H3K27-altered diffuse midline gliomas– a cancer of deranged neuromaturation?

H3K27-altered diffuse midline gliomas (DMGs) are a group of tumours that arise in midline structures of the neural axis and portend a dismal prognosis. In recent years, significant strides have been made in the understanding of DMG biology, including discovery of inciting histone-3 mutations, linkage of tumorigenesis with H3K27-trimethylation (H3K27me3) loss, and the identification of associated ‘second-hit’ onco-driver mutations. The oncogenic potential of H3K27me3 loss-induced transcriptional repression prompts the consideration of deranged neuromaturation–a consequence of H3K27me3 loss-related dysregulation of pluripotency and lineage-differentiation genes during embryogenesis–as another potential contributor to midline gliomagenesis. Indeed, the existence of an oligodendrocyte precursor cell (OPC)-like subpopulation in DMGs hints at the possibility of H3K27me3 loss-induced arrested differentiation in hindbrain neuroprogenitors forming a glioma stem cell core that is capable of constant self-renewal and unchecked growth. Further, the sustenance of DMG survival is supported by a plethora of pro-tumorigenic processes–ranging from onco-metabolic shifts; to establishment of a hypo-immunogenic tumour micro-environment; to mitogenic signalling via glioma-neuronal synaptic networks. In this review, we revisit existing evidence of the various processes contributing to DMG pathogenesis and string them into a chronological tapestry of events that seeks to elucidate the entire midline gliomagenesis process from its inception.