The Bermuda Triangle of paediatric brain cancers: epigenetics, developmental timing window and cell of origin

Paediatric brain cancers are aggressive tumours that urgently need deeper understanding of their cellular and molecular vulnerabilities to facilitate the development of effective treatments. These tumours frequently arise from epigenetic alterations in specific immature cell states of the developing prenatal or neonatal brain. In this review, we propose a "three-event" model composed of an epigenetic event, developmental timing window and the cell of origin for tumour initiation in paediatric brain tumours. We focus on three types of paediatric gliomas: diffuse midline gliomas (DMG), diffuse hemispheric gliomas (DHG) and posterior fossa A ependymomas (PFA-EPN), which reflect our proposed three-event model. Additionally, we discuss the methods and models used to study these three events separately or simultaneously. Taken together, this review highlights the spatio-temporal vulnerable cell states during brain development and which molecular drivers hijack these cues to induce cell state stalling and tumour initiation. The next steps to expand our understanding of the order of events and their use in therapy are further discussed.