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Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit.

ABSTRACT: Pediatric high-grade gliomas (pHGG) are a molecularly diverse group of malignancies, each incredibly aggressive and in dire need of treatment advancements. Genomic analysis has revolutionized our understanding of these tumors, identifying biologically relevant subgroups with differing canonical mutational profiles that vary based on tumor location and age. In particular, the discovery of recurrent histone H3 mutations (H3K27M in diffuse midline glioma, H3G34R/V in hemispheric pediatric high-grade gliomas) as unique "oncohistone" drivers revealed epigenetic dysregulation as a hallmark of pediatric high-grade gliomas oncogenesis. While reversing this signature through epigenetic programming has proven effective in several pre-clinical survival models, early results from pediatric high-grade gliomas clinical trials suggest that epigenetic modifier monotherapy will likely not provide long-term disease control. In this review we summarize the genetic, epigenetic, and cellular heterogeneity of pediatric high-grade gliomas, and highlight potential paths forward for epigenetic programming in this devastating disease.

SUBMITTER: Groves A

PROVIDER: S-EPMC9795020 | biostudies-literature | 2022

REPOSITORIES: biostudies-literature

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Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit.

Groves Andrew A Cooney Tabitha M TM

Frontiers in cell and developmental biology 20221214

Pediatric high-grade gliomas (pHGG) are a molecularly diverse group of malignancies, each incredibly aggressive and in dire need of treatment advancements. Genomic analysis has revolutionized our understanding of these tumors, identifying biologically relevant subgroups with differing canonical mutational profiles that vary based on tumor location and age. In particular, the discovery of recurrent histone H3 mutations (H3K27M in diffuse midline glioma, H3G34R/V in hemispheric pediatric high-grad ...[more]

PMID: 36589742

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Project description:Pediatric high-grade glioma (HGG) is a type of malignancy that carries a poor prognosis. The genetic analysis of HGGs has previously identified useful mutations, the targeting of which has improved prognosis. Thus, further research into the more common mutations, such as H3 histone variants (HIST1H3B and H3F3A) and BRAF V600E, may be useful in identifying tumors with different prognoses, as the mutations are considered to drive two distinct oncogenic programs. The present study performed a retrospective analysis of pediatric HGGs. In total, 42 cases of HGG, including 32 cases (76.1%) of anaplastic astrocytoma and 10 cases (23.8%) of glioblastoma multiforme (GBM), were assessed. The median age of the patients was 7 years (range, 0-32 years). Mutations on histone H3, in particular the K27M and G34R mutations in the distinct variants HIST1H3B and H3F3A, in addition to the presence of the BRAF V600E mutation, were analyzed in 24 patients. The H3F3A K27M mutation was identified in 7 patients (29.1%), while the HIST1H3B K27M mutation was only observed in 1 patient with GBM. In addition, 5 patients harbored a BRAF V600E mutation (21%), while the H3F3A G34R mutation was not recorded in any of the patients. The overall survival of the wild-type patients at 20 months was 68% [confidence interval (CI): 38-85%] compared with 28% (CI: 0.4-60%) in patients with the H3F3A K27M mutation. These results suggested that patients with the H3F3A K27M mutation had a worse prognosis compared with wild-type patients (P=0.0045). Moreover, 3/5 patients with the BRAF V600E mutation had HGGs that were derived from a previous low-grade glioma (LGG; P=0.001). In conclusion, these results suggested that histone H3 mutations may help predict the outcome in patients with HGG. In addition, the BRAF V600E mutation was found to be associated with an increased risk of anaplastic progression. The novel data of the present study may help better define the clinical and radiological characteristics of glioma.

Project description:Background: Transcranial direct current stimulation (tDCS) has been used extensively in patient populations to facilitate motor network plasticity. However, it has not been studied in patients with brain tumors. We aimed to determine the feasibility of a preoperative motor training and tDCS intervention in patients with glioma. In an exploratory manner, we assessed changes in motor network connectivity following this intervention and related these changes to predicted electrical field strength from the stimulated motor cortex. Methods: Patients with left-sided glioma (n=8) were recruited in an open label proof of concept pilot trial and participated in four consecutive days of motor training combined with tDCS. The motor training consisted of a 60-min period where the subject learned to play the piano with their right hand. Concurrently, they received 40 min of 2 mA anodal tDCS of the left motor cortex. Patients underwent task and resting state fMRI before and after this intervention. Changes in both the connectivity of primary motor cortex (M1) and general connectivity across the brain were assessed. Patient specific finite element models were created and the predicted electrical field (EF) resulting from stimulation was computed. The magnitude of the EF was extracted from left M1 and correlated to the observed changes in functional connectivity. Results: There were no adverse events and all subjects successfully completed the study protocol. Left M1 increased both local and global connectivity. Voxel-wide measures, not constrained by a specific region, revealed increased global connectivity of the frontal pole and decreased global connectivity of the supplementary motor area. The magnitude of EF applied to the left M1 correlated with changes in global connectivity of the right M1. Conclusion: In this proof of concept pilot study, we demonstrate for the first time that tDCS appears to be feasible in glioma patients. In our exploratory analysis, we show preoperative motor training combined with tDCS may alter sensorimotor network connectivity. Patient specific modeling of EF in the presence of tumor may contribute to understanding the dose-response relationship of this intervention. Overall, this suggests the possibility of modulating neural networks in glioma patients.

Dataset Information

Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit.

Publications

Epigenetic programming of pediatric high-grade glioma: Pushing beyond proof of concept to clinical benefit.

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