The diverse landscape of histone-mutant pediatric high-grade gliomas

Pediatric high-grade gliomas (pHGGs) are the leading cause of tumor-related death in children, with diffuse midline gliomas representing the worst prognoses. Despite decades of clinical trials, no effective treatment has been found, and we are in desperate need of novel therapeutics. The discovery of highly recurrent histone H3 mutations in pHGGs represents a major breakthrough in our understanding of tumor initiation and development. In this review, we summarize our current knowledge of the molecular pathology of these tumors, including their genomic/epigenetic alterations, mechanism of action, and partner mutations contributing to tumor progression.