Compendium of Cancer Genome Aberrations

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

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[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]
[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]
{{Under Construction}}
<span style="color:#0070C0">(''General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use [https://www.genenames.org/ <u>HUGO-approved gene names and symbols</u>] (italicized when appropriate), [https://varnomen.hgvs.org/ <u>HGVS-based nomenclature for variants</u>], as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see'' </span><u>''[[Author_Instructions]]''</u><span style="color:#0070C0"> ''and [[Frequently Asked Questions (FAQs)|<u>FAQs</u>]] as well as contact your [[Leadership|<u>Associate Editor</u>]] or [mailto:CCGA@cancergenomics.org <u>Technical Support</u>].)''</span>
==Primary Author(s)*==
==Primary Author(s)*==


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|-
|-
|Subtype(s)
|Subtype(s)
|Diffuse midline glioma, H3 K27-altered
|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
|}
|}


Line 38: Line 34:
|+
|+
|Acceptable
|Acceptable
|Age-related clonal haematopoiesis (ARCH)
|Diffuse Intrinsic Pontine Glioma
|-
|-
|Not Recommended
|Not Recommended
Line 45: Line 41:


==Gene Rearrangements==
==Gene Rearrangements==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 54: Line 49:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''||<span class="blue-text">EXAMPLE:</span> ''BCR::ABL1''||<span class="blue-text">EXAMPLE:</span> The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.||<span class="blue-text">EXAMPLE:</span> t(9;22)(q34;q11.2)
|''NTRK3''
|<span class="blue-text">EXAMPLE:</span> Common (CML)
|''ZKSCAN1::NTRK3''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|Novel fusion
|<span class="blue-text">EXAMPLE:</span> Yes (WHO, NCCN)
|
|<span class="blue-text">EXAMPLE:</span>
|Rare
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). BCR::ABL1 is generally favorable in CML (add reference).
|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>
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CIC''
|''NTRK3''
|<span class="blue-text">EXAMPLE:</span> ''CIC::DUX4''
|''BTBD1::CPEB1::''
|<span class="blue-text">EXAMPLE:</span> Typically, the last exon of ''CIC'' is fused to ''DUX4''. The fusion breakpoint in ''CIC'' is usually intra-exonic and removes an inhibitory sequence, upregulating ''PEA3'' genes downstream of ''CIC'' including ''ETV1'', ''ETV4'', and ''ETV5''.
 
|<span class="blue-text">EXAMPLE:</span> t(4;19)(q25;q13)
''NTRK3''
|<span class="blue-text">EXAMPLE:</span> Common (CIC-rearranged sarcoma)
|Novel fusion
|<span class="blue-text">EXAMPLE:</span> D
|
|
|<span class="blue-text">EXAMPLE:</span>
|Rare
 
|T
''DUX4'' has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
|No
|<ref name=":0" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ALK''
|''NTRK2''
|<span class="blue-text">EXAMPLE:</span> ''ELM4::ALK''
|''VCL::NTRK2''




Other fusion partners include ''KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1''
|Novel fusion
|<span class="blue-text">EXAMPLE:</span> Fusions result in constitutive activation of the ''ALK'' tyrosine kinase. The most common ''ALK'' fusion is ''EML4::ALK'', with breakpoints in intron 19 of ''ALK''. At the transcript level, a variable (5’) partner gene is fused to 3’ ''ALK'' at exon 20. Rarely, ''ALK'' fusions contain exon 19 due to breakpoints in intron 18.
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Rare (Lung adenocarcinoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|<span class="blue-text">EXAMPLE:</span>
|Rare
 
|T
Both balanced and unbalanced forms are observed by FISH (add references).
|No
|<ref name=":0" />
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''ABL1''
|''FGFR2''
|<span class="blue-text">EXAMPLE:</span> N/A
|''FGFR2::VPS35''
|<span class="blue-text">EXAMPLE:</span> Intragenic deletion of exons 2–7 in ''EGFR'' removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.
|Novel fusion
|<span class="blue-text">EXAMPLE:</span> N/A
|<span class="blue-text">EXAMPLE:</span> Recurrent (IDH-wildtype Glioblastoma)
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|
|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>
|-
|-
|
|
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==Individual Region Genomic Gain/Loss/LOH==
==Individual Region Genomic Gain/Loss/LOH==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 114: Line 107:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|1
7
|Gain
|<span class="blue-text">EXAMPLE:</span> Loss
|chr1q
|<span class="blue-text">EXAMPLE:</span>
chr7
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|<span class="blue-text">EXAMPLE:</span> No
|<span class="blue-text">EXAMPLE:</span>
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 references).
|-
|<span class="blue-text">EXAMPLE:</span>
8
|<span class="blue-text">EXAMPLE:</span> Gain
|<span class="blue-text">EXAMPLE:</span>
chr8
|<span class="blue-text">EXAMPLE:</span>
Unknown
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|<span class="blue-text">EXAMPLE:</span>
|D
Common recurrent secondary finding for t(8;21) (add references).
|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>
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|2
17
|Gain
|<span class="blue-text">EXAMPLE:</span> Amp
|chr2
|<span class="blue-text">EXAMPLE:</span>
17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]
|<span class="blue-text">EXAMPLE:</span>
''ERBB2''
|<span class="blue-text">EXAMPLE:</span> D, P, T
|
|
|<span class="blue-text">EXAMPLE:</span>
|D
Amplification of ''ERBB2'' is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.
|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).
|}
 


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>


''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 and fill in the table
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>
{| class="wikitable sortable"
|-
|-
!Chromosome Number!!Gain/Loss/Amp/LOH!!Region
|7
|Amp
|chr7q21.2
|''CDK6''
|P
|No
|Found in H3 K28M-mutant cases; confers shorter OS<ref name=":1" />
|-
|-
|10||Loss||Monosomy 10 or 10q loss
|7
|Amp
|chr7q31.2
|''MET''
|P
|No
|Found in in H3 K28M-mutant cases; confers shorter OS<ref name=":1" />
|-
|-
|Xq21.1||Loss||ATRX loss
|8
|Amp
|chr8q24
|''MYC''
|D
|No
|Documented frequency of 6% (14/245) in H3 K28M-mutant cases<ref name=":1" />
|-
|-
|17p13.1||overexpression||TP53
|9
|Del
|chr9p21.2
|''CDKN2A/B''
|P
|No
|Found in H3 K28M-mutant cases; confers better prognosis<ref name=":1" /><ref name=":2" />
|-
|-
|4q12||gain/amplification||PDGFRA (1,8) - ~50% of DIPG
|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>
|-
|-
|8q24.2||gain/amplification||MYC/PVT1 (1,8) ~35%
|12
|-
|Amp
|12q14.1/7q21.2/11q13.3||gain/amplification||CDK4/6, CCND1-3 (1) ~20%
|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" />
|-
|-
|2p25.1||gain/amplification||ID2 (1) ~10%
|12
|Amp
|Chr12p13
|''CCND2''
|D
|No
|Documented frequency of 5% (12/245) of H3 K28M-mutant cases<ref name=":1" />
|-
|-
|7q31.2||gain/amplification||MET (1) ~7%
|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>
|-
|-
| ||losses||5q, 6q, 17p, 21q common (8)
|16
|Loss
|chr16q
|  
|D
|No
|Documented frequency of 36% (18/50) in H3.1 K28M-mutant cases<ref name=":5" /> 
|-
|-
| ||gains||1q, 2 (1)
|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==
==Characteristic Chromosomal or Other Global Mutational Patterns==
Put your text here and fill in the table <span style="color:#0070C0">(I''nstructions: Included in this category are alterations such as hyperdiploid; gain of odd number chromosomes including typically chromosome 1, 3, 5, 7, 11, and 17; co-deletion of 1p and 19q; complex karyotypes without characteristic genetic findings; chromothripsis; microsatellite instability; homologous recombination deficiency; mutational signature pattern; etc. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.'')</span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 201: Line 248:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Complex  chromosomal profile, defined as ≥5 chromosomes with copy number alterations
Co-deletion of 1p and 18q
|<span class="blue-text">EXAMPLE:</span> See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
|<span class="blue-text">EXAMPLE:</span> Common (Oligodendroglioma)
|<span class="blue-text">EXAMPLE:</span> D, P
|
|
|
|Common (70.6%)
|P
|No
|Associated  with shorter OS<ref name=":6" />
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|Low tumour  mutation burden (TMB)
Microsatellite instability - hypermutated
|
|
|<span class="blue-text">EXAMPLE:</span> Common (Endometrial carcinoma)
|<span class="blue-text">EXAMPLE:</span> P, T
|
|
|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" />
|
|
|
|}
|}


==Gene Mutations (SNV/INDEL)==
==Gene Mutations (SNV/INDEL)==
Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.'') </span>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
Line 237: Line 279:
!Clinical Relevance Details/Other Notes
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|''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


<br />
p.K28M/I
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|
|<span class="blue-text">EXAMPLE:</span> Oncogene
|Common
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|D/P
|<span class="blue-text">EXAMPLE:</span> T
|Yes (WHO)
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|Encodes histone H3.3. Fulfils WHO essential  criterion for diagnosis in setting of a diffuse midline glioma with H3 K28me3  loss
|<span class="blue-text">EXAMPLE:</span> Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''TP53''; Variable LOF mutations
|''H3C2''
<br />
|GOF
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
 
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
p.K28M/I
|<span class="blue-text">EXAMPLE:</span> Common (breast cancer)
|<span class="blue-text">EXAMPLE:</span> P
|
|
|<span class="blue-text">EXAMPLE:</span> >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
|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
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|''H3C3''
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|GOF
|<span class="blue-text">EXAMPLE:</span> Oncogene
 
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
p.K28M/I
|<span class="blue-text">EXAMPLE:</span> T
|
|
|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<ref name=":1" />
|-
|''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>
|-
|''TERT'' promoter
|GOF
|
|Rare
|
|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
|''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<ref name=":1" />
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
|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).
Present in 11/144 (8%) of H3.3 K28M-mutant  cases<ref name=":1" /><ref name=":7" />
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" />
|-
|''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" />
|-
|''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.
|}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
==Genes and Main Pathways Involved==


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


Put your text here and fill in the table <span style="color:#0070C0">(''Instructions: Please include references throughout the table. Do not delete the table.)''</span>
==Genes and Main Pathways Involved==
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF'' and ''MAP2K1''; Activating mutations
|''TP53'': Variable LOF and GOF mutations
|<span class="blue-text">EXAMPLE:</span> MAPK signaling
|p53 pathway
|<span class="blue-text">EXAMPLE:</span> Increased cell growth and proliferation
|LOF – loss  of tumour suppressive control
 
GOF – oncogenic  properties including effect on antitumor immune response (PMID:  36859359)
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''CDKN2A''; Inactivating mutations
|''PIK3CA;  PIK3R1''; GOF mutations
|<span class="blue-text">EXAMPLE:</span> Cell cycle regulation
|PI3K-AKT-MTOR  pathway
|<span class="blue-text">EXAMPLE:</span> Unregulated cell division
|Hyperactivation  of the PI3K/AKT/mTOR signaling pathway, leading to  cell growth, division, and survival
|-
|-
|<span class="blue-text">EXAMPLE:</span> ''KMT2C'' and ''ARID1A''; Inactivating mutations
|''CDKN2A/B;'' LOF via deletion
|<span class="blue-text">EXAMPLE:</span> Histone modification, chromatin remodeling
|Cell cycle  control
|<span class="blue-text">EXAMPLE:</span> Abnormal gene expression program
|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==




Put your text here <span style="color:#0070C0">(''Instructions: Include recommended testing type(s) to identify the clinically significant genetic alterations.'')</span>
==Familial Forms==


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


Put your text here <span style="color:#0070C0">(''Instructions: Include associated hereditary conditions/syndromes that cause this entity or are caused by this entity.'') </span>
==Familial Forms==
==Additional Information==




Put your text here
==Links==


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.


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==References==
==References==




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<references />
==Notes==
==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 [[Leadership|''<u>Associate Editor</u>'']] or other CCGA representative.  When pages have a major update, the new author will be acknowledged at the beginning of the page, and those who contributed previously will be acknowledged below as a prior author.


Prior Author(s):
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>.
<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:CNS5]]
[[Category:DISEASE]]
[[Category:DISEASE]]
[[Category:Diseases D]]
[[Category:Diseases D]]
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