K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas

By Dong-Anh Khuong-Quang, P. Buczkowicz, P. Rakopoulos, Xiao-yang Liu, A. Fontebasso, E. Bouffet, U. Bartels, S. Albrecht, J. Schwartzentruber, Louis Letourneau and 17 more. Acta Neuropathologica, 2012

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Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/39a1a21e553ec542d0ced2743b6bfa513dab8fa6

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Citations in the corpus

Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. (2013, background): “Interestingly, K27M and G34R/V mutations are associated not only with clinical parameters such as patient age or tumor location, but they also exhibit a mutation-specific gene expression and DNA methylation profile (Khuong-Quang et al., 2012; Sturm et al., 2012).”
Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma (2013, neutral): “They were also wild type for TP53 , which is mutated in most GBMs or diffuse intrinsic pontine gliomas 5,53 with the H3F3A p.Lys27Met alteration.”
Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. (2012, background): “001), and the age distribution confirmed reported associations of certain mutations with GBM in children (H3F3A K27), adolescent patients (H3F3A G34), and young adult patients (IDH1) (Khuong-Quang et al., 2012; Schwartzentruber et al., 2012; Yan et al., 2009) (Figure S1C; Table S2).”
Glioma Subclassifications and Their Clinical Significance (2017, background): “K27M mutations of H3F3A in DIPGs have significant prognostic implications and are associated with worse survival than wild-type DIPGs, which by necessity carry HIST1H3B mutations [36].”
Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma (2017, background): “…2014; Castel et al., 2015; Fontebasso et al., 2013, 2014; Grasso et al., 2015; International Cancer Genome Consortium PedBrain Tumor Project, 2016; Khuong-Quang et al., 2012; Korshunov et al., 2015; Paugh et al., 2010, 2011; Puget et al., 2012; Schwartzentruber et al., 2012; Sturm et al., 2012;…”
The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma (2014, methodology): “To summarize samples altered in RTK-RAS-PI3K pathways, we identified the relevant genes in the Kyoto Encyclopedia of Genes and Genomes (KEGG), Ingenuity and the National Cancer Institute (NCI)-Nature Protein Interaction Database and limited analysis to the following genes that had at least one somat”
Neuronal Activity Promotes Glioma Growth through Neuroligin-3 Secretion (2015, neutral): “…thalamic HGGs typically occurring inmid-childhood, cortical gliomas of childhood occurring in older children and young adults, and HGG of later adulthood occurring chiefly in the frontotemporal lobes (Khuong-Quang et al., 2012; Schwartzentruber et al., 2012; Sturm et al., 2012; Wu et al., 2012).”