Insights from Tumour Heterogeneity into the Oncogenesis and Resistance of Paediatric Diffuse Midline Gliomas

Diffuse intrinsic pontine gliomas (DIPG), and more broadly diffuse midline gliomas (DMG), represent the most severe and common forms of malignant brain tumours in children and adolescents. They arise in the pons, thalamus, or spinal cord, and harbour a unique mutation in histone H3 genes involving the substitution of lysine 27 by methionine (H3K27M). Hallmarks of these tumours are their extraordinary invasive capacity and resistance to treatment, leading to a dramatically poor prognosis with a median survival below 2 years.

Despite recent progress in our understanding of these tumours and their epigenetic oncogenesis, limited advances have been achieved in the clinic. We have developed a dedicated research program to tackle this incurable disease by combining clinical data, in vitro and in vivo modelling, and molecular and cellular analyses.

In this seminar, I will focus on how, despite the apparent homogeneity of DMG linked to a universal driver event altering H3K27 methylation, our molecular analyses support the stratification of paediatric diffuse midline gliomas into distinct subtypes. I will also present data on genetic instability and radioresistance mechanisms within these different subtypes, and discuss how these findings impact our current and future research strategies.