Pediatric diffuse midline glioma: Understanding the mechanisms and assessing the next generation of personalized therapeutics

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Abstract

Diffuse midline glioma (DMG) is a pediatric cancer that originates in the midline structures of the brain. Prognosis of DMG patients remains poor due to the infiltrative nature of these tumors and the protection they receive from systemically delivered therapeutics via an intact blood–brain barrier (BBB), making treatment difficult. While the cell of origin remains disputed, it is believed to reside in the ventral pons. Recent research has pointed toward epigenetic dysregulation inducing an OPC-like transcriptomic signature in DMG cells. This epigenetic dysregulation is typically caused by a mutation (K27M) in one of two histone genes— H3F3A or HIST1H3B –and can lead to a differentiation block that increases these cells oncogenic potential. Standard treatment with radiation is not sufficient at overcoming the aggressivity of this cancer and only confers a survival benefit of a few months, and thus, discovery of new therapeutics is of utmost importance. In this review, we discuss the cell of origin of DMGs, as well as the underlying molecular mechanisms that contribute to their aggressivity and resistance to treatment. Additionally, we outline the current standard of care for DMG patients and the potential future therapeutics for this cancer that are currently being tested in preclinical and clinical trials.

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The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered. The 2016 edition has added newly recognized neoplasms, and has deleted some entities, variants and patterns that no longer have diagnostic and/or biological relevance. Other notable changes include the addition of brain invasion as a criterion for atypical meningioma and the introduction of a soft tissue-type grading system for the now combined entity of solitary fibrous tumor / hemangiopericytoma-a departure from the manner by which other CNS tumors are graded. Overall, it is hoped that the 2016 CNS WHO will facilitate clinical, experimental and epidemiological studies that will lead to improvements in the lives of patients with brain tumors.

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David N Louis, Arie Perry, Pieter Wesseling … (2021)

The fifth edition of the WHO Classification of Tumors of the Central Nervous System (CNS), published in 2021, is the sixth version of the international standard for the classification of brain and spinal cord tumors. Building on the 2016 updated fourth edition and the work of the Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy, the 2021 fifth edition introduces major changes that advance the role of molecular diagnostics in CNS tumor classification. At the same time, it remains wedded to other established approaches to tumor diagnosis such as histology and immunohistochemistry. In doing so, the fifth edition establishes some different approaches to both CNS tumor nomenclature and grading and it emphasizes the importance of integrated diagnoses and layered reports. New tumor types and subtypes are introduced, some based on novel diagnostic technologies such as DNA methylome profiling. The present review summarizes the major general changes in the 2021 fifth edition classification and the specific changes in each taxonomic category. It is hoped that this summary provides an overview to facilitate more in-depth exploration of the entire fifth edition of the WHO Classification of Tumors of the Central Nervous System.

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Andrew Bannister, Tony Kouzarides (2011)

Chromatin is not an inert structure, but rather an instructive DNA scaffold that can respond to external cues to regulate the many uses of DNA. A principle component of chromatin that plays a key role in this regulation is the modification of histones. There is an ever-growing list of these modifications and the complexity of their action is only just beginning to be understood. However, it is clear that histone modifications play fundamental roles in most biological processes that are involved in the manipulation and expression of DNA. Here, we describe the known histone modifications, define where they are found genomically and discuss some of their functional consequences, concentrating mostly on transcription where the majority of characterisation has taken place.

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Author and article information

Contributors

Nicolina Jovanovich

Ahmed Habib

Jeffery Head

Farrukh Hameed

Sameer Agnihotri

Pascal O Zinn:

ORCID: https://orcid.org/0000-0003-0091-5887

Journal

Journal ID (nlm-ta): Neurooncol Adv

Journal ID (iso-abbrev): Neurooncol Adv

Journal ID (publisher-id): noa

Title: Neuro-Oncology Advances

Publisher: Oxford University Press (US )

ISSN (Electronic): 2632-2498

Publication date Collection: Jan-Dec 2023

Publication date (Electronic): 12 April 2023

Publication date PMC-release: 12 April 2023

Volume: 5

Issue: 1

Electronic Location Identifier: vdad040

Affiliations

Hillman Cancer Center, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Department of Neurosurgery, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Hillman Cancer Center, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Department of Neurosurgery, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Hillman Cancer Center, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Department of Neurosurgery, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Hillman Cancer Center, University of Pittsburgh Medical Center , Pittsburgh, Pennsylvania, USA

Author notes

Corresponding Authors: Pascal O. Zinn, MD, PhD, 5150 Centre Ave. Suite 433, Pittsburgh, PA 15232, USA ( zinnpo@ 123456upmc.edu )

Sameer Agnihtroi, PhD, 4401 Penn Avenue, Office 7126, Pittsburgh, PA 15224, USA ( sameer.agnihotri@ 123456chp.edu ).

Author information

Pascal O Zinn https://orcid.org/0000-0003-0091-5887

Article

Publisher ID: vdad040

DOI: 10.1093/noajnl/vdad040

PMC ID: 10162114

PubMed ID: 37152806

SO-VID: 2b5cd23b-3129-49fd-aee8-c862b44dbb99

License:

This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( https://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date: 05 May 2023

Page count

Pages: 12

Funding

Funded by: University of Pittsburgh, DOI 10.13039/100007921;

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