Diffuse Midline Glioma-Pons

Diffuse Midline Glioma-Pons (DMG-P, formerly Diffuse Intrinsic Pontine Glioma (DIPG)) is almost uniformly fatal, predominantly affects children, and is the most common brainstem tumor of childhood. DMG-P is diagnosed based on characteristic magnetic resonance imaging (MRI) findings in a child with typical clinical features, and biopsy for tissue diagnosis and/or molecular interrogation is being increasing required as part of clinical trials. Surgical resection is not considered an option due to critical tumor location, and the beneficial effects of radiation therapy are only transient and considered palliative. Chemotherapy, given as single or multiple agents, with and without radiation, has had no significant impact on the outcome of these tumors. Clinical trials using novel treatment strategies and new therapeutic agents have not improved prognosis in the past two decades. Recent integrated genomic studies have identified three subgroups of DMG-P based on the histone mutational status. Chromatin remodeling defects in the developing brain due to recurrent somatic driver mutations affecting the histone 3 variant proteins, H3.3/3.1 (H3.3-K27M, H3.1-K27M) or overexpression of EZHIP in H3 wild-type tumors in association with mutations involving specific genes (TP53, PDGFRA, MYC/PVT1, ACVR1) likely play a pivotal role in the pathogenesis of DMG-P tumors. Current and future clinical trials in DMG-P should be based on molecular classification of tumor tissue obtained from biopsy and include diagnostic, predictive, and prognostic biomarkers, as this will help improve treatment stratification, specific targeted therapies, monitoring of therapeutic efficacy, and accurate prognostication.