H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers

Abstract

Pediatric glioblastoma (pedGBM) is an extremely aggressive pediatric brain tumor, accounting for ~6% of all central nervous system neoplasms in children. Approximately half of pedGBM harbor recurrent somatic mutations in histone 3 variants or, infrequently, IDH1/2. The remaining subset of pedGBM is highly heterogeneous, and displays a variety of genomic and epigenetic features. In the current study, we aimed to further stratify an H3-/IDH-wild type (wt) pedGBM cohort assessed through genome-wide molecular profiling. As a result, we identified three molecular subtypes of these tumors, differing in their genomic and epigenetic signatures as well as in their clinical behavior. We designated these subtypes 'pedGBM_MYCN' (enriched for MYCN amplification), 'pedGBM_RTK1' (enriched for PDGFRA amplification) and 'pedGBM_RTK2' (enriched for EGFR amplification). These molecular subtypes were associated with significantly different outcomes, i.e. pedGBM_RTK2 tumors show a significantly longer survival time (median OS 44 months), pedGBM_MYCN display extremely poor outcomes (median OS 14 months), and pedGBM_RTK1 tumors harbor an intermediate prognosis. In addition, the various molecular subtypes of H3-/IDH-wt pedGBM were clearly distinguishable from their adult counterparts, underlining their biological distinctiveness. In conclusion, our study demonstrates significant molecular heterogeneity of H3-/IDH-wt pedGBM in terms of DNA methylation and cytogenetic alterations. The recognition of three molecular subtypes of H3-/IDH-wt pedGBM further revealed close correlations with biological parameters and clinical outcomes and may therefore, be predictive of response to standard treatment protocols, but could also be useful for stratification for novel, molecularly based therapies.

Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma

“…These groups overlap with other methylation-based classification groups (PDGFRA versus EGFR versus MYCN (Korshunov et al., 2017); “GBM_pedRTK” versus “GBM_MYCN” versus “HGG_MID” (molecularneuropathology.org/mnp), however, are uniquely defined here spanning anatomical locations and integrated with sequencing data. Further exploration of these heterogeneous subgroups in order to refine integrated molecular diagnostics to prioritize patient subpopulations for stratified treatment remains a priority.…”

“…For 441 cases, Illumina 450k methylation BeadArray data was available, which provides robust classification into clinically meaningful epigenetic subgroups marked by recurrent genetic alterations (Korshunov et al., 2015, Korshunov et al., 2017). We used the Heidelberg brain tumor classifier to assign tumors into following subgroups: H3G34R/V (n = 51), H3K27M (n = 119), HGG WT (n = 156), IDH1 (n = 36), low-grade glioma (LGG)-like (n = 27), pleomorphic xanthoastrocytoma (PXA)-like (n = 43), and “other” (n = 9) (Figure S2A), visualized by hierarchical clustering (Figure 2A) (Table S2).…”

Challenging the indiscriminate use of temozolomide in pediatric high‐grade gliomas: A review of past, current, and emerging therapies

“…pHGG harboring EGFR amplifications have been associated with longer survival rates, with a median OS of 44 months . Nimotuzumab is a humanized monoclonal antibody against EGFR, blocking binding to its ligands.…”

“…Conversely, diffuse midline gliomas with H3K27M mutation, which are known to respond poorly to temozolomide, largely present unmethylated MGMT gene promoter and constitute up to 60% of non‐brainstem midline pHGG . Similarly, H3‐/IDH‐wild‐type pHGG mainly present an unmethylated MGMT promoter . Therefore, the distribution of the MGMT promoter methylation status across molecular subtypes may attenuate its potential prognostic significance in pHGG, which yet remains to be established.…”

“…MYCN‐amplified pHGG carry a very poor prognosis with median OS 14 months . Aurora kinase A inhibitors have been advocated in patients with MYCN‐amplified tumors; and BET bromodomain inhibitors may have a role in suppressing MYC‐associated transcriptional activity …”