Liquid biopsy in H3K27M diffuse midline glioma

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.

Keywords: H3K27M; ONC201; cell-free tumor DNA; diffuse midline glioma; liquid biopsy.

Figure 1.

Past, present, and future of H3K27M focused liquid biopsy. Seminal work identified disease-specific proteins in cerebrospinal fluid (CSF)—as well as patient serum and urine. The current state of the art is focused on serial quantification of H3K27M circulating tumor DNA in CSF and plasma using accurate droplet digital PCR assays and correlation with radiographic imaging to identify if liquid biopsy could be leveraged to predict response to treatment and help resolve pseudoprogression. Newer liquid biopsy approaches will leverage alternative and novel biomarkers such as mutant/modified histones derived from H3K27M mutant cells, routine, low-burden CSF collection via Ommaya reservoirs, as well as highly accurate and rapid sequencing approaches to simultaneously assay H3K27M along with other mutations (Created with BioRender.com).