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

Abstract

SummaryWe collated data from 157 unpublished cases of pediatric high-grade glioma and diffuse intrinsic pontine glioma and 20 publicly available datasets in an integrated analysis of >1,000 cases. We identified co-segregating mutations in histone-mutant subgroups including loss of FBXW7 in H3.3G34R/V, TOP3A rearrangements in H3.3K27M, and BCOR mutations in H3.1K27M. Histone wild-type subgroups are refined by the presence of key oncogenic events or methylation profiles more closely resembling lower-grade tumors. Genomic aberrations increase with age, highlighting the infant population as biologically and clinically distinct. Uncommon pathway dysregulation is seen in small subsets of tumors, further defining the molecular diversity of the disease, opening up avenues for biological study and providing a basis for functionally defined future treatment stratification.

A pilot precision medicine trial for children with diffuse intrinsic pontine glioma—PNOC003: A report from the Pacific Pediatric Neuro‐Oncology Consortium

“…Patients with recurrent tumors are labeled with “‐pr”. Annotations in blue show whether these mutations were identified with cancer relevant mutations in specified databases, and genes frequently involved as the major driver mutations in DIPGs uploaded on PedcBioPortal for Cancer Genomics . Copy gain and loss for indicated genes reflect focal events; whole chromosome gain/loss are not displayed.…”

The genetic landscape of gliomas arising after therapeutic radiation

“…However, in contrast to IDH-wildtype glioblastomas in the cerebral hemispheres of adults [8, 9], radiation-associated high-grade gliomas only rarely harbor EGFR amplification or mutation and instead more frequently demonstrate PDGFRA or MET amplifications or mutations. Compared with both high-grade gliomas in children and IDH-wildtype glioblastomas in adults [8, 9, 19, 32], radiation-associated high-grade gliomas only rarely harbor NF1 inactivation and instead more frequently demonstrate BRAF rearrangement or RRAS2 focal high-level amplifications, the latter of which is not known to be recurrently present in any spontaneous glioma subtype. These findings highlight potential vulnerabilities to targeted therapeutics, particularly kinase inhibitors targeting activated PDGFRA, MET, or MEK.…”

“…Diffuse lower-grade gliomas in the cerebral hemispheres of younger adults are genetically defined by a recurrent hotspot mutation in either the IDH1 or IDH2 oncogenes, with additional TERT promoter mutation and chromosomes 1p and 19q co-deletion in oligodendroglial neoplasms versus additional ATRX and TP53 mutations in diffuse astrocytic neoplasms [10, 13]. In children, diffuse gliomas arising in midline structures of the CNS are defined by p.K27M mutation in the H3F3A , HIST1H3B , or HIST1H3C genes, which are accompanied by a spectrum of additional alterations frequently involving TP53 , PPM1D , ACVR1 , PDGFRA , and PIK3CA [19, 30, 32]. In contrast, diffuse gliomas arising in the cerebral hemispheres of children are often defined by mutually exclusive H3F3A p.G34R/V or SETD2 mutations, which are accompanied by frequent TP53 , ATRX , and PDGFRA alterations [14, 19, 21, 32].…”

“…In children, diffuse gliomas arising in midline structures of the CNS are defined by p.K27M mutation in the H3F3A , HIST1H3B , or HIST1H3C genes, which are accompanied by a spectrum of additional alterations frequently involving TP53 , PPM1D , ACVR1 , PDGFRA , and PIK3CA [19, 30, 32]. In contrast, diffuse gliomas arising in the cerebral hemispheres of children are often defined by mutually exclusive H3F3A p.G34R/V or SETD2 mutations, which are accompanied by frequent TP53 , ATRX , and PDGFRA alterations [14, 19, 21, 32]. However, the genetic alterations that are responsible for secondary gliomas arising after radiation therapy are largely unknown, with some studies suggesting differences with their spontaneous counterparts based on either gene expression analysis or single gene testing for IDH½ mutation or EGFR amplification [5, 12, 16, 20, 21, 24].…”

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

“…High‐grade gliomas (HGG) comprise 8% to 12% of all primary brain tumors in children . Survival rates have not improved over several decades, and their prognosis remains extremely poor with a median overall survival (OS) of 10 to 18 months . This is at least partly due to historic assumptions that pediatric HGGs (pHGG) are similar to adult HGGs (aHGG) and should thus be treated similarly.…”