Biology Introduction:

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


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