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)*==


Put your text here (Example: Jane Smith, PhD, Institute of Genomics)
Laveniya Satgunaseelan, FRCPA, Royal Prince Alfred Hospital


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


==Cancer Category/Type==
{| 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
|}


Put your text here
==Related Terminology==


==Cancer Sub-Classification / Subtype==
{| class="wikitable"
|+
|Acceptable
|Diffuse Intrinsic Pontine Glioma
|-
|Not Recommended
|N/A
|}


Put your text here
==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::''


==Definition / Description of Disease==
''NTRK3''
|Novel fusion
|
|Rare
|T
|No
|<ref name=":0" />
|-
|''NTRK2''
|''VCL::NTRK2''


Put your text here


==Synonyms / Terminology==
|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>
|-
|
|
|
|
|
|
|
|
|}


Put your text here
==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).


==Epidemiology / Prevalence==
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
''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


==Clinical Features==
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" />


Put your text here
More common in patients ≥ 20 years<ref name=":4" />
|-
|12
|Amp
|Chr12p13
|''CCND2''
|D
|No
|Documented frequency of 5% (12/245) of H3 K28M-mutant cases<ref name=":1" />
|-
|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>
|-
|16
|Loss
|chr16q
|
|D
|No
|Documented frequency of 36% (18/50) in H3.1 K28M-mutant cases<ref name=":5" /> 
|-
|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>
|}


==Sites of Involvement==


Put your text here
==Characteristic Chromosomal or Other Global Mutational Patterns==
{| class="wikitable sortable"
|-
!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<ref name=":6" />
|-
|Low tumour  mutation burden (TMB)
|
|
|D
|
|0.49 somatic  mutations per Megabase (Mb) (range 0.09–9.01)<ref name=":3" />
|-
|Alternative  lengthening of telomeres (ALT) genomic signature
|
|Common (28.4%)
|D
|
|<ref name=":3" />
|}


==Morphologic Features==
==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
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


==Immunophenotype==
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


Put your text here and/or fill in the table
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


{| class="wikitable sortable"
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
|-
|-
!Finding!!Marker
|''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
|-
|-
|Positive (universal)||EXAMPLE CD1
|''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.
|-
|-
|Positive (subset)||EXAMPLE CD2
|''EGFR''
|-
|GOF
|Negative (universal)||EXAMPLE CD3
 
|-
(p.G598V, p.A289T/V, e20 insertions incl
|Negative (subset)||EXAMPLE CD4
 
|}
p.M766delinsMASV, p.A767delinsASVD,


==Chromosomal Rearrangements (Gene Fusions)==
p.A767delinsASVG, p.D770delinsDN,


Put your text here and/or fill in the table
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
|-
|''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" />
|-
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
|''ATRX''
|Variable LOF mutations
|
|Recurrent
|
|No
|Present in 19% (28/144) of H3.3 K28M-mutant  cases<ref name=":1" />
 
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>
|-
|-
|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 5%
|''TERT'' promoter
|GOF
|
|Rare
|
|No
|Present in 4% (11/304) of H3 K28M-mutant cases<ref name=":7" />
|-
|-
|EXAMPLE t(8;21)(q22;q22)||EXAMPLE 5'RUNX1 / 3'RUNXT1||EXAMPLE der(8)||EXAMPLE 5%
|''ACVR1''
|}
|GOF mutations (p.G328E/V/W; p. R258G; p.R206H;  p.G356D)
|
==Characteristic Chromosomal Aberrations / Patterns==
|Common
|
|No
|''ACVR1'' GOF mutations associated with cases in  hindbrain (WHO).


Put your text here


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


Put your text here and/or fill in the table


{| 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" /> 
|-
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|''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" /> 
|-
|-
|EXAMPLE 8||EXAMPLE Gain||EXAMPLE chr8:0-1000000
|''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" />
|-
|-
|EXAMPLE 7||EXAMPLE Loss||EXAMPLE chr7:0-1000000
|''PPM1D''
|}
|GOF mutations
 
==Gene Mutations (SNV/INDEL)==
(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
 
(p.N455K; p.K565E;  p.N577K; p.K687E)
|
|Recurrent
|
|No
|''FGFR1'' GOF mutations associated with cases in  diencephalon (WHO).


Put your text here and/or fill in the tables
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" />
|-
|''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" />
|-
|-
!Gene!!Mutation!!Oncogene/Tumor Suppressor/Other!!Presumed Mechanism (LOF/GOF/Other; Driver/Passenger)!!Prevalence (COSMIC/TCGA/Other)
|''NF1''
|LOF
|
|Common
|
|No
|Present in 89/304 (31%) of  H3 K28M-mutant cases<ref name=":7" />
 
More common in patients ≥ 20 years<ref name=":7" />
|-
|-
|EXAMPLE TP53||EXAMPLE R273H||EXAMPLE Tumor Suppressor||EXAMPLE LOF||EXAMPLE 20%
|''ATM''
|}
|LOF
|
===Other Mutations===
|Recurrent
{| class="wikitable sortable"
|
|No
|Present in 7/162 (7%) of H3 K28M-mutant cases<ref name=":3" />
|-
|-
!Type!!Gene/Region/Other
|''PTEN''
|LOF
|
|Recurrent
|
|No
|Present in 15/304 (5%) of  H3 K28M-mutant cases<ref name=":7" />
|-
|-
|Concomitant Mutations||EXAMPLE IDH1 R123H
|''PTPN11''
|
|
|Recurrent
|
|No
|Present in 21/304 (7%) of H3 K28M-mutant cases<ref name=":7" /> 
|-
|-
|Secondary Mutations||EXAMPLE Trisomy 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
|-
|-
|Mutually Exclusive||EXAMPLE EGFR Amplification
| 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==
 
 
 
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


==Epigenomics (Methylation)==
-         DMG_H3.3-K27M_BRAF


Put your text here
-         DMG_H3.3-K27M_FGFR1


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''TP53'': Variable LOF and GOF mutations
|p53 pathway
|LOF – loss  of tumour suppressive control


Put your text here
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==


==Diagnostic Testing Methods==


Put your text here


==Clinical Significance (Diagnosis, Prognosis and Therapeutic Implications)==
Genetic diagnostic testing methods include:


Diagnosis: Put your text here
-         Immunohistochemistry to detect H3 K28me3 loss


Prognosis: Put your text here
-         Next generation sequencing to detect entity defining alterations in histone H3 genes and ''EGFR''


Therapeutic: Put your text here
-         Methylation profiling for detection of diffuse midline glioma subtypes


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


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==Other 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 links 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>
(use "Cite" icon at top of page)
<references />
<references />
===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>.
[[Category:CNS5]]
[[Category:DISEASE]]
[[Category:Diseases D]]
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