Introduction to DIPG

What is DIPG?

Diffuse intrinsic brainstem glioma (DIPG) accounts for 10-15% of all new pediatric brain tumor diagnoses and is the leading cause of brain tumor-related death in children.1 Median age at diagnosis is 6 to 7 years2,3, and patients commonly present with cranial nerve deficits, upper motor neuron signs, and ataxia.1 Typical MRI appearance is a T1-hypointense, T2-hyperintense, variably contrast enhancing, expansile mass involving ≥ 50% of the pons. Though often not apparent at diagnosis, several recent studies have demonstrated leptomeningeal dissemination and spread to proximal areas of brain at autopsy.3,4 Prognosis for DIPG is dismal, with a median overall survival of less than one year.1 Standard treatment at diagnosis consists of local radiation therapy, but this intervention is only useful to improve symptoms and prolong survival by 2 to 3 months in some.4 Chemotherapeutic strategies, including targeted agents, have proven uniformly ineffectual to date.1,5,6

DIPG is generally diagnosed on the basis of clinical and radiographic findings. Historically, histopathological diagnosis has not been routinely performed due to perceived risks of brainstem biopsy7 but was instead reserved for patients with atypical imaging characteristics. The consequence of this paradigm is scarcity of tissue and thus grave limitation of our understanding of the molecular biology of DIPG. In recent years, tissue has become more available through collaborative determination to overcome barriers to tissue procurement. This has been accomplished in the following ways:

  1. Efforts to study and implement safe surgical techniques for brainstem biopsy, which were pioneered in Europe8-11 and have become more recently accepted in the United States12, and
  2. Initiation of programs for tissue collection at autopsy, which have been instigated by family advocacy groups and physicians.3,13,14

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.15-19 In small cohorts of DIPG patients, approximately 50% had TP53 mutations, and 19% had amplification of EGFR.20-23 Other studies have shown that 36% of DIPGs showed gains in PDGFRA, and a small number showed low-level gains in PARP1.19 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.22 This work confirms that the biology of pediatric high-grade tumors and DIPG are different from adult high-grade gliomas.

In 2012, high-throughput sequencing studies24-26 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.24,26-32 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-methylation28,33,34 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.28 A subset of histone H3 wild-type DIPG show catastrophic shattering of chromosome 2p leading to high-level amplification of MYCN and ID2.28 In 2014, additional genomic studies revealed recurrent activating mutations of ACVR1 in 20-32% of DIPG.28,32,35 ACVR1, which activates the BMP-TGFβ pathway, holds importance in mouse embryogenesis36 and left-right patterning. ACVR1 is the causative germline aberration of fibrodysplasia ossificans progressiva(FOP).37,38 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 TP5328,29,32,35, PPM1D39, RB28,29,32,35, PDGFRA40,41, and PTEN14, as well as (RTK)-PI3K-MAPK pathway activation27,29,32,35, EGFR amplification20,32, and amplification of checkpoint regulators.20

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.42 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.27 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.27

Role of the DIPG Registry

Despite our improved biologic understanding, therapeutic translation to improve survival in DIPG remains a significant hurdle and represents a profoundly unmet need in pediatric neuro-oncology. The international DIPG Registry was created to provide a database of demographic, clinical, radiologic, and pathologic data, as well as a bioinformatics repository of molecular data of DIPG patients across the world. The long-term objective of this registry is to establish and maintain a hypothesis-driven research infrastructure that will support a wide spectrum of interdisciplinary and translational projects to study DIPG. Data collected will form a research continuum from basic biology to clinical practice that will ultimately address our primary goals to accomplish improved understand the biology of DIPG, development of more effective targeted therapies, and development of novel approaches for uniform diagnosis, classification, response assessment, and multidisciplinary treatment and follow-up that will improve survival and care of patients with DIPG.

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