade gliomas (HGG) in children are diffuse midline gliomas (DMGs), which carry the worst prognosis of all HGG, with a 2-year survival of less than 10%. DMGs are characterized by H3K27M mutation, rampant genomic instability, infiltrative growth, and radio-re...

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Autores principales: Pedersen, Henriette, Schmiegelow, Kjeld, Hamerlik, Petra
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600397/
https://www.ncbi.nlm.nih.gov/pubmed/33007840
http://dx.doi.org/10.3390/cancers12102813
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author Pedersen, Henriette
Schmiegelow, Kjeld
Hamerlik, Petra
author_facet Pedersen, Henriette
Schmiegelow, Kjeld
Hamerlik, Petra
author_sort Pedersen, Henriette
collection PubMed
description SIMPLE SUMMARY: Approximately 50% of high-grade gliomas (HGG) in children are diffuse midline gliomas (DMGs), which carry the worst prognosis of all HGG, with a 2-year survival of less than 10%. DMGs are characterized by H3K27M mutation, rampant genomic instability, infiltrative growth, and radio-resistance. Recent large-scale profiling studies have identified some of the key molecular drivers underpinning DMG biology and therapeutic resistance. Here, we provide a comprehensive overview of studies that focus on DMG in the context of radio-resistance. We speculate that the aberrant activation of DNA damage response pathway (DDR) represents a druggable vulnerability, which could be leveraged to radio-sensitize DMGs. ABSTRACT: Malignant gliomas (MG) are among the most prevalent and lethal primary intrinsic brain tumors. Although radiotherapy (RT) is the most effective nonsurgical therapy, recurrence is universal. Dysregulated DNA damage response pathway (DDR) signaling, rampant genomic instability, and radio-resistance are among the hallmarks of MGs, with current therapies only offering palliation. A subgroup of pediatric high-grade gliomas (pHGG) is characterized by H3K27M mutation, which drives global loss of di- and trimethylation of histone H3K27. Here, we review the most recent literature and discuss the key studies dissecting the molecular biology of H3K27M-mutated gliomas in children. We speculate that the aberrant activation and/or deactivation of some of the key components of DDR may be synthetically lethal to H3K27M mutation and thus can open novel avenues for effective therapeutic interventions for patients suffering from this deadly disease.
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spelling pubmed-76003972020-11-01 Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas Pedersen, Henriette Schmiegelow, Kjeld Hamerlik, Petra Cancers (Basel) Review SIMPLE SUMMARY: Approximately 50% of high-grade gliomas (HGG) in children are diffuse midline gliomas (DMGs), which carry the worst prognosis of all HGG, with a 2-year survival of less than 10%. DMGs are characterized by H3K27M mutation, rampant genomic instability, infiltrative growth, and radio-resistance. Recent large-scale profiling studies have identified some of the key molecular drivers underpinning DMG biology and therapeutic resistance. Here, we provide a comprehensive overview of studies that focus on DMG in the context of radio-resistance. We speculate that the aberrant activation of DNA damage response pathway (DDR) represents a druggable vulnerability, which could be leveraged to radio-sensitize DMGs. ABSTRACT: Malignant gliomas (MG) are among the most prevalent and lethal primary intrinsic brain tumors. Although radiotherapy (RT) is the most effective nonsurgical therapy, recurrence is universal. Dysregulated DNA damage response pathway (DDR) signaling, rampant genomic instability, and radio-resistance are among the hallmarks of MGs, with current therapies only offering palliation. A subgroup of pediatric high-grade gliomas (pHGG) is characterized by H3K27M mutation, which drives global loss of di- and trimethylation of histone H3K27. Here, we review the most recent literature and discuss the key studies dissecting the molecular biology of H3K27M-mutated gliomas in children. We speculate that the aberrant activation and/or deactivation of some of the key components of DDR may be synthetically lethal to H3K27M mutation and thus can open novel avenues for effective therapeutic interventions for patients suffering from this deadly disease. MDPI 2020-09-30 /pmc/articles/PMC7600397/ /pubmed/33007840 http://dx.doi.org/10.3390/cancers12102813 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Review
Pedersen, Henriette
Schmiegelow, Kjeld
Hamerlik, Petra
Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas
title Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas
title_full Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas
title_fullStr Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas
title_full_unstemmed Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas
title_short Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas
title_sort radio-resistance and dna repair in pediatric diffuse midline gliomas
topic Review
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600397/
https://www.ncbi.nlm.nih.gov/pubmed/33007840
http://dx.doi.org/10.3390/cancers12102813
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