CNS5:Diffuse midline glioma, H3 K27-altered: Difference between revisions

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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	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	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	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). Present in 28/37 (76%) of H3.1 K28M-mutant cases; 7/144 (5%) of H3.3 K28M-mutant cases^[3] More frequent at relapse/recurrence (27.3%) compared to primary diagnosis (10/3%)^[5]
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 (5^th 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.

[:0-1] 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).

[2] 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)

[:1-3] 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.

[:2-4] 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)

[:3-5] 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).

[:7-6] 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)

[7] 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.

[:4-8] 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)

[:5-9] 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.

[:6-10] 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)

[11] 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).

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CNS5:Diffuse midline glioma, H3 K27-altered: Difference between revisions

Latest revision as of 19:50, 25 February 2026

Contents

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

References

Notes

Navigation menu

@@ Line 1: / Line 1: @@
-{{Under Construction}}
+{{DISPLAYTITLE:Diffuse midline glioma, H3 K27-altered}}
+[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]
 ==Primary Author(s)*==
@@ Line 5: / Line 7: @@
 Linda Cooley, MD, MBA, Children's Mercy Hospital
+==WHO Classification of Disease==
-__TOC__
+{| class="wikitable"
+!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
+|}
-==Cancer Category/Type==
+==Related Terminology==
-Put your text here
+{| class="wikitable"
+|+
+|Acceptable
+|Diffuse Intrinsic Pontine Glioma
+|-
+|Not Recommended
+|N/A
+|}
-==Cancer Sub-Classification / Subtype==
+==Gene Rearrangements==
+{| class="wikitable sortable"
+|-
+!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
+|<ref name=":0">{{Cite journal|last=Dahl|first=Nathan A.|last2=Donson|first2=Andrew M.|last3=Sanford|first3=Bridget|last4=Wang|first4=Dong|last5=Walker|first5=Faye M.|last6=Gilani|first6=Ahmed|last7=Foreman|first7=Nicholas K.|last8=Tinkle|first8=Christopher L.|last9=Baker|first9=Suzanne J.|date=2021-03-22|title=NTRK Fusions Can Co-Occur With H3K27M Mutations and May Define Druggable Subclones Within Diffuse Midline Gliomas|url=https://pubmed.ncbi.nlm.nih.gov/33749791|journal=Journal of Neuropathology and Experimental Neurology|volume=80|issue=4|pages=345–353|doi=10.1093/jnen/nlab016|issn=1554-6578|pmc=7985828|pmid=33749791}}</ref>
+|-
+|''NTRK3''
+|''BTBD1::CPEB1::''
-Put your text here
+''NTRK3''
+|Novel fusion
+|
+|Rare
+|T
+|No
+|<ref name=":0" />
+|-
+|''NTRK2''
+|''VCL::NTRK2''
-==Definition / Description of Disease==
-Put your text here
+|Novel fusion
+|
+|Rare
+|T
+|No
+|<ref name=":0" />
+|-
+|''FGFR2''
+|''FGFR2::VPS35''
+|Novel fusion
+|
+|Rare
+|T
+|No
+|<ref>{{Cite journal|last=Johnson|first=Benjamin N.|last2=Vanwoerden|first2=Salome|date=2021-02|title=Future directions in personality pathology development research from a trainee perspective: Suggestions for theory, methodology, and practice|url=https://pubmed.ncbi.nlm.nih.gov/32891979|journal=Current Opinion in Psychology|volume=37|pages=66–71|doi=10.1016/j.copsyc.2020.08.006|issn=2352-2518|pmc=7895861|pmid=32891979}}</ref>
+|-
+|
+|
+|
+|
+|
+|
+|
+|
+|}
-==Synonyms / Terminology==
+==Individual Region Genomic Gain/Loss/LOH==
+{| class="wikitable sortable"
+|-
+!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<ref name=":1">{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Carvalho|first3=Diana|last4=Izquierdo|first4=Elisa|last5=Fazal-Salom|first5=Janat|last6=Taylor|first6=Kathryn R.|last7=Bjerke|first7=Lynn|last8=Clarke|first8=Matthew|last9=Vinci|first9=Mara|date=2017-10-09|title=Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma|url=https://pubmed.ncbi.nlm.nih.gov/28966033|journal=Cancer Cell|volume=32|issue=4|pages=520–537.e5|doi=10.1016/j.ccell.2017.08.017|issn=1878-3686|pmc=5637314|pmid=28966033}}</ref>
+|-
+|2
+|Gain
+|chr2
+|
+|D
+|No
+|Documented frequency of 48% (24/50) in H3.1 K28M-mutant cases<ref name=":1" />
+|-
+|4
+|Amp
+|chr4q12
+|''PDGFRA/KIT/KDR''
+|P
+|No
+|''PDGFRA'' amplification associated with  cases in hindbrain, diencephalon, telencephalon (WHO).
-Put your text here
+Documented frequency of 37% (90/345) in H3 K28M-mutant cases;  confers shorter overall survival (OS)<ref name=":1" /><ref name=":2">{{Cite journal|last=Dufour|first=Charlotte|last2=Perbet|first2=Romain|last3=Leblond|first3=Pierre|last4=Vasseur|first4=Romain|last5=Stechly|first5=Laurence|last6=Pierache|first6=Adeline|last7=Reyns|first7=Nicolas|last8=Touzet|first8=Gustavo|last9=Le Rhun|first9=Emilie|date=2020-01|title=Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant|url=https://pubmed.ncbi.nlm.nih.gov/31348837|journal=Brain Pathology (Zurich, Switzerland)|volume=30|issue=1|pages=179–190|doi=10.1111/bpa.12768|issn=1750-3639|pmc=8018027|pmid=31348837}}</ref>
-==Epidemiology / Prevalence==
+''PDGFRA'' alterations more frequent in  cases taken before radiotherapy<ref name=":3">{{Cite journal|last=Pfaff|first=Elke|last2=Schramm|first2=Kathrin|last3=Blattner-Johnson|first3=Mirjam|last4=Jones|first4=Barbara C.|last5=Stark|first5=Sebastian|last6=Balasubramanian|first6=Gnana Prakash|last7=Previti|first7=Christopher|last8=Autry|first8=Robert J.|last9=Fiesel|first9=Petra|date=2025-10-11|title=Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM|url=https://pubmed.ncbi.nlm.nih.gov/41076459|journal=Acta Neuropathologica|volume=150|issue=1|pages=42|doi=10.1007/s00401-025-02945-9|issn=1432-0533|pmc=12515216|pmid=41076459}}</ref>
+|-
+|2
+|Amp
+|chr2p24.3
+|''MYCN/ID2''
+|P
+|No
+|Documented frequency of 6% (14/345) in H3 K28M-mutant cases;  confers shorter OS<ref name=":1" />
+|-
+|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
-Put your text here
+Documented  frequency of 2%  (6/304) in H3 K28M-mutant cases<ref name=":7">{{Cite journal|last=Williams|first=Erik A.|last2=Brastianos|first2=Priscilla K.|last3=Wakimoto|first3=Hiroaki|last4=Zolal|first4=Amir|last5=Filbin|first5=Mariella G.|last6=Cahill|first6=Daniel P.|last7=Santagata|first7=Sandro|last8=Juratli|first8=Tareq A.|date=2023-09|title=A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4|url=https://pubmed.ncbi.nlm.nih.gov/37524847|journal=Acta Neuropathologica|volume=146|issue=3|pages=515–525|doi=10.1007/s00401-023-02609-6|issn=1432-0533|pmc=10412483|pmid=37524847}}</ref>; confers shorter OS<ref>{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Carvalho|first3=Diana|last4=Izquierdo|first4=Elisa|last5=Fazal-Salom|first5=Janat|last6=Taylor|first6=Kathryn R.|last7=Bjerke|first7=Lynn|last8=Clarke|first8=Matthew|last9=Vinci|first9=Mara|date=2017-10-09|title=Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma|url=https://pubmed.ncbi.nlm.nih.gov/28966033|journal=Cancer Cell|volume=32|issue=4|pages=520–537.e5|doi=10.1016/j.ccell.2017.08.017|issn=1878-3686|pmc=5637314|pmid=28966033}}</ref>
+|-
+|7
+|Amp
+|chr7q21.2
+|''CDK6''
+|P
+|No
+|Found in H3 K28M-mutant cases; confers shorter OS<ref name=":1" />
+|-
+|7
+|Amp
+|chr7q31.2
+|''MET''
+|P
+|No
+|Found in in H3 K28M-mutant cases; confers shorter OS<ref name=":1" />
+|-
+|8
+|Amp
+|chr8q24
+|''MYC''
+|D
+|No
+|Documented frequency of 6% (14/245) in H3 K28M-mutant cases<ref name=":1" />
+|-
+|9
+|Del
+|chr9p21.2
+|''CDKN2A/B''
+|P
+|No
+|Found in H3 K28M-mutant cases; confers better prognosis<ref name=":1" /><ref name=":2" />
+|-
+|10
+|Del
+|Chr10q23
+|''PTEN''
+|D
+|No
+|Documented frequency of 10/304 (3%) of H3 K28M-mutant cases<ref name=":4">{{Cite journal|last=Williams|first=Erik A.|last2=Brastianos|first2=Priscilla K.|last3=Wakimoto|first3=Hiroaki|last4=Zolal|first4=Amir|last5=Filbin|first5=Mariella G.|last6=Cahill|first6=Daniel P.|last7=Santagata|first7=Sandro|last8=Juratli|first8=Tareq A.|date=2023-09|title=A comprehensive genomic study of 390 H3F3A-mutant pediatric and adult diffuse high-grade gliomas, CNS WHO grade 4|url=https://pubmed.ncbi.nlm.nih.gov/37524847|journal=Acta Neuropathologica|volume=146|issue=3|pages=515–525|doi=10.1007/s00401-023-02609-6|issn=1432-0533|pmc=10412483|pmid=37524847}}</ref>
+|-
+|12
+|Amp
+|chr12q15
+|''MDM2''
+|D
+|No
+|Documented frequency of 3% (8/304) in H3 K28M-mutant cases<ref name=":4" />
-==Clinical Features==
+More common in patients ≥ 20 years<ref name=":4" />
+|-
-Put your text here and fill in the table
+|12
-{| class="wikitable"
+|Amp
-|'''Signs and Symptoms'''
+|Chr12p13
-|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
+|''CCND2''
+|D
-EXAMPLE B-symptoms (weight loss, fever, night sweats)
+|No
+|Documented frequency of 5% (12/245) of H3 K28M-mutant cases<ref name=":1" />
-EXAMPLE Fatigue
+|-
+|17
-EXAMPLE Lymphadenopathy (uncommon)
+|Amp
+|Chr17p11
+|''TOP3A''
+|D
+|No
+|Documented frequency of 7% (17/245) of H3 K28M-mutant cases<ref name=":5">{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Carvalho|first3=Diana|last4=Izquierdo|first4=Elisa|last5=Fazal-Salom|first5=Janat|last6=Taylor|first6=Kathryn R.|last7=Bjerke|first7=Lynn|last8=Clarke|first8=Matthew|last9=Vinci|first9=Mara|date=2017-10-09|title=Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma|url=https://pubmed.ncbi.nlm.nih.gov/28966033|journal=Cancer Cell|volume=32|issue=4|pages=520–537.e5|doi=10.1016/j.ccell.2017.08.017|issn=1878-3686|pmc=5637314|pmid=28966033}}</ref>
+|-
+|16
+|Loss
+|chr16q
+|
+|D
+|No
+|Documented frequency of 36% (18/50) in H3.1 K28M-mutant cases<ref name=":5" />
 |-
-|'''Laboratory Findings'''
+|17
-|EXAMPLE Cytopenias
+|Loss
+|chr17p
-EXAMPLE Lymphocytosis (low level)
+|
+|P
+|No
+|Documented frequency of 26.5% (10/49) in H3 K28M-mutant cases;  associated with significantly shorter OS<ref name=":6">{{Cite journal|last=Dufour|first=Charlotte|last2=Perbet|first2=Romain|last3=Leblond|first3=Pierre|last4=Vasseur|first4=Romain|last5=Stechly|first5=Laurence|last6=Pierache|first6=Adeline|last7=Reyns|first7=Nicolas|last8=Touzet|first8=Gustavo|last9=Le Rhun|first9=Emilie|date=2020-01|title=Identification of prognostic markers in diffuse midline gliomas H3K27M-mutant|url=https://pubmed.ncbi.nlm.nih.gov/31348837|journal=Brain Pathology (Zurich, Switzerland)|volume=30|issue=1|pages=179–190|doi=10.1111/bpa.12768|issn=1750-3639|pmc=8018027|pmid=31348837}}</ref>
 |}
-==Sites of Involvement==
-Put your text here
-==Morphologic Features==
-Put your text here
-==Immunophenotype==
-Put your text here and fill in the table
+==Characteristic Chromosomal or Other Global Mutational Patterns==
 {| class="wikitable sortable"
 |-
-!Finding!!Marker
+!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
 |-
-|Positive (universal)||EXAMPLE CD1
+|Complex  chromosomal profile, defined as ≥5 chromosomes with copy number alterations
+|
+|Common (70.6%)
+|P
+|No
+|Associated  with shorter OS<ref name=":6" />
 |-
-|Positive (subset)||EXAMPLE CD2
+|Low tumour  mutation burden (TMB)
+|
+|
+|D
+|
+|0.49 somatic  mutations per Megabase (Mb) (range 0.09–9.01)<ref name=":3" />
 |-
-|Negative (universal)||EXAMPLE CD3
+|Alternative  lengthening of telomeres (ALT) genomic signature
-|-
+|
-|Negative (subset)||EXAMPLE CD4
+|Common (28.4%)
+|D
+|
+|<ref name=":3" />
 |}
-==Chromosomal Rearrangements (Gene Fusions)==
+==Gene Mutations (SNV/INDEL)==
+{| class="wikitable sortable"
+|-
+!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
-Put your text here and fill in the table
+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
-{| class="wikitable sortable"
+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
 |-
-!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
+|''H3C2''
-!Diagnostic Significance (Yes, No or Unknown)
+|GOF
-!Prognostic Significance (Yes, No or Unknown)
-!Therapeutic Significance (Yes, No or Unknown)
+p.K28M/I
-!Notes
+|
+|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
 |-
-|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
+|''H3C3''
-EXAMPLE 30% (add reference)
+|GOF
-|Yes
-|No
+p.K28M/I
-|Yes
+|
-|EXAMPLE
+|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
-The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
+p.K28M/I
-|}
+|
+|Common
-==Individual Region Genomic Gain/Loss/LOH==
+|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
-Put your text here and fill in the table
+p.K28M/I
+|
+|
+|
+|
+|10 other histone H3 genes encoding histone H3  isoforms in which mutations at K28 could occur, however, cases currently not  documented.
-{| class="wikitable sortable"
+Would fulfils WHO essential criterion for  diagnosis in setting of a diffuse midline glioma with H3 K28me3 loss.
 |-
-!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
+|''EGFR''
-!Diagnostic Significance (Yes, No or Unknown)
+|GOF
-!Prognostic Significance (Yes, No or Unknown)
-!Therapeutic Significance (Yes, No or Unknown)
+(p.G598V, p.A289T/V, e20 insertions incl
-!Notes
-|-
+p.M766delinsMASV, p.A767delinsASVD,
-|EXAMPLE
+p.A767delinsASVG, p.D770delinsDN,
-|EXAMPLE Loss
-|EXAMPLE
-chr7:1- 159,335,973 [hg38]
+p.D770delinsDNPH,
-|EXAMPLE
-chr7
+p.N771delinsNPH)
-|Yes
+|
-|Yes
+|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<ref name=":1" />
+|-
+|''ATRX''
+|Variable LOF mutations
+|
+|Recurrent
+|
 |No
-|EXAMPLE
+|Present in 19% (28/144) of H3.3 K28M-mutant  cases<ref name=":1" />
-Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).
+More common in patients ≥ 20 years<ref name=":7" /> and in cases taken before radiotherapy<ref>{{Cite journal|last=Pfaff|first=Elke|last2=Schramm|first2=Kathrin|last3=Blattner-Johnson|first3=Mirjam|last4=Jones|first4=Barbara C.|last5=Stark|first5=Sebastian|last6=Balasubramanian|first6=Gnana Prakash|last7=Previti|first7=Christopher|last8=Autry|first8=Robert J.|last9=Fiesel|first9=Petra|date=2025-10-11|title=Molecular characterization and clinical features of diffuse midline glioma in the pediatric precision oncology registry INFORM|url=https://pubmed.ncbi.nlm.nih.gov/41076459|journal=Acta Neuropathologica|volume=150|issue=1|pages=42|doi=10.1007/s00401-025-02945-9|issn=1432-0533|pmc=12515216|pmid=41076459}}</ref>
+|-
+|''TERT'' promoter
+|GOF
+|
+|Rare
+|
+|No
+|Present in 4% (11/304) of H3 K28M-mutant cases<ref name=":7" />
 |-
-|EXAMPLE
+|''ACVR1''
+|GOF mutations (p.G328E/V/W; p. R258G; p.R206H;  p.G356D)
+|
+|Common
+|
+|No
+|''ACVR1'' GOF mutations associated with cases in  hindbrain (WHO).
-|EXAMPLE Gain
-|EXAMPLE
-chr8:1-145,138,636 [hg38]
+Present in 28/37 (76%) of H3.1 K28M-mutant  cases; 7/144 (5%) of H3.3 K28M-mutant cases<ref name=":1" />
-|EXAMPLE
-chr8
+More frequent at relapse/recurrence (27.3%)  compared to primary diagnosis (10/3%)<ref name=":3" />
+|-
+|''BCOR''
+|Variable LOF mutations
+|
+|Recurrent
+|
 |No
+|Present in 7/37 (19%) of H3.1 K28M-mutant cases<ref name=":1" />
+|-
+|''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<ref name=":1" />
+|-
+|''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<ref name=":1" />
+|-
+|''PPM1D''
+|GOF mutations
+(p.L513*; p.C478*;  p.S468*;   p.W427*;  p.Q404*;  p.S516*;   p.E405*;  p.E525*)
+|
+|Recurrent
+|
 |No
-|EXAMPLE
+|Present in 13/144 (9%) of H3.3 K28M-mutant  cases<ref name=":1" />
+|-
+|''FGFR1''
+|GOF mutations
-Common recurrent secondary finding for t(8;21) (add reference).
+(p.N455K; p.K565E;  p.N577K; p.K687E)
-|}
+|
-==Characteristic Chromosomal Patterns==
+|Recurrent
+|
+|No
+|''FGFR1'' GOF mutations associated with cases in  diencephalon (WHO).
-Put your text here
+Present in 11/144 (8%) of H3.3 K28M-mutant  cases<ref name=":1" /><ref name=":7" />
-{| class="wikitable sortable"
+More common in patients ≥ 20 years<ref name=":7" />
 |-
-!Chromosomal Pattern
+|''BRAF''
-!Diagnostic Significance (Yes, No or Unknown)
+|p.v600E
-!Prognostic Significance (Yes, No or Unknown)
+|
-!Therapeutic Significance (Yes, No or Unknown)
+|Recurrent
-!Notes
+|
+|No
+|Present in 5/162 (3%) to 13/304 (4%) of H3  K28M-mutant cases<ref name=":7" /><ref name=":3" />
+Four of 5/162 cases found at relapse /  recurrence<ref name=":3" />
 |-
-|EXAMPLE
+|''NF1''
+|LOF
+|
+|Common
+|
+|No
+|Present in 89/304 (31%) of  H3 K28M-mutant cases<ref name=":7" />
-Co-deletion of 1p and 18q
+More common in patients ≥ 20 years<ref name=":7" />
-|Yes
+|-
+|''ATM''
+|LOF
+|
+|Recurrent
+|
+|No
+|Present in 7/162 (7%) of H3 K28M-mutant cases<ref name=":3" />
+|-
+|''PTEN''
+|LOF
+|
+|Recurrent
+|
 |No
+|Present in 15/304 (5%) of  H3 K28M-mutant cases<ref name=":7" />
+|-
+|''PTPN11''
+|
+|
+|Recurrent
+|
+|No
+|Present in 21/304 (7%) of H3 K28M-mutant cases<ref name=":7" />
+|-
+|''PDGFRA''
+|GOF
+|
+|Recurrent
+|
 |No
-|EXAMPLE:
+|''PDGFRA'' amplification associated with cases in hindbrain, diencephalon,  telencephalon (WHO).
+Present in 14/304 (5%) of H3 K28M-mutant cases
+|-
+| colspan="7" |
+|}Note: A more extensive list of mutations can be found in [https://www.cbioportal.org/ <u>cBioportal</u>], [https://cancer.sanger.ac.uk/cosmic <u>COSMIC</u>], and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
+==Epigenomic Alterations==
-See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
-|}
-==Gene Mutations (SNV/INDEL)==
-Put your text here and fill in the table
+Diffuse midline gliomas, H3 K7-altered has distinct methylation profiling clusters (PMID: 38066305; DKFZ Heidelberg v12.7), including:
-{| class="wikitable sortable"
+-         DMG_H3.1-K27M
-|-
-!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
-|-
-|EXAMPLE: TP53; Variable LOF mutations
-EXAMPLE:
+-         DMG_H3.3-K27M
-EGFR; Exon 20 mutations
+-         DMG_EGFR
-EXAMPLE: BRAF; Activating mutations
+-         DMG_EZHIP
-|EXAMPLE: TSG
-|EXAMPLE: 20% (COSMIC)
-EXAMPLE: 30% (add Reference)
+-         DMG_EZHIP_FGFR1
-|EXAMPLE: IDH1 R123H
-|EXAMPLE: EGFR amplification
-|
-|
-|
-|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
-<br />
-|}
-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==
+-         DMG_H3.3-K27M_BRAF
-Put your text here
+-         DMG_H3.3-K27M_FGFR1
 ==Genes and Main Pathways Involved==
-Put your text here and fill in the table
 {| class="wikitable sortable"
 |-
 !Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 |-
-|EXAMPLE: BRAF and MAP2K1; Activating mutations
+|''TP53'': Variable LOF and GOF mutations
-|EXAMPLE: MAPK signaling
+|p53 pathway
-|EXAMPLE: Increased cell growth and proliferation
+|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
 |-
-|EXAMPLE: CDKN2A; Inactivating mutations
+|''CDKN2A/B;'' LOF via deletion
-|EXAMPLE: Cell cycle regulation
+|Cell cycle  control
-|EXAMPLE: Unregulated cell division
+|LOF leads  to loss of p16INK4A, p14ARF, & p15INK4B, leading to uncontrolled cell  proliferation, impaired senescence and increased self-renewal
 |-
-|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+|''BRAF, NF1''; GOF / LOF respectively
-|EXAMPLE:  Histone modification, chromatin remodeling
+|MAPK pathway
-|EXAMPLE:  Abnormal gene expression program
+|Constitutive activation of the MAPK pathway  leading to uncontrolled cellular proliferation, and resistance to apoptosis
 |}
 ==Genetic Diagnostic Testing Methods==
-Put your text here
-==Familial Forms==
-Put your text here
+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
-==Additional Information==
+==Familial Forms==
-Put your text here
-==Links==
-Put your text placeholder here (use "Link" icon at top of page)
+As per the WHO Classification of CNS Tumors (5<sup>th</sup> 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 "Cite" icon at top of page)
-===EXAMPLE Book===
-#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
+(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==
-<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
+Prior Author(s):
+<nowiki>*</nowiki>''Citation of this Page'': “Diffuse midline glioma, H3 K27-altered”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/CNS5:Diffuse midline glioma, H3 K27-altered</nowiki>.
+[[Category:CNS5]]
+[[Category:DISEASE]]
+[[Category:Diseases D]]

CNS5:Diffuse midline glioma, H3 K27-altered: Difference between revisions

Latest revision as of 19:50, 25 February 2026

Primary Author(s)*

WHO Classification of Disease

Related Terminology

Gene Rearrangements

Individual Region Genomic Gain/Loss/LOH

Characteristic Chromosomal or Other Global Mutational Patterns

Gene Mutations (SNV/INDEL)

Epigenomic Alterations

Genes and Main Pathways Involved

Genetic Diagnostic Testing Methods

Familial Forms

References

Notes

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