Pediatric-type Diffuse High-grade Gliomas

2024-12-13   Scott Ryall, PhD 

1.Brigham and Women's Hospital, Harvard Medical School, Boston , MA (USA)

Classification

Definition

The 2021 WHO guidelines for CNS tumor classification recognizes two new families of tumors that acknowledge the key diagnostic differences between pediatric-type and other diffuse gliomas: i) pediatric-type diffuse low-grade gliomas and ii) pediatric-type diffuse high-grade gliomas. 1 Pediatric-type diffuse high-grade glioma includes 4 entities: i) Diffuse midline glioma, H3 K27-altered, ii) Diffuse hemispheric glioma, H3 G34-mutant, iii) Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype and iv) Infant-type hemispheric glioma. 1 The former was included in the 2016 WHO classification guidelines 2 but has since had its name updated to reflect the inclusion of events other than H3 p.K27M in these tumors. 3,4 The other three entities are newly recognized and require an integrated histopathological and molecular approach for effective diagnostics. Importantly, glioblastoma is no longer used to describe a pediatric-type tumor.

Additional details are described in the 2021 WHO Classification of Tumors of the Central Nervous System.


Paediatric-type Diffuse High-grade GliomasGenetic Event(s)
Diffuse midline glioma, H3 K27-alteredThe age at diagnosis of diffuse midline glioma, H3 K27-altered is unique to the specific oncogentic alterations driving the subclass: i) H3.3 p.K27M-mutant (Median: 7.5 years [1-32 years], ii) H3.1 or 3.2 p.K27M-mutant (Median: 5 years [2-12 years], iii) H3-wildtype with EZHIP overexpression (Median: 12 years [1-54 years], and iv) EGFR-mutant (Median 7.5 years [2-26 years]. 5-8 These tumors are driven by one of 4 oncogentic alterations of which, three (i-iii) result in loss of H3 p.K27me3 leading to aberrant gene expression. 9,10 These alterations are i) H3.3 p.K27M-mutant, ii) H3.1 or 3.2 p.K27M-mutant, iii) H3-wildtype with EZHIP overexpression, and iv) EGFR-mutant. The H3 K27-mutant subtypes (i-ii) are defined by somatic heterozygous mutations that substitute a lysine to methionine or, rarely, isoleucine at position 27 of histone H3. 11-14 Co-occurrence of H3 p.K27M/I with mutations in IDH1/IDH2, H3.3 p.G34R/V, TERT promoter mutations, CDKN2A/CDKN2B deletions, or MGMT promoter methylation are extremely rare. 5 However, they are found to co-occur with collaborating mutations including those in TP53, PPM1D, ATM, BRAF with H3.3 and PIK3CA, PIK3R1, and PTEN with H3.1/2. 15-18 PDGFRA amplifcations, FGFR1 mutations, and ACVR1 mutations are also observed and appear linked to the tumor's location within the brain. 5 The EZHIP subtype is driven by overexpression of EZHIP, which acts as an endogenous H3 p.K27M mimic. 8,19 Lastly, the EGFR-subtype most often arises due to small in-frame insertions/duplications in EGFR's tyrosine kinase domain or p.A289T/V mutations in the extracellular domain. 7,20
Diffuse hemispheric glioma, H3 G34-mutantDiffuse hemispheric glioma, H3 G34-mutant tumors are primarily seen in adolescents with a median age at diagnosis of 15-19 years. 5,6 These tumors are defined by a missense mutation that substitutes glycine with arginine (95%) or valine (5%) at position 34 of histone variant H3.3 (p.G34R/V). 11,12,21 Importantly, this mutation is restricted to histone H3.3 and is not seen in the other histone genes. 5,11,12,22 Co-occuring mutations in TP53 and ATRX are common, arising in ~90% and 95% of G34-mutant tumors, respectively whereas alterations in IDH1/IDH2 and/or H3 p.K27M/I are mutually exclusive. 5,22 DNA methylation analysis of H3 G34-mutant tumors revealed global DNA hypomethylation with MGMT promoter methylation and classifies these tumors as a distinct entity from other high-grade lesions. 5,6,23
Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtypeThe age at diagnosis of diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype tumors is approximately 10 years, with a highly variable range. 5 However, published series have, thus far, primarily focussed on pediatric cohorts and likely underestimate the occurrence in the adult population. 5,24 These tumors must lack mutations in histone H3 or IDH1/IDH2. These tumors often harbor amplifications in PDGFRA, EGFR, or MYCN, and/or mutations in TP53, NF1, PDGFRA, and EGFR . 5,18,24,25 DNA methylation analysis identifies three molecular subgroups of diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype tumors with distinct DNA methylation profiles: i) pHGG RTK1, ii) pHGG RTK2, and iii) pHGG MYCN. 6,24 These profiles are enriched for PDGFRA amplifications, EGFR amplifications and TERT promoter mutations and MYCN amplifications, respectively.
Infant-type hemispheric gliomaThe median age at diagnosis of infant-type hemispheric glioma is approximately 3 months (0-12 months). 26,27 These tumors are driven by structural rearragements involving NTRK1/NTRK2/NTRK3, ALK, ROS1, or MET. 26,27. These structural rearragements can be inter- or intra-chromosomal and may result from small interstitial deletions or amplifications. These events cause dysregulated kinase expression resulting in up-regulation of the canonical PI3K and/or MAPK pathways, ultimately leading to tumorigenesis. 26,27 These tumors generally only harbor this single event, and have no recurrent or co-occuring molecular alterations.

Article Bibliography

Reference NumberPubmed IDLast YearTitleAuthors
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4309238262019EZHIP/CXorf67 mimics K27M mutated oncohistones and functions as an intrinsic inhibitor of PRC2 function in aggressive posterior fossa ependymoma.Hübner JM et al
5289660332017Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma.Mackay A et al
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7323038402020Pediatric bithalamic gliomas have a distinct epigenetic signature and frequent EGFR exon 20 insertions resulting in potential sensitivity to targeted kinase inhibition.Mondal G et al
8321937872020Histone H3 wild-type DIPG/DMG overexpressing EZHIP extend the spectrum diffuse midline gliomas with PRC2 inhibition beyond H3-K27M mutation.Castel D et al
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12222862162012Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.Wu G et al
13226613202012K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.Khuong-Quang DA et al
14263996312015Histone H3F3A and HIST1H3B K27M mutations define two subgroups of diffuse intrinsic pontine gliomas with different prognosis and phenotypes.Castel D et al
15247052502014Recurrent somatic mutations in ACVR1 in pediatric midline high-grade astrocytoma.Fontebasso AM et al
16247052512014The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.Wu G et al
17247052522014Recurrent activating ACVR1 mutations in diffuse intrinsic pontine glioma.Taylor KR et al
18247052542014Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations.Buczkowicz P et al
19310861752019PFA ependymoma-associated protein EZHIP inhibits PRC2 activity through a H3 K27M-like mechanism.Jain SU et al
20331308812021A subset of pediatric-type thalamic gliomas share a distinct DNA methylation profile, H3K27me3 loss and frequent alteration of EGFR.Sievers P et al
21340566082021Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults.Picart T et al
22264824742016Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity.Korshunov A et al
23230796542012Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.Sturm D et al
24284013342017H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers.Korshunov A et al
25297636232018Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial.Mackay A et al
26315548172019Alterations in ALK/ROS1/NTRK/MET drive a group of infantile hemispheric gliomas.Guerreiro Stucklin AS et al
27322383602020Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes.Clarke M et al

Citation

Scott Ryall

Pediatric-type Diffuse High-grade Gliomas

Atlas Genet Cytogenet Oncol Haematol. 2024-12-13

Online version: http://atlasgeneticsoncology.org/solid-tumor/209308