Spatial and temporal homogeneity of driver mutations in diffuse intrinsic pontine glioma

Hamid Nikbakht, Eshini Panditharatna, Leonie G. Mikael, Rui Li, Tenzin Gayden, Matthew Osmond, Cheng-Ying Ho, Madhuri Kambhampati, Eugene I. Hwang, Damien Faury, Alan Siu, Simon Papillon-Cavanagh, Denise Bechet, Keith L. Ligon, Benjamin Ellezam, Wendy J. Ingram, Caedyn Stinson, Andrew S. Moore, Katherine E. Warren, Jason Karamchandani, Roger J. Packer, Nada Jabado, Jacek Majewski, Javad Nazarian

Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M-including H3.2K27M-mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis. These H3K27M ubiquitously-associated mutations involve alterations in TP53 cell-cycle (TP53/PPM1D) or specific growth factor pathways (ACVR1/PIK3R1). Later oncogenic alterations arise in sub-clones and often affect the PI3K pathway. Our findings are consistent with early tumour spread outside the brainstem including the cerebrum. The spatial and temporal homogeneity of main driver mutations in DIPG implies they will be captured by limited biopsies and emphasizes the need to develop therapies specifically targeting obligate oncohistone partnerships.