Diffuse Paediatric-Type High-Grade Glioma, H3-Wildtype and IDH-Wildtype

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Primary Author(s)*

Madina Sukhanova, PhD FACMG Northwestern University

Cancer Category/Type

Glioma

Cancer Sub-Classification / Subtype

Paediatric-type diffuse high-grade gliomas with three molecular subtypes: RTK2, RTK1, and MYCN

Definition / Description of Disease

This is a distinct entity in the World Health Organization (WHO) classification system within the section of paediatric-type diffuse high-grade gliomas. Distinct methylation profiles and molecular alterations define three subtypes: dpHGG RTK1, dpHGG RTK2, and dpHGG MYCN. Gliomas arising after therapeutic radiation are predominantly of the pHGG RTK1 subtype. Known tumorigenic drivers include TP53, MYCN, ID2, and genes from RAS/MAPK and PI3K pathways.[1] [2] [3] [4]

Synonyms / Terminology

None

Epidemiology / Prevalence

The 2021 WHO classified this entity as pediatric-type, based on well defined studies focusing on a pediatric population with gliomas characterised by IDH-/H3-wildtype status[4][5][6]. Therefore, the frequency of this tumor type in adults in unknown. The median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.[6]

Clinical Features

The clinical features are dependent on the tumour location. Symptoms can include seizures and motor or sensory deficits.

Signs and Symptoms Seizures and motor or sensory deficits.
Imaging Findings MRI characteristics are comparable to other high-grade glioma tumour types. MRI typically reveals well-defined margins and homogeneous contrast-enhancement and mild perilesional edema.[7][8]

Sites of Involvement

Main site: supratentorial brain.

Other sites: brainstem, and cerebellum.[6]

Although most of molecular subtypes of dpHGG involve the supratentorial compartment (96% of dpHGG RTK2; 86% of dpHGG MYCN; 82% of dpHGG RTK1 tumors), a lesser proporton can involve infratentorial/brainstem sites (4% of dpHGG RTK2;14% of dpHGG MYCN; 18% of dpHGG RTK1 cases).[6]

Morphologic Features

The morphology of dHGGs, H3-/IDH-wildtype, shows glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated, primitive morphology and areas of glial differentiation can also be noted within the same case. The pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli admixed with spindle-shaped and epithelioid cells; the architecture of these tumours can show areas of diffuse infiltration, in combinaiton with circumscribed nodules.[7]

Immunophenotype

Finding Marker
Positive (universal) Neoplastic glial component – GFAP, and/or OLIG2[3][4]
Positive (subset) dpHGG MYCN molecular subtype can be positive for neuronal markers
Negative (universal)  IDH1 R132H

H3 p.K28me3 (K27me3) (preserved expression)[7]

Negative (subset) dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2

Chromosomal Rearrangements (Gene Fusions)

Fusions listed in the table below were identified in a single study, thus, frequencies in dpHGG H3/IGH-wt should be interpreted with caution.[9]

Chromosomal Rearrangement Genes in Fusion (5’ or 3’ Segments) Structural variation Prevalence Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
t(3;3)(p21.31;p25.2) FYCO1::RAF1 deletion 11%[9] Unknown Unknown Unknown Results in constitutive activation of kinase domain[9]
t(7;7)(q31.2;q31.32) PTPRZ1::MET deletion 22%[9] Unknown Unknown Unknown Concurrent MET amp is frequently noted[9]
t(7;7)(q31.2;q31.32) CAPZA2::MET deletion 11%[9] Unknown Unknown Unknown Concurrent MET amp is frequently noted[9]
t(9;9)(p31.32;p21.33) GKAP1::NTRK2 deletion 11%[9] Unknown Unknown Unknown Results in constitutive dimerization of receptor[9]

Individual Region Genomic Gain/Loss/LOH

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
2 Amplification chr2:15,940,550-15,947,004 [GRCh38] 2p24.3 Yes [50% dpHGG MYCN subtype] Worse OS[4][6] Unknown MYCN amplification[6][10]
2 Amplification chr2:8,682,056-8,684,461 [GRCh38] 2p25.1 No, but recurrent secondary finding [66% of dpHGG MYCN subtype] Unknown Unknown ID2 amplification is often (66%) co-amplified with MYCN[6][10]
4 Amplification/Mutation chr4:51819533-54425718 [GRCh38] 4q12 Yes [33% of dpHGG RTK1 subtype] No[6] Unknown PDGFRA alterations[6][11]
7 Amplification chr7:55,019,017-55,211,628 [GRCh38] 7p11.2 Yes [50% of dpHGG RTK2 subtype] No[6] Unknown EGFR amplification[6]
8 Amplification chr8:127,736,231-127,742,951 [GRCh38] 8q24.21 No, but recurrent in dpHGG MYCN subtype [8%] Unknown Unknown MYC amplification[6]
9 Homozygous loss CDKN2A - chr9:21,967,752-21,995,324 [GRCh38]

CDKN2B - chr9: 9:22,002,903-22,009,313 [GRCh38]

9p21.3 No Worse outcome[6] Unknown Deletions result in bi-allelic loss of CDKN2A/B seen in 6% MYCN subtype, 27% RTK1 subtype; 72% RTK2 subtype.[6][9]
12 / 7 Amplification CDK4 - chr12:57,747,727-57,752,310 [GRCh38]

CDK6 - chr7:92,604,921-92,836,573 [GRCh38]

12q14.1 / 7q21.2 No Unknown Unknown Ampifications of CDK4/6 seen in 22% MYCN subtype, 9% RTK1 subtype; 17% RTK2 subtype.[6]

Characteristic Chromosomal Patterns

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
Chromosome 7 gain No Yes No Recurrent finding in 47% MYCN subtype; 12% RTK1 subtype; 28% RTK2 subtype.[6]
Chromosome 10q loss No No No Recurrent finding in 42% MYCN subtype; 12% RTK1 subtype; 50% RTK2 subtype.[6]

Gene Mutations (SNV/INDEL)

Gene; Genetic Alteration Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other) Prevalence (COSMIC / TCGA / Other) Concomitant Mutations Mutually Exclusive Mutations Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
PDGFRA Receptor Not stated in literature; referred to in the WHO Classification[11] unclear IDH1/2, H3
Unknown Unknown Unknown
TERT promoter Enzyme/ acts as TCG 26% MYCN subtype; 64% RTK2 subtype[6] unclear IDH1/2, H3 Unknown Unknown Unknown
TP53 TSG 67% MYCN subtype; 48% RTK1 subtype; 50% RTK2 subtype[6][9] unclear IDH1/2, H3 Unknown Unknown Unknown

Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

Epigenomic Alterations

Methylation profiling can be used in the diagnosis of this tumor entity and can help to differentiate between three molecular profiles, pHGG RTK1, pHGG RTK2, and pHGG MYCN. Methylation of MGMT has been noted in 11% of pHGG MYCN cases and 18% of RTK1 cases.[6] MGMT promoter methylation can be seen in 18% of the RTK1 subtype, 11% in the MYCN subtype and is rare in the RTK2 subtype.

Genes and Main Pathways Involved

The pHGG, H3/IDH-wildtype frequently reveals variants in genes encoding members of the TAS/MAPK and PI3K pathways.[9]

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
MET; activating alterations MAPK/ERK pathway activation Increased cell growth and proliferation
RAF1; activating alterations MAPK/ERK pathway activation Increased cell growth and proliferation
NTRK2; activating alterations MAPK/ERK pathway activation Increased cell growth and proliferation

Genetic Diagnostic Testing Methods

  • Chromosome microarray  
  • Next generation sequencing  
  • DNA methylation profiling

Familial Forms

Germline mutations of genes involved in the mismatch repair (MMR) system can be associated with a proportion of pHGG cases,[12][13][14] typically of the pHGG RTK1 subtype.

References

  1. Buczkowicz, Pawel; et al. (2014-05). "Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations". Nature Genetics. 46 (5): 451–456. doi:10.1038/ng.2936. ISSN 1546-1718. PMC 3997489. PMID 24705254. Check date values in: |date= (help)
  2. Sturm, Dominik; et al. (2016-02-25). "New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs". Cell. 164 (5): 1060–1072. doi:10.1016/j.cell.2016.01.015. ISSN 1097-4172. PMC 5139621. PMID 26919435.
  3. 3.0 3.1 Korshunov, Andrey; et al. (2015-05). "Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers". Acta Neuropathologica. 129 (5): 669–678. doi:10.1007/s00401-015-1405-4. ISSN 1432-0533. PMID 25752754. Check date values in: |date= (help)
  4. 4.0 4.1 4.2 4.3 Mackay, Alan; et al. (2017-10-09). "Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma". Cancer Cell. 32 (4): 520–537.e5. doi:10.1016/j.ccell.2017.08.017. ISSN 1878-3686. PMC 5637314. PMID 28966033.
  5. Mackay, Alan; et al. (2018-05-14). "Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial". Cancer Cell. 33 (5): 829–842.e5. doi:10.1016/j.ccell.2018.04.004. ISSN 1878-3686. PMC 5956280. PMID 29763623.
  6. 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 6.10 6.11 6.12 6.13 6.14 6.15 6.16 6.17 6.18 6.19 Korshunov, Andrey; et al. (2017-09). "H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers". Acta Neuropathologica. 134 (3): 507–516. doi:10.1007/s00401-017-1710-1. ISSN 1432-0533. PMID 28401334. Check date values in: |date= (help)
  7. 7.0 7.1 7.2 Tauziède-Espariat, A.; et al. (2020-07-09). "The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts". Acta Neuropathologica Communications. 8 (1): 104. doi:10.1186/s40478-020-00974-x. ISSN 2051-5960. PMC 7346460 Check |pmc= value (help). PMID 32646492 Check |pmid= value (help).
  8. Tauziède-Espariat, A.; et al. (2019-06-10). "An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN)". Acta Neuropathologica Communications. 7 (1): 87. doi:10.1186/s40478-019-0738-y. ISSN 2051-5960. PMC 6556947. PMID 31177990.
  9. 9.00 9.01 9.02 9.03 9.04 9.05 9.06 9.07 9.08 9.09 9.10 9.11 Deng, Maximilian Y.; et al. (2021-09-20). "Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B". Nature Communications. 12 (1): 5530. doi:10.1038/s41467-021-25708-y. ISSN 2041-1723. PMC 8452680 Check |pmc= value (help). PMID 34545083 Check |pmid= value (help).
  10. 10.0 10.1 Capper, David; et al. (2018-03-22). "DNA methylation-based classification of central nervous system tumours". Nature. 555 (7697): 469–474. doi:10.1038/nature26000. ISSN 1476-4687. PMC 6093218. PMID 29539639.
  11. 11.0 11.1 WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). https://publications.iarc.fr/601.
  12. Dodgshun, Andrew J.; et al. (2020-11). "Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns". Acta Neuropathologica. 140 (5): 765–776. doi:10.1007/s00401-020-02209-8. ISSN 1432-0533. PMID 32895736 Check |pmid= value (help). Check date values in: |date= (help)
  13. Alphones, Sheena; et al. (2021-08). "Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature". Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery. 37 (8): 2521–2530. doi:10.1007/s00381-021-05229-1. ISSN 1433-0350. PMID 34097097 Check |pmid= value (help). Check date values in: |date= (help)
  14. Amayiri, Nisreen; et al. (2016-01-15). "High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan". International Journal of Cancer. 138 (2): 380–385. doi:10.1002/ijc.29724. ISSN 1097-0215. PMID 26293621.


Notes

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