| Diffuse intrinsic pontine glioma (DIPG) is a devastating, inoperable paediatric brain neoplasm with no effective therapy and near 100% fatality. Diagnosis is based mainly on radiological findings and numerous clinical trials using adjuvant chemotherapy over the last four decades have not shown a survival benefit compared to radiation alone. Although the delicate location of these lesions is a contributing factor to the dismal outcomes seen in these children, most of these clinical trials were designed based on adult protocols, with assumptions that paediatric brainstem tumours, whose histology most often resembles high-grade supratentorial glioblastoma (GBM) of adults, would respond to similar therapies.;By combining histological review, methylation profiling, whole-genome and whole-exome sequencing, gene expression profiling, and copy number analysis of a large cohort of DIPG, we describe differences to adult disease, uncover mutations in novel cancer drivers, histone H3 mutation in 78.5% and ACVR1 mutations in 21.25% of DIPG patients, respectively and discover that DIPGs are three molecularly distinct subgroups (H3-K27M, Silent and MYCN). The H3-K27M subgroup is highly p.Lys27Met histone H3 mutated and associated with additional hits including activating mutations in ACVR1, frequent RB1 and TP53 deletions, PVT-1/MYC or PDGFRA gains/amplifications, genomic instability and alternative lengthening of telomeres. Histone mutations confer a worse overall survival (p = 0.0026). The MYCN subgroup is not associated with histone mutations and is instead characterized by hypermethylation and chromothripsis of chromosome 2p with high-level amplifications of MYCN and ID2. The Silent subgroup affects younger children, has genomes with minimal genomic instability and fewer mutations. Histologically, DIPG represent a spectrum of grade II-IV disease with vast regional differences and frequent leptomeningeal dissemination.;Our results show that this seemingly homogeneous entity in fact comprises three distinct subgroups with different genomic, molecular and histopathological features. This complexity needs to be considered when designing new therapeutic approaches in order to improve outcome for these children. |
