Genomic drivers of distinct pediatric brain tumors: diffuse midline gliomas and adamantinomatous craniopharyngiomas

Abstract

Pediatric brain tumors are distinct from their adult counterparts. This thesis examines genomic drivers of two distinct pediatric brain tumors: a fast growing and uniformly fatal diffuse midline glioma and a slower growing but nevertheless devastating adamantinomatous craniopharyngiomas. Here we analyze whole genome sequences of 170 pediatric high-grade gliomas and find that truncating mutations in PPM1D are clonal driver events in 11% of diffuse midlines gliomas and are enriched in primary diffuse intrinsic pontine gliomas. Although PPM1D mutations have previously been reported in diffuse midline gliomas, their role in de novo gliomagenesis has not been systematically explored. Through the development of novel mouse models, we show that PPM1D mutations potentiate gliomagenesis and that PPM1D activity is required for in vivo oncogenesis. Finally, we apply integrative phosphoproteomic and functional genomics assays and find that the oncogenic effects of PPM1D truncation converge on regulators of cell-cycle, DNA-damage response, and p53 pathways, revealing therapeutic vulnerabilities. Together, these findings highlight PPM1D mutations to represent a targetable driver of diffuse midline gliomas. Furthermore, we also analyze whole genome sequences of 33 adamantinomatous craniopharyngiomas. Consistent with previous studies, we find recurrent CTNNB1 mutation in 70% of our cohort. Future studies will involve comprehensive characterization of the copy number alterations and structural variations in these tumors with the goal of identifying novel driver alterations.