Relatively little was known about the biology of DIPG, in part because the infrequency of biopsy makes tumor tissue samples rare. Hypotheses about DIPG biology have generally relied on extrapolation from histologically similar high-grade glial tumors arising outside the brainstem. Recently, autopsy driven studies and the increased use of stereotactic biopsy for DIPG has increased our knowledge about DIPG biology.
There appear to be significant differences in the frequency of specific copy number abnormalities between pediatric and adult high-grade gliomas overall.1-5 In small cohorts of DIPG patients, approximately 50% had TP53 mutations, and 19% had amplification of EGFR.6-9 Other studies have shown that 36% of DIPGs showed gains in PDGFRA, and a small number showed low-level gains in PARP1.5 Recent work with samples from a relatively large cohort of DIPG patients demonstrated that 47% of samples showed focal amplification of genes in the receptor tyrosine kinase-Ras-phosphoinositide 3-kinase signaling pathway, most commonly in PDGFRA and MET; 30% showed focal amplifications of cell-cycle regulatory genes controlling retinoblastoma (RB) phosphorylation; and 21% showed amplifications in both pathways.8 This work confirms that the biology of pediatric high-grade tumors and DIPG are different from adult high-grade gliomas.
Recent Developments in Understanding DIPG Biology:
In 2012, high-throughput sequencing studies10-12 yielded unprecedented insight into the genomic framework of DIPG and sparked intense study of the biologic basis of this fatal disease. This groundbreaking work uncovered novel point mutations of highly conserved chromatin remodeling genes H3F3A, HIST1H3B and HIST1H3C, all resulting in a lysine to methionine substitution at residue 27 (K27M), which have since been reported in 70-96% of DIPG specimens.10,12-18 Though mechanisms that underlie the oncogenic potential of H3 mutations in DIPG are not completely understood, in vitro and in vivo data support epigenetically-driven alterations of gene expression through global reduction of H3K27 tri-methylation14,19,20 and a methylation-driven subgroup of histone H3-mutant DIPG (H3-K27M), that share other genomic and molecular aberrations including TP53/PPM1D mutations, PDGFRA or PVT-1/MYC amplifications, alternative lengthening of telomeres (ALT) and unstable genomes.14 A subset of histone H3 wild-type DIPG show catastrophic shattering of chromosome 2p leading to high-level amplification of MYCN and ID2.14 In 2014, additional genomic studies revealed recurrent activating mutations of ACVR1 in 20-32% of DIPG.14,18,21 ACVR1, which activates the BMP-TGFβ pathway, holds importance in mouse embryogenesis22 and left-right patterning. ACVR1 is the causative germline aberration of fibrodysplasia ossificans progressiva(FOP).23,24 DIPG is the first context in which it has been described as an oncogene. Recent sequencing studies have also reported genetic aberrations in DIPG, including frequent mutation of TP5314,15,18,21, PPM1D25, RB14,15,18,21, PDGFRA26,27, and PTEN14, as well as (RTK)-PI3K-MAPK pathway activation13,15,18,21, EGFR amplification6,18, and amplification of checkpoint regulators.6
DIPGs represent a varied histological spectrum. In 108 biopsies reported across 13 studies, pathology showed 37 anaplastic astrocytomas (WHO grade III), 27 glioblastoma (WHO grade IV), 20 diffuse astrocytomas (WHO grade II), 3 anaplastic oligoastrocytomas (WHO grade III), 1 oligoastrocytoma (WHO grade II), 1 oligodendroglioma (WHO grade II), 15 malignant gliomas NOS, and 4 undefined tumors.28 A detailed histological review of 72 DIPG (53 autopsy and 19 biopsy/surgical) cases with well documented clinical history and biological data reported 44 glioblastoma (WHO grade IV), 18 anaplastic astrocytoma (WHO grade III), 8 diffuse astrocytomas (WHO grade II) and 2 cases with features of primitive neuroectodermal tumors (WHO grade IV) and documented 1/3 of DIPG patients with leptomeningeal dissemination of their tumor.13 Furthermore, the study revealed that K27M histone H3 mutation status in DIPG was predictive of survival independent of histologic grade, including multiple cases of K27M-H3 mutant WHO grade II diffuse astrocytomas (at autopsy), which nevertheless behaved clinically like high-grade astrocytomas.13
- Barrow, J. et al. Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas. Neuro Oncol 13, 212-22 (2011).
- Bax, D.A. et al. A distinct spectrum of copy number aberrations in pediatric high-grade gliomas. Clin Cancer Res 16, 3368-77 (2010).
- Paugh, B.S. et al. Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease. J Clin Oncol 28, 3061-8 (2010).
- Qu, H.Q. et al. Genome-wide profiling using single-nucleotide polymorphism arrays identifies novel chromosomal imbalances in pediatric glioblastomas. Neuro Oncol 12, 153-63 (2010).
- Zarghooni, M. et al. Whole-genome profiling of pediatric diffuse intrinsic pontine gliomas highlights platelet-derived growth factor receptor alpha and poly (ADP-ribose) polymerase as potential therapeutic targets. J Clin Oncol 28, 1337-44 (2010).
- Gilbertson, R.J. et al. ERBB1 is amplified and overexpressed in high-grade diffusely infiltrative pediatric brain stem glioma. Clin Cancer Res 9, 3620-4 (2003).
- Louis, D.N., Rubio, M.P., Correa, K.M., Gusella, J.F. & von Deimling, A. Molecular genetics of pediatric brain stem gliomas. Application of PCR techniques to small and archival brain tumor specimens. J Neuropathol Exp Neurol 52, 507-15 (1993).
- Paugh, B.S. et al. Genome-wide analyses identify recurrent amplifications of receptor tyrosine kinases and cell-cycle regulatory genes in diffuse intrinsic pontine glioma. J Clin Oncol 29, 3999-4006 (2011).
- Zhang, S. et al. p53 gene mutations in pontine gliomas of juvenile onset. Biochem Biophys Res Commun 196, 851-7 (1993).
- Khuong-Quang, D.A. et al. K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas. Acta Neuropathol 124, 439-47 (2012).
- Schwartzentruber, J. et al. Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma. Nature 482, 226-31 (2012).
- Wu, G. et al. Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas. Nat Genet 44, 251-3 (2012).
- Buczkowicz, P., Bartels, U., Bouffet, E., Becher, O. & Hawkins, C. Histopathological spectrum of paediatric diffuse intrinsic pontine glioma: diagnostic and therapeutic implications. Acta Neuropathol 128, 573-81 (2014).
- Buczkowicz, P. et al. Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations. Nat Genet (2014).
- Fontebasso, A.M. et al. Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma. Nat Genet 46, 462-6 (2014).
- Saratsis, A.M. et al. Comparative multidimensional molecular analyses of pediatric diffuse intrinsic pontine glioma reveals distinct molecular subtypes. Acta Neuropathol (2013).
- Sturm, D. et al. Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma. Cancer Cell 22, 425-37 (2012).
- Wu, G. et al. The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nat Genet 46, 444-50 (2014).
- Bender, S. et al. Reduced H3K27me3 and DNA hypomethylation are major drivers of gene expression in K27M mutant pediatric high-grade gliomas. Cancer Cell 24, 660-72 (2013).
- Chan, K.M. et al. The histone H3.3K27M mutation in pediatric glioma reprograms H3K27 methylation and gene expression. Genes Dev 27, 985-90 (2013).
- Taylor, K.R. et al. Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma. Nat Genet (2014).
- Mishina, Y., Crombie, R., Bradley, A. & Behringer, R.R. Multiple roles for activin-like kinase-2 signaling during mouse embryogenesis. Dev Biol 213, 314-26 (1999).
- Kaplan, F.S. et al. Classic and atypical fibrodysplasia ossificans progressiva (FOP) phenotypes are caused by mutations in the bone morphogenetic protein (BMP) type I receptor ACVR1. Hum Mutat 30, 379-90 (2009).
- Song, G.A. et al. Molecular consequences of the ACVR1(R206H) mutation of fibrodysplasia ossificans progressiva. J Biol Chem 285, 22542-53 (2010).
- Zhang, L. et al. Exome sequencing identifies somatic gain-of-function PPM1D mutations in brainstem gliomas. Nat Genet 46, 726-30 (2014).
- Paugh, B.S. et al. Novel oncogenic PDGFRA mutations in pediatric high-grade gliomas. Cancer Res 73, 6219-29 (2013).
- Puget, S. et al. Mesenchymal transition and PDGFRA amplification/mutation are key distinct oncogenic events in pediatric diffuse intrinsic pontine gliomas. PLoS One 7, e30313 (2012).
- Jansen, M.H., van Vuurden, D.G., Vandertop, W.P. & Kaspers, G.J. Diffuse intrinsic pontine gliomas: a systematic update on clinical trials and biology. Cancer Treat Rev 38, 27-35 (2012).