Compendium of Cancer Genome Aberrations

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

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{{DISPLAYTITLE:Diffuse midline glioma, H3 K27-altered}}
 
[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]
==Primary Author(s)*==
==Primary Author(s)*==


Line 5: Line 7:


Linda Cooley, MD, MBA, Children's Mercy Hospital
Linda Cooley, MD, MBA, Children's Mercy Hospital
==WHO Classification of Disease==


__TOC__
{| class="wikitable"
 
!Structure
==Cancer Category/Type==
!Disease
 
|-
Put your text here
|Book
 
|Central Nervous System Tumours (5th ed.)
==Cancer Sub-Classification / Subtype==
|-
|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
|}


Put your text here
==Related Terminology==


==Definition / Description of Disease==
Put your text here
==Synonyms / Terminology==
Put your text here
==Epidemiology / Prevalence==
Put your text here
==Clinical Features==
Put your text here and fill in the table
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
|Acceptable
 
|Diffuse Intrinsic Pontine Glioma
EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
EXAMPLE Fatigue
 
EXAMPLE Lymphadenopathy (uncommon)
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|EXAMPLE Cytopenias
|N/A
 
EXAMPLE Lymphocytosis (low level)
|}
|}


==Sites of Involvement==
==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''


==Morphologic Features==


Put your text here
|Novel fusion
 
|
==Immunophenotype==
|Rare
 
|T
Put your text here and fill in the table
|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>
|-
|
|
|
|
|
|
|
|
|}


==Individual Region Genomic Gain/Loss/LOH==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Finding!!Marker
!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
|-
|-
|Positive (universal)||EXAMPLE CD1
|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> 
|-
|-
|Positive (subset)||EXAMPLE CD2
|2
|Gain
|chr2
|
|D
|No
|Documented frequency of 48% (24/50) in H3.1 K28M-mutant cases<ref name=":1" /> 
|-
|-
|Negative (universal)||EXAMPLE CD3
|4
|-
|Amp
|Negative (subset)||EXAMPLE CD4
|chr4q12
|}
|''PDGFRA/KIT/KDR''
|P
|No
|''PDGFRA'' amplification associated with  cases in hindbrain, diencephalon, telencephalon (WHO).


==Chromosomal Rearrangements (Gene Fusions)==
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>


Put your text here and fill in the table
''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


{| class="wikitable sortable"
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>
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|7
!Diagnostic Significance (Yes, No or Unknown)
|Amp
!Prognostic Significance (Yes, No or Unknown)
|chr7q21.2
!Therapeutic Significance (Yes, No or Unknown)
|''CDK6''
!Notes
|P
|No
|Found in H3 K28M-mutant cases; confers shorter OS<ref name=":1" />
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
|7
EXAMPLE 30% (add reference)
|Amp
|Yes
|chr7q31.2
|''MET''
|P
|No
|Found in in H3 K28M-mutant cases; confers shorter OS<ref name=":1" />
|-
|8
|Amp
|chr8q24
|''MYC''
|D
|No
|No
|Yes
|Documented frequency of 6% (14/245) in H3 K28M-mutant cases<ref name=":1" />
|EXAMPLE
 
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).
|}
==Individual Region Genomic Gain/Loss/LOH==
 
Put your text here and fill in the table
{| class="wikitable sortable"
|-
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|9
|Del
|chr9p21.2
|''CDKN2A/B''
|P
|No
|Found in H3 K28M-mutant cases; confers better prognosis<ref name=":1" /><ref name=":2" />
|-
|-
|10||Loss||Monosomy 10 or 10q loss
|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>
|-
|-
|Xq21.1||Loss||ATRX loss
|12
|Amp
|chr12q15
|''MDM2''
|D
|No
|Documented frequency of 3% (8/304) in H3 K28M-mutant cases<ref name=":4" />
 
More common in patients ≥ 20 years<ref name=":4" />
|-
|-
|17p13.1||overexpression||TP53
|12
|Amp
|Chr12p13
|''CCND2''
|D
|No
|Documented frequency of 5% (12/245) of H3 K28M-mutant cases<ref name=":1" />
|-
|-
|4q12||gain/amplification||PDGFRA (1,8) - ~50% of DIPG
|17
|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>
|-
|-
|8q24.2||gain/amplification||MYC/PVT1 (1,8) ~35%
|16
|Loss
|chr16q
|  
|D
|No
|Documented frequency of 36% (18/50) in H3.1 K28M-mutant cases<ref name=":5" /> 
|-
|-
|12q14.1/7q21.2/11q13.3||gain/amplification||CDK4/6, CCND1-3 (1) ~20%
|17
|Loss
|chr17p
|
|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>
|}
 
 
==Characteristic Chromosomal or Other Global Mutational Patterns==
{| class="wikitable sortable"
|-
|-
|2p25.1||gain/amplification||ID2 (1) ~10%
!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
|-
|-
|7q31.2||gain/amplification||MET (1) ~7%
|Complex  chromosomal profile, defined as ≥5 chromosomes with copy number alterations
|
|Common (70.6%)
|P
|No
|Associated  with shorter OS<ref name=":6" />
|-
|-
| ||losses||5q, 6q, 17p, 21q common (8)
|Low tumour  mutation burden (TMB)
|
|
|D
|
|0.49 somatic  mutations per Megabase (Mb) (range 0.09–9.01)<ref name=":3" />
|-
|-
| ||gains||1q, 2 (1)
|Alternative  lengthening of telomeres (ALT) genomic signature
|
|Common (28.4%)
|D
|
|<ref name=":3" />
|}
|}
==Gene Mutations (SNV/INDEL)==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!Gain / Loss / Amp / LOH!!Minimal Region Genomic Coordinates [Genome Build]!!Minimal Region Cytoband
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
!Diagnostic Significance (Yes, No or Unknown)
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!Prognostic Significance (Yes, No or Unknown)
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!Therapeutic Significance (Yes, No or Unknown)
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!Notes
!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
|-
|-
|EXAMPLE
|''H3-3B''
|GOF


7
p.K28M/I
|EXAMPLE Loss
|
|EXAMPLE
|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


chr7:1- 159,335,973 [hg38]
p.K28M/I
|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
|-
|''H3C3''
|GOF


chr7
p.K28M/I
|Yes
|
|Yes
|Common
|No
|D/P
|EXAMPLE
|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


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).
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
|-
|-
|EXAMPLE
|''Other  histone H3 genes''
|GOF


8
p.K28M/I
|EXAMPLE Gain
|
|EXAMPLE
|
|
|
|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


chr8:1-145,138,636 [hg38]
(p.G598V, p.A289T/V, e20 insertions incl
|EXAMPLE


chr8
p.M766delinsMASV, p.A767delinsASVD,
|No
|No
|No
|EXAMPLE


Common recurrent secondary finding for t(8;21) (add reference).
p.A767delinsASVG, p.D770delinsDN,
|}
==Characteristic Chromosomal Patterns==


Put your text here
p.D770delinsDNPH,


{| class="wikitable sortable"
p.N771delinsNPH)
|
|Rare
|D/P
|Yes (WHO)
|Fulfils WHO essential criterion for diagnosis  in setting of a diffuse midline glioma with H3 K28me3 loss
|-
|-
!Chromosomal Pattern
|''TP53''
!Diagnostic Significance (Yes, No or Unknown)
|Variable LOF and GOF mutations
!Prognostic Significance (Yes, No or Unknown)
|
!Therapeutic Significance (Yes, No or Unknown)
|Common
!Notes
|
|No
|Present in 68% (98/144) of H3.3 K28M-mutant  cases; 11/37 (30%) of H3.1 K28M-mutant cases<ref name=":1" />
|-
|-
|EXAMPLE
|''ATRX''
|Variable LOF mutations
|
|Recurrent
|
|No
|Present in 19% (28/144) of H3.3 K28M-mutant  cases<ref name=":1" />


Co-deletion of 1p and 18q
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>
|Yes
|-
|''TERT'' promoter
|GOF
|
|Rare
|
|No
|No
|Present in 4% (11/304) of H3 K28M-mutant cases<ref name=":7" />
|-
|''ACVR1''
|GOF mutations (p.G328E/V/W; p. R258G; p.R206H;  p.G356D)
|
|Common
|
|No
|No
|EXAMPLE:
|''ACVR1'' GOF mutations associated with cases in  hindbrain (WHO).


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
Present in 28/37 (76%) of H3.1 K28M-mutant  cases; 7/144 (5%) of H3.3 K28M-mutant cases<ref name=":1" />
 


{| class="wikitable sortable"
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" /> 
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC / TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
|''PIK3R1''
!'''Diagnostic Significance (Yes, No or Unknown)'''
|GOF mutations (p.K567E; p.K379E; p.P612L; p.R358*; p.G376R)
!Prognostic Significance (Yes, No or Unknown)
|
!Therapeutic Significance (Yes, No or Unknown)
|Recurrent
!Notes
|
|No
|Present in 4/37 (11%) of H3.1 K28M-mutant  cases; 11/144 (8%) of H3.3 K28M-mutant cases<ref name=":1" />
|-
|-
|EXAMPLE: TP53; Variable LOF mutations
|''PPM1D''
|GOF mutations


EXAMPLE:
(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<ref name=":1" />
|-
|''FGFR1''
|GOF mutations


EGFR; Exon 20 mutations
(p.N455K; p.K565E;  p.N577K; p.K687E)
|
|Recurrent
|
|No
|''FGFR1'' GOF mutations associated with cases in  diencephalon (WHO).


EXAMPLE: BRAF; Activating mutations
Present in 11/144 (8%) of H3.3 K28M-mutant  cases<ref name=":1" /><ref name=":7" />
|EXAMPLE: TSG
|EXAMPLE: 20% (COSMIC)


EXAMPLE: 30% (add Reference)
More common in patients ≥ 20 years<ref name=":7" />
|EXAMPLE: IDH1 R123H
|-
|EXAMPLE: EGFR amplification
|''BRAF''
|p.v600E
|
|
|Recurrent
|
|
|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" />
|-
|''NF1''
|LOF
|
|
|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
|Common
<br />
|
|}
|No
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.
|Present in 89/304 (31%) of  H3 K28M-mutant cases<ref name=":7" />
 
More common in patients ≥ 20 years<ref name=":7" />  
|-
|''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
|''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==
==Epigenomic Alterations==


Put your text here
 
 
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==
==Genes and Main Pathways Involved==
Put your text here and fill in the table
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!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==
==Genetic Diagnostic Testing Methods==


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


==Familial Forms==
==Familial Forms==


Put your text here


==Additional Information==


Put your text here
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.


==Links==
==References==


Put your text placeholder here (use "Link" icon at top of page)


==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 />
<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.
==Notes==


==Notes==
Prior Author(s):
<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.
<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>.
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[[Category:Diseases D]]
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