Abstract 3047: Spatial heterogeneity in diffuse intrinsic pontine gliomas treated with a PDGFR inhibitor

Abstract

Abstract Diffuse intrinsic pontine gliomas (DIPG) are lethal pediatric brain tumors that arise in the pons. To understand the spatial heterogeneity in DIPG, we performed ultra-deep sequencing and copy number profiling of 44 multi-region autopsy samples from 10 DIPG patients after phase I treatment with the PDGFR inhibitor crenolanib. Our study recapitulated the previously reported temporal order of driver mutation acquisition starting with histone H3 K27M followed by cell cycle (TP53 and PPM1D) or growth factor pathways (AVCR1, or PIK3R1), with mutations affecting PI3K and MAPK pathways being late, subclonal events. Further, we observed that aneuploidy was likely an early event as copy number heterogeneity was minimal in most patients. Compared to previous DIPG studies, we observed an enrichment in subclonal mutations and convergent evolution of PI3K alterations. This enrichment may have been due to selection for crenolanib resistance, or to the prior treatment history of the patients within the cohort. We also detailed intra-patient clonal composition among tumor samples and identified founder clones that were dominant in only a single location, which we considered to be non-migratory “occupier” clones, in four patients. By contrast, in six other cases, we observed clones that frequently invaded other sites. Interestingly, in one case with TP53 convergent evolution, aneuploidy clone carrying TP53 R273H mutation invades all other sequenced tumor sites whereas another clone with TP53 R248W does not. These results indicate the importance of understanding spatial heterogeneity within DIPG patients, which is crucial to the identification of effective treatments. Citation Format: Sasi Arunachalam, Samuel W. Brady, Xiaotu Ma, Karol Szlachta, Heather Mulder, John Easton, Christopher L. Tinkle, Cynthia Wetmore, Suzanne J. Baker, Jinghui Zhang. Spatial heterogeneity in diffuse intrinsic pontine gliomas treated with a PDGFR inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 3047.