New Developments in the Pathogenesis, Therapeutic Targeting, and Treatment of H3K27M-Mutant Diffuse Midline Glioma

Abstract

H3K27M-mutant diffuse midline gliomas (DMGs) are rare childhood central nervous system tumors that carry a dismal prognosis. Thus, innovative treatment approaches are greatly needed to improve clinical outcomes for these patients. Here, we discuss current trends in research of H3K27M-mutant diffuse midline glioma. This review highlights new developments of molecular pathophysiology for these tumors, as they relate to epigenetics and therapeutic targeting. We focus our discussion on combinatorial therapies addressing the inherent complexity of treating H3K27M-mutant diffuse midline gliomas and incorporating recent advances in immunotherapy, molecular biology, genetics, radiation, and stereotaxic surgical diagnostics.

Keywords: H3K27M-mutant; biopsy; chemotherapy; diffuse intrinsic pontine glioma (DIPG); diffuse midline glioma; immunotherapy; radiotherapy.

Figure 1

H3K27M mutation and tumorigenesis in diffuse midline glioma. The H3K27M mutation is a recurrent somatic gain-of-function missense mutation (AAG → ATG), resulting in a lysine 27 to methionine (p. Lys27Met: K27M) substitution in histone 3 (H3) variants (purple quadrant). The blue line represents double-stranded DNA wrapped around histones (short, segmented cylinders) regulating normal gene expression. The H3K27M mutation leads to the global loss of H3K27 trimethylation (green hexagons) and subsequent gain of H3K27 acetylation (blue circles), which is linked to oncogenesis (gene amplification, mutation, and deletion) and, subsequently, tumorigenesis [1].

Figure 2

H3K27M-mutant diffuse midline glioma on MR imaging. Classic appearance of H3K27M-mutant diffuse midline glioma on MR-imaging: hyperintense signal on an axial T2-weighted fluid-attenuated inversion recovery (FLAIR) image (A), hypointense signal on an axial T1-weighted post-contrast image (B), and isointense signal on a sagittal T1-weighted post-contrast image (C).