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Review
. 2020 Sep 30;12(10):2813.
doi: 10.3390/cancers12102813.

Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas

Henriette Pedersen  1 , Kjeld Schmiegelow  2   3 , Petra Hamerlik  1   4
Affiliations
Review

Radio-Resistance and DNA Repair in Pediatric Diffuse Midline Gliomas

Henriette Pedersen et al. Cancers (Basel). .

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.

Keywords: DNA damage response; H3K27M mutation; pediatric high-grade gliomas; radio-resistance.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Molecular subtypes of diffuse intrinsic pontine glioma (DIPG). DIPGs can be divided into three distinct molecular subtypes: MYCN, Silent, and H3 K27M.
Figure 2
Figure 2
Magnetic resonance imaging (MRI) of DIPG tumor from an individual patient (white arrows). (A) Sagittal T1-weighted. (B) Sagittal T1-weighted. (C) Axial T2-weighted.
Figure 3
Figure 3
H3K27M is the major oncogenic driver in pediatric high-grade gliomas (pHGG). (A) The polycomb repressive complex 2 (PRC2) complex mediates the di- and trimethylation of H3K27 in healthy brains. (B) The H3K27M mutation in diffuse midline gliomas (DMG) leads to global loss of di- and trimethylation of histone H3K27 (H3K27me2 and H3K27me3) by inactivating the PRC2 complex.
Figure 4
Figure 4
DNA damage response pathway (DDR). In response to DNA damage, which can be induced by the exposure to either endogenous or exogenous factors, cells activate DDR. Depending on the extent and type of DNA damage (single-strand DNA break (SSB) versus double-strand DNA break (DSB)), the DDR can trigger cell cycle arrest, apoptosis, cellular senescence, or DNA repair. A number of DDR components have been successfully targeted in pre-clinical settings.
Figure 5
Figure 5
Potential treatment strategy to overcome radio-resistance in H3K27M-mutated pHGG. (A) H3K27M mutation confers radio-resistance in pHGG due to the de-regulation of DNA repair machineries. (B) Combinational approach, where radiotherapy (RT) is combined with DNA repair inhibitors, may pave the way for overcoming the radio-resistance of H3K27M-mutated pHGG.
See this image and copyright information in PMC

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