CNS5:Diffuse midline glioma, H3 K27-altered: Difference between revisions
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(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span><references /> | (use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span> | ||
<references /> | |||
==Notes== | ==Notes== | ||
Latest revision as of 19:50, 25 February 2026
Central Nervous System Tumours (WHO Classification, 5th ed.)
Primary Author(s)*
Laveniya Satgunaseelan, FRCPA, Royal Prince Alfred Hospital
Linda Cooley, MD, MBA, Children's Mercy Hospital
WHO Classification of Disease
| Structure | Disease |
|---|---|
| Book | Central Nervous System Tumours (5th ed.) |
| Category | Gliomas, glioneuronal tumours, and neuronal tumours |
| Family | Gliomas, glioneuronal tumours, and neuronal tumours |
| Type | Paediatric-type diffuse high-grade gliomas |
| Subtype(s) | Diffuse midline glioma, H3.3 K27–mutant; diffuse midline glioma, H3.1 or H3.2 K27–mutant; diffuse midline glioma, H3-wildtype with EZHIP overexpression; diffuse midline glioma, EGFR-mutant |
Related Terminology
| Acceptable | Diffuse Intrinsic Pontine Glioma |
| Not Recommended | N/A |
Gene Rearrangements
| Driver Gene | Fusion(s) and Common Partner Genes | Molecular Pathogenesis | Typical Chromosomal Alteration(s) | Prevalence -Common >20%, Recurrent 5-20% or Rare <5% (Disease) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|---|
| NTRK3 | ZKSCAN1::NTRK3 | Novel fusion | Rare | T | No | [1] | |
| NTRK3 | BTBD1::CPEB1::
NTRK3 |
Novel fusion | Rare | T | No | [1] | |
| NTRK2 | VCL::NTRK2
|
Novel fusion | Rare | T | No | [1] | |
| FGFR2 | FGFR2::VPS35 | Novel fusion | Rare | T | No | [2] | |
Individual Region Genomic Gain/Loss/LOH
| Chr # | Gain, Loss, Amp, LOH | Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size] | Relevant Gene(s) | Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| 1 | Gain | chr1q | D | No | Documented frequency of 38% (19/50) in H3.1 K28M-mutant cases[3] | |
| 2 | Gain | chr2 | D | No | Documented frequency of 48% (24/50) in H3.1 K28M-mutant cases[3] | |
| 4 | Amp | chr4q12 | PDGFRA/KIT/KDR | P | No | PDGFRA amplification associated with cases in hindbrain, diencephalon, telencephalon (WHO).
Documented frequency of 37% (90/345) in H3 K28M-mutant cases; confers shorter overall survival (OS)[3][4] PDGFRA alterations more frequent in cases taken before radiotherapy[5] |
| 2 | Amp | chr2p24.3 | MYCN/ID2 | P | No | Documented frequency of 6% (14/345) in H3 K28M-mutant cases; confers shorter OS[3] |
| 7 | Amp | chr7p11.2 | EGFR | D/P | Yes | EGFR amplification fulfils the WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss
Documented frequency of 2% (6/304) in H3 K28M-mutant cases[6]; confers shorter OS[7] |
| 7 | Amp | chr7q21.2 | CDK6 | P | No | Found in H3 K28M-mutant cases; confers shorter OS[3] |
| 7 | Amp | chr7q31.2 | MET | P | No | Found in in H3 K28M-mutant cases; confers shorter OS[3] |
| 8 | Amp | chr8q24 | MYC | D | No | Documented frequency of 6% (14/245) in H3 K28M-mutant cases[3] |
| 9 | Del | chr9p21.2 | CDKN2A/B | P | No | Found in H3 K28M-mutant cases; confers better prognosis[3][4] |
| 10 | Del | Chr10q23 | PTEN | D | No | Documented frequency of 10/304 (3%) of H3 K28M-mutant cases[8] |
| 12 | Amp | chr12q15 | MDM2 | D | No | Documented frequency of 3% (8/304) in H3 K28M-mutant cases[8]
More common in patients ≥ 20 years[8] |
| 12 | Amp | Chr12p13 | CCND2 | D | No | Documented frequency of 5% (12/245) of H3 K28M-mutant cases[3] |
| 17 | Amp | Chr17p11 | TOP3A | D | No | Documented frequency of 7% (17/245) of H3 K28M-mutant cases[9] |
| 16 | Loss | chr16q | D | No | Documented frequency of 36% (18/50) in H3.1 K28M-mutant cases[9] | |
| 17 | Loss | chr17p | P | No | Documented frequency of 26.5% (10/49) in H3 K28M-mutant cases; associated with significantly shorter OS[10] |
Characteristic Chromosomal or Other Global Mutational Patterns
| Chromosomal Pattern | Molecular Pathogenesis | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|
| Complex chromosomal profile, defined as ≥5 chromosomes with copy number alterations | Common (70.6%) | P | No | Associated with shorter OS[10] | |
| Low tumour mutation burden (TMB) | D | 0.49 somatic mutations per Megabase (Mb) (range 0.09–9.01)[5] | |||
| Alternative lengthening of telomeres (ALT) genomic signature | Common (28.4%) | D | [5] |
Gene Mutations (SNV/INDEL)
| Gene | Genetic Alteration | Tumor Suppressor Gene, Oncogene, Other | Prevalence -
Common >20%, Recurrent 5-20% or Rare <5% (Disease) |
Diagnostic, Prognostic, and Therapeutic Significance - D, P, T | Established Clinical Significance Per Guidelines - Yes or No (Source) | Clinical Relevance Details/Other Notes |
|---|---|---|---|---|---|---|
| H3-3A | GOF
p.K28M/I |
Common | D/P | Yes (WHO) | Encodes histone H3.3. Fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss | |
| H3-3B | GOF
p.K28M/I |
Common | D/P | Yes (WHO) | Encodes histone H3.3. Fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss | |
| H3C2 | GOF
p.K28M/I |
Common | D/P | Yes (WHO) | Encodes histone H3.1. Fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss | |
| H3C3 | GOF
p.K28M/I |
Common | D/P | Yes (WHO) | Encodes histone H3.1. Fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss | |
| H3C14 | GOF
p.K28M/I |
Common | D/P | Yes (WHO) | Encodes histone H3.2. Fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss | |
| Other histone H3 genes | GOF
p.K28M/I |
10 other histone H3 genes encoding histone H3 isoforms in which mutations at K28 could occur, however, cases currently not documented.
Would fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss. | ||||
| EGFR | GOF
(p.G598V, p.A289T/V, e20 insertions incl p.M766delinsMASV, p.A767delinsASVD, p.A767delinsASVG, p.D770delinsDN, p.D770delinsDNPH, p.N771delinsNPH) |
Rare | D/P | Yes (WHO) | Fulfils WHO essential criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss | |
| TP53 | Variable LOF and GOF mutations | Common | No | Present in 68% (98/144) of H3.3 K28M-mutant cases; 11/37 (30%) of H3.1 K28M-mutant cases[3] | ||
| ATRX | Variable LOF mutations | Recurrent | No | Present in 19% (28/144) of H3.3 K28M-mutant cases[3]
More common in patients ≥ 20 years[6] and in cases taken before radiotherapy[11] | ||
| TERT promoter | GOF | Rare | No | Present in 4% (11/304) of H3 K28M-mutant cases[6] | ||
| ACVR1 | GOF mutations (p.G328E/V/W; p. R258G; p.R206H; p.G356D) | Common | No | ACVR1 GOF mutations associated with cases in hindbrain (WHO).
| ||
| BCOR | Variable LOF mutations | Recurrent | No | Present in 7/37 (19%) of H3.1 K28M-mutant cases[3] | ||
| PIK3CA | GOF mutations (p.C420R; p.E545A/G/K; p.Q546K; p.E542K; p.E726A; p.R88Q; p.H1047R; p.Y1038F) | Recurrent | No | Present in 7/37 (19%) of H3.1 K28M-mutant cases; 15/144 (10%) of H3.3 K28M-mutant cases[3] | ||
| PIK3R1 | GOF mutations (p.K567E; p.K379E; p.P612L; p.R358*; p.G376R) | Recurrent | No | Present in 4/37 (11%) of H3.1 K28M-mutant cases; 11/144 (8%) of H3.3 K28M-mutant cases[3] | ||
| PPM1D | GOF mutations
(p.L513*; p.C478*; p.S468*; p.W427*; p.Q404*; p.S516*; p.E405*; p.E525*) |
Recurrent | No | Present in 13/144 (9%) of H3.3 K28M-mutant cases[3] | ||
| FGFR1 | GOF mutations
(p.N455K; p.K565E; p.N577K; p.K687E) |
Recurrent | No | FGFR1 GOF mutations associated with cases in diencephalon (WHO).
Present in 11/144 (8%) of H3.3 K28M-mutant cases[3][6] More common in patients ≥ 20 years[6] | ||
| BRAF | p.v600E | Recurrent | No | Present in 5/162 (3%) to 13/304 (4%) of H3 K28M-mutant cases[6][5]
Four of 5/162 cases found at relapse / recurrence[5] | ||
| NF1 | LOF | Common | No | Present in 89/304 (31%) of H3 K28M-mutant cases[6]
More common in patients ≥ 20 years[6] | ||
| ATM | LOF | Recurrent | No | Present in 7/162 (7%) of H3 K28M-mutant cases[5] | ||
| PTEN | LOF | Recurrent | No | Present in 15/304 (5%) of H3 K28M-mutant cases[6] | ||
| PTPN11 | Recurrent | No | Present in 21/304 (7%) of H3 K28M-mutant cases[6] | |||
| PDGFRA | GOF | Recurrent | No | PDGFRA amplification associated with cases in hindbrain, diencephalon, telencephalon (WHO).
Present in 14/304 (5%) of H3 K28M-mutant cases | ||
Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Epigenomic Alterations
Diffuse midline gliomas, H3 K7-altered has distinct methylation profiling clusters (PMID: 38066305; DKFZ Heidelberg v12.7), including:
- DMG_H3.1-K27M
- DMG_H3.3-K27M
- DMG_EGFR
- DMG_EZHIP
- DMG_EZHIP_FGFR1
- DMG_H3.3-K27M_BRAF
- DMG_H3.3-K27M_FGFR1
Genes and Main Pathways Involved
| Gene; Genetic Alteration | Pathway | Pathophysiologic Outcome |
|---|---|---|
| TP53: Variable LOF and GOF mutations | p53 pathway | LOF – loss of tumour suppressive control
GOF – oncogenic properties including effect on antitumor immune response (PMID: 36859359) |
| PIK3CA; PIK3R1; GOF mutations | PI3K-AKT-MTOR pathway | Hyperactivation of the PI3K/AKT/mTOR signaling pathway, leading to cell growth, division, and survival |
| CDKN2A/B; LOF via deletion | Cell cycle control | LOF leads to loss of p16INK4A, p14ARF, & p15INK4B, leading to uncontrolled cell proliferation, impaired senescence and increased self-renewal |
| BRAF, NF1; GOF / LOF respectively | MAPK pathway | Constitutive activation of the MAPK pathway leading to uncontrolled cellular proliferation, and resistance to apoptosis |
Genetic Diagnostic Testing Methods
Genetic diagnostic testing methods include:
- Immunohistochemistry to detect H3 K28me3 loss
- Next generation sequencing to detect entity defining alterations in histone H3 genes and EGFR
- Methylation profiling for detection of diffuse midline glioma subtypes
Familial Forms
As per the WHO Classification of CNS Tumors (5th edition 2021), there are no specific cancer predisposition syndromes associated with diffuse midline glioma, H3 K27-altered, however, it may occur in the setting of Li-Fraumeni syndrome or mismatch repair deficiency.
References
(use the "Cite" icon at the top of the page) (Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted.)
- ↑ 1.0 1.1 1.2 Dahl, Nathan A.; et al. (2021-03-22). "NTRK Fusions Can Co-Occur With H3K27M Mutations and May Define Druggable Subclones Within Diffuse Midline Gliomas". Journal of Neuropathology and Experimental Neurology. 80 (4): 345–353. doi:10.1093/jnen/nlab016. ISSN 1554-6578. PMC 7985828 Check
|pmc=value (help). PMID 33749791 Check|pmid=value (help). - ↑ Johnson, Benjamin N.; et al. (2021-02). "Future directions in personality pathology development research from a trainee perspective: Suggestions for theory, methodology, and practice". Current Opinion in Psychology. 37: 66–71. doi:10.1016/j.copsyc.2020.08.006. ISSN 2352-2518. PMC 7895861 Check
|pmc=value (help). PMID 32891979 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 3.00 3.01 3.02 3.03 3.04 3.05 3.06 3.07 3.08 3.09 3.10 3.11 3.12 3.13 3.14 3.15 3.16 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.
- ↑ 4.0 4.1 Dufour, Charlotte; et al. (2020-01). "Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant". Brain Pathology (Zurich, Switzerland). 30 (1): 179–190. doi:10.1111/bpa.12768. ISSN 1750-3639. PMC 8018027 Check
|pmc=value (help). PMID 31348837. Check date values in:|date=(help) - ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Pfaff, Elke; et al. (2025-10-11). "Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM". Acta Neuropathologica. 150 (1): 42. doi:10.1007/s00401-025-02945-9. ISSN 1432-0533. PMC 12515216 Check
|pmc=value (help). PMID 41076459 Check|pmid=value (help). - ↑ 6.00 6.01 6.02 6.03 6.04 6.05 6.06 6.07 6.08 6.09 Williams, Erik A.; et al. (2023-09). "A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4". Acta Neuropathologica. 146 (3): 515–525. doi:10.1007/s00401-023-02609-6. ISSN 1432-0533. PMC 10412483 Check
|pmc=value (help). PMID 37524847 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 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.
- ↑ 8.0 8.1 8.2 Williams, Erik A.; et al. (2023-09). "A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4". Acta Neuropathologica. 146 (3): 515–525. doi:10.1007/s00401-023-02609-6. ISSN 1432-0533. PMC 10412483 Check
|pmc=value (help). PMID 37524847 Check|pmid=value (help). Check date values in:|date=(help) - ↑ 9.0 9.1 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.
- ↑ 10.0 10.1 Dufour, Charlotte; et al. (2020-01). "Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant". Brain Pathology (Zurich, Switzerland). 30 (1): 179–190. doi:10.1111/bpa.12768. ISSN 1750-3639. PMC 8018027 Check
|pmc=value (help). PMID 31348837. Check date values in:|date=(help) - ↑ Pfaff, Elke; et al. (2025-10-11). "Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM". Acta Neuropathologica. 150 (1): 42. doi:10.1007/s00401-025-02945-9. ISSN 1432-0533. PMC 12515216 Check
|pmc=value (help). PMID 41076459 Check|pmid=value (help).
Notes
Prior Author(s): *Citation of this Page: “Diffuse midline glioma, H3 K27-altered”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 02/25/2026, https://ccga.io/index.php/CNS5:Diffuse midline glioma, H3 K27-altered.