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Liquid biopsy in H3K27M diffuse midline glioma
Jina Patel1, Rayan Aittaleb1, Robert Doherty1
1Department of Pediatrics, Michigan Medicine, Ann Arbor, Michigan, USA.
Abstract:
Diffuse midline glioma (DMG) with H3K27M mutation is an aggressive and difficult to treat pediatric brain tumor. Recurrent gain of function mutations in H3.3 (H3.3A) and H3.1 (H3C2) at the 27th lysine to methionine (H3K27M) are seen in over 2/3 of DMGs, and are associated with a worse prognosis. Due to the anatomical location of DMG, traditional biopsy carries risk for neurologic injury as it requires penetration of vital midline structures. Further, radiographic (MRI) monitoring of DMG often shows nonspecific changes, which makes therapeutic monitoring difficult. This indicates a critical need for more minimally invasive methods, such as liquid biopsy, to understand, diagnose, and monitor H3K27M DMG. Here, we review the use of all modalities to date to detect biomarkers of H3K27M in cerebrospinal fluid (CSF), blood, and urine, and compare their effectiveness in detection, diagnosis, and monitoring treatment response. We provide specific detail of recent efforts to monitor CSF and plasma H3K27M cell-free DNA in patients undergoing therapy with the imipridone ONC201. Lastly, we discuss the future of therapeutic monitoring of H3K27M-DMG, including biomarkers such as mitochondrial DNA, mutant and modified histones, and novel sequencing-based approaches for improved detection methods.
Insights
Liquid biopsy offers a minimally invasive approach for detecting H3K27M mutations in pediatric diffuse midline glioma (DMG). This method aids in diagnosis and monitoring treatment response for this aggressive brain tumor.
Area of Science:
- Neuro-oncology
- Molecular Biology
- Pediatric Oncology
Background:
- Diffuse midline glioma (DMG) with H3K27M mutation is a challenging pediatric brain tumor with poor prognosis.
- Traditional biopsy and MRI monitoring pose risks and limitations for DMG diagnosis and treatment assessment.
- There is a critical need for minimally invasive biomarkers for H3K27M DMG detection and monitoring.
Purpose of the Study:
- To review current liquid biopsy modalities for detecting H3K27M biomarkers in DMG.
- To compare the effectiveness of different liquid biopsy approaches in diagnosis and treatment monitoring.
- To discuss future directions in H3K27M DMG therapeutic monitoring.
Main Methods:
- Review of existing literature on liquid biopsy techniques for H3K27M detection.
- Analysis of biomarker detection in cerebrospinal fluid (CSF), blood, and urine.
- Examination of cell-free DNA (cfDNA) monitoring in CSF and plasma during ONC201 therapy.
Main Results:
- Liquid biopsy modalities show promise for detecting H3K27M biomarkers.
- cfDNA monitoring in CSF and plasma is being explored for treatment response assessment.
- Emerging biomarkers include mitochondrial DNA, mutant histones, and novel sequencing approaches.
Conclusions:
- Liquid biopsy represents a significant advancement for H3K27M DMG management.
- Further research into novel biomarkers and sequencing methods will enhance diagnostic and monitoring capabilities.
- Minimally invasive monitoring is crucial for improving outcomes in pediatric H3K27M DMG.
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