H3 K27M-Altered Diffuse Midline Gliomas: A Review

Wiśniewski, Karol; Ghaly, Andrew; Drummond, Katharine J.; Fahlström, Andreas

doi:10.1055/s-0043-1771192

Cited by 4 publications

(3 citation statements)

References 98 publications

(238 reference statements)

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“…By classifying brain tumors according to their unique DNA methylation patterns, this approach has revolutionized how we diagnose cases where traditional histology alone may not provide clear answers. This advancement has notably transformed the diagnostic strategy for CNS tumors with uncertain characteristics [ 37 , 39 , 40 , 41 ].…”

Section: Resultsmentioning

confidence: 99%

Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma

Miguel Llordes,

Medina Pérez,

Curto Simón

et al. 2023

JCM

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Object: Diffuse midline glioma (DMG) is a highly aggressive and lethal brain tumor predominantly affecting children and young adults. Previously known as diffuse intrinsic pontine glioma (DIPG) or grade IV brain stem glioma, DMG has recently been reclassified as “diffuse midline glioma” according to the WHO CNS5 nomenclature, expanding the DMG demographic. Limited therapeutic options result in a poor prognosis, despite advances in diagnosis and treatment. Radiotherapy has historically been the primary treatment modality to improve patient survival. Methods: This systematic literature review aims to comprehensively compile information on the diagnosis and treatment of DMG from 1 January 2012 to 31 July 2023. The review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) statement and utilized databases such as PubMed, Cochrane Library, and SciELO. Results: Currently, molecular classification of DMG plays an increasingly vital role in determining prognosis and treatment options. Emerging therapeutic avenues, including immunomodulatory agents, anti-GD2 CAR T-cell and anti-GD2 CAR-NK therapies, techniques to increase blood–brain barrier permeability, isocitrate dehydrogenase inhibitors, oncolytic and peptide vaccines, are being explored based on the tumor’s molecular composition. However, more clinical trials are required to establish solid guidelines for toxicity, dosage, and efficacy. Conclusions: The identification of the H3K27 genetic mutation has led to the reclassification of certain midline tumors, expanding the DMG demographic. The field of DMG research continues to evolve, with encouraging findings that underscore the importance of highly specific and tailored therapeutic strategies to achieve therapeutic success.

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Section: Resultsmentioning

confidence: 99%

Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma

Miguel Llordes,

Medina Pérez,

Curto Simón

et al. 2023

JCM

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“…A pivotal advancement in recent years has involved epigenetic investigations to identify H3K27 alterations common in DMGs and similar midline gliomas within the thalamus, spine, and brainstem regions [4][5][6][7]. These alterations can include mutations in H3.3, H3.1, or H3.2; EZHIP overexpression; or EGFR mutants [8][9][10]. According to the 2021 World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS), pediatric-type diffuse high-grade gliomas are now classified into four types of tumors: diffuse midline gliomas, H3 K27 altered; diffuse hemispheric gliomas, H3 G34 mutant; diffuse pediatric-type high-grade gliomas, H3 wildtype and IDH (isocitrate dehydrogenase) wildtype; and infant-type hemispheric gliomas, each having distinct prognoses and molecular characteristics [10].…”

Section: Introduction Diffuse Midline Gliomas (Dmgs): Definition Clas...mentioning

confidence: 99%

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

Qazi,

Talebi,

Trieu

2024

Biomedicines

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This hypothesis-generating study characterized the mRNA expression profiles and prognostic impacts of antigen-presenting cell (APC) markers (CD14, CD163, CD86, and ITGAX/CD11c) in pediatric brainstem diffuse midline glioma (pbDMG) tumors. We also assessed the mRNA levels of two therapeutic targets, transforming growth factor beta 2 (TGFB2) and interferon gamma receptor 2 (IFNGR2), for their biomarker potentials in these highly aggressive pbDMG tumors. The expressions of CD14, CD163, and ITGAX/CD11c mRNAs exhibited significant decreases of 1.64-fold (p = 0.037), 1.75-fold (p = 0.019), and 3.33-fold (p < 0.0001), respectively, in pbDMG tumors relative to those in normal brainstem/pons samples. The pbDMG samples with high levels of TGFB2 in combination with low levels of APC markers, reflecting the cold immune state of pbDMG tumors, exhibited significantly worse overall survival outcomes at low expression levels of CD14, CD163, and CD86. The expression levels of IFNGR2 and TGFB2 (1.51-fold increase (p = 0.002) and 1.58-fold increase (p = 5.5 × 10−4), respectively) were significantly upregulated in pbDMG tumors compared with normal brainstem/pons samples. We performed multivariate Cox proportional hazards modelling that showed TGFB2 was a prognostic indicator (HR for patients in the TGFB2high group of pbDMG patients = 2.88 (1.12–7.39); p = 0.028) for poor overall survival (OS) and was independent of IFNGR2 levels, the age of the patient, and the significant interaction effect observed between IFNGR2 and TGFB2 (p = 0.015). Worse survival outcomes in pbDMG patients when comparing high versus low TGFB2 levels in the context of low IFNGR2 levels suggest that the abrogation of the TGFB2 mRNA expression in the immunologically cold tumor microenvironment can be used to treat pbDMG patients. Furthermore, pbDMG patients with low levels of JAK1 or STAT1 mRNA expression in combination with high levels of TGFB2 also exhibited poor OS outcomes, suggesting that the inclusion of (interferon-gamma) IFN-γ to stimulate and activate JAK1 and STAT1 in anti-tumor APC cells present the brainstem TME can enhance the effect of the TGFB2 blockade.

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“…The review article included in this issue highlights the differences between the adult and pediatric midline glioma. 2 The authors have done a commendable job of reviewing 97 articles for this study. At present, research focuses on identifying the new targeted therapies, but we are miles away from any practical utility.…”

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confidence: 99%

Glioma, The Road Ahead

Jagetia

2023

Indian Journal of Neurosurgery

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H3 K27M-Altered Diffuse Midline Gliomas: A Review

Cited by 4 publications

References 98 publications

Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma

Epidemiology, Diagnostic Strategies, and Therapeutic Advances in Diffuse Midline Glioma

Transforming Growth Factor Beta 2 (TGFB2) and Interferon Gamma Receptor 2 (IFNGR2) mRNA Levels in the Brainstem Tumor Microenvironment (TME) Significantly Impact Overall Survival in Pediatric DMG Patients

Glioma, The Road Ahead

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