Compendium of Cancer Genome Aberrations

CNS5:Diffuse hemispheric glioma, H3 G34-mutant: Difference between revisions

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{{DISPLAYTITLE:Diffuse hemispheric glioma, H3 G34-mutant}}
{{DISPLAYTITLE:Diffuse hemispheric glioma, H3 G34-mutant}}
[[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}}
{{Under Construction}}
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Xiaolin Hu, PhD, Sema4 OpCo Inc.
Xiaolin Hu, PhD, Sema4 OpCo Inc.


==WHO Classification of Disease==
==WHO Classification of Disease==
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==Definition / Description of Disease==
==Related Terminology==
 
Diffuse hemispheric glioma, H3 G34–mutant (G34-DHG) is a newly recognized tumor entity that is characterized by point mutations in the ''H3-3A'' (''H3-3A'') gene, encoding for histone variant H3.3  <ref name=":0">{{Cite journal|last=Schwartzentruber|first=Jeremy|last2=Korshunov|first2=Andrey|last3=Liu|first3=Xiao-Yang|last4=Jones|first4=David T. W.|last5=Pfaff|first5=Elke|last6=Jacob|first6=Karine|last7=Sturm|first7=Dominik|last8=Fontebasso|first8=Adam M.|last9=Quang|first9=Dong-Anh Khuong|date=2012-01-29|title=Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma|url=https://pubmed.ncbi.nlm.nih.gov/22286061|journal=Nature|volume=482|issue=7384|pages=226–231|doi=10.1038/nature10833|issn=1476-4687|pmid=22286061}}</ref><ref>{{Cite journal|last=Wu|first=Gang|last2=Broniscer|first2=Alberto|last3=McEachron|first3=Troy A.|last4=Lu|first4=Charles|last5=Paugh|first5=Barbara S.|last6=Becksfort|first6=Jared|last7=Qu|first7=Chunxu|last8=Ding|first8=Li|last9=Huether|first9=Robert|date=2012-01-29|title=Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas|url=https://pubmed.ncbi.nlm.nih.gov/22286216|journal=Nature Genetics|volume=44|issue=3|pages=251–253|doi=10.1038/ng.1102|issn=1546-1718|pmc=3288377|pmid=22286216}}</ref>. Point mutations tend to be clustered at codon 34 including c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or rarely c.104G>T p.G35V (G34V) <ref name=":0" />. This distinct tumor entity is an aggressive glioma arising from the cerebral hemispheres. G34-DHG is designated as CNS WHO grade 4 in in the WHO 5th edition <ref name=":3">Ellison, DW, Korshunov A, Northcott PA, Taylor MD, Kaur K, Clifford SC. Medulloblastoma, WNT-activated. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). <nowiki>https://publications.iarc.fr/601</nowiki>.</ref>.
 
Please note that historically, numbering of the amino acid sequences of histone genes has begun at the second codon, as the amino acid encoded by the first codon (methionine) is cleaved post-translationally. Therefore, H3.3 G34 represents the legacy nomenclature of what is now referred to as H3.3 G35 <ref>{{Cite journal|last=Leske|first=Henning|last2=Dalgleish|first2=Raymond|last3=Lazar|first3=Alexander J.|last4=Reifenberger|first4=Guido|last5=Cree|first5=Ian A.|date=2021-06|title=A common classification framework for histone sequence alterations in tumours: an expert consensus proposal|url=https://pubmed.ncbi.nlm.nih.gov/33779999|journal=The Journal of Pathology|volume=254|issue=2|pages=109–120|doi=10.1002/path.5666|issn=1096-9896|pmid=33779999}}</ref>.
 
==Synonyms / Terminology==
 
Pediatric glioblastoma, H3.3 G34–mutant (not recommended)


==Epidemiology / Prevalence==
G34-DHG is reported to account for approximately 15% of high grade gliomas (HGSs) and typically affect adolescents and young adults with a median age at diagnosis of 15.8 years old <ref>{{Cite journal|last=Picart|first=Thiébaud|last2=Barritault|first2=Marc|last3=Poncet|first3=Delphine|last4=Berner|first4=Lise-Prune|last5=Izquierdo|first5=Cristina|last6=Tabouret|first6=Emeline|last7=Figarella-Branger|first7=Dominique|last8=Idbaïh|first8=Ahmed|last9=Bielle|first9=Franck|date=2021-01|title=Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults|url=https://pubmed.ncbi.nlm.nih.gov/34056608|journal=Neuro-Oncology Advances|volume=3|issue=1|pages=vdab061|doi=10.1093/noajnl/vdab061|issn=2632-2498|pmc=8156974|pmid=34056608}}</ref><ref name=":1">{{Cite journal|last=Crowell|first=Cameron|last2=Mata-Mbemba|first2=Daddy|last3=Bennett|first3=Julie|last4=Matheson|first4=Kara|last5=Mackley|first5=Michael|last6=Perreault|first6=Sébastien|last7=Erker|first7=Craig|date=2022-01|title=Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors|url=https://pubmed.ncbi.nlm.nih.gov/36105387|journal=Neuro-Oncology Advances|volume=4|issue=1|pages=vdac133|doi=10.1093/noajnl/vdac133|issn=2632-2498|pmc=9466272|pmid=36105387}}</ref>. Studies have shown that there is a gender difference with male to female ratio of 1.4:1 <ref name=":4">{{Cite journal|last=Korshunov|first=Andrey|last2=Capper|first2=David|last3=Reuss|first3=David|last4=Schrimpf|first4=Daniel|last5=Ryzhova|first5=Marina|last6=Hovestadt|first6=Volker|last7=Sturm|first7=Dominik|last8=Meyer|first8=Jochen|last9=Jones|first9=Chris|date=2016-01|title=Histologically distinct neuroepithelial tumors with histone 3 G34  mutation are molecularly similar and comprise a single nosologic  entity|url=https://pubmed.ncbi.nlm.nih.gov/26482474|journal=Acta Neuropathologica|volume=131|issue=1|pages=137–146|doi=10.1007/s00401-015-1493-1|issn=1432-0533|pmid=26482474}}</ref><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>.
==Clinical Features==
Site dependent neurological symptoms including epileptic seizure, focal deficit, increased intracranial hypertension (headache, nausea and vomiting) <ref>{{Cite journal|last=Picart|first=Thiébaud|last2=Barritault|first2=Marc|last3=Poncet|first3=Delphine|last4=Berner|first4=Lise-Prune|last5=Izquierdo|first5=Cristina|last6=Tabouret|first6=Emeline|last7=Figarella-Branger|first7=Dominique|last8=Idbaïh|first8=Ahmed|last9=Bielle|first9=Franck|date=2021|title=Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults|url=https://pubmed.ncbi.nlm.nih.gov/34056608|journal=Neuro-Oncology Advances|volume=3|issue=1|pages=vdab061|doi=10.1093/noajnl/vdab061|issn=2632-2498|pmc=8156974|pmid=34056608}}</ref>.
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|epileptic seizure, focal deficit, increased intracranial hypertension
|Acceptable
|-
|N/A
|'''Laboratory Findings'''
|Not applicable
|}
 
==Sites of Involvement==
 
*Usually involves cerebral hemispheres
 
*Occasionally across the midline and disseminate to leptomeningeal structures.
 
*MRI typically shows a bulky cortical mass, most commonly seen in the parietal or temporal lobe. Multifocal lesions and/or leptomeningeal dissemination can be seen along with necrosis, cysts, hemorrhage and calcification <ref>{{Cite journal|last=Vettermann|first=Franziska J.|last2=Felsberg|first2=Jörg|last3=Reifenberger|first3=Guido|last4=Hasselblatt|first4=Martin|last5=Forbrig|first5=Robert|last6=Berding|first6=Georg|last7=la Fougère|first7=Christian|last8=Galldiks|first8=Norbert|last9=Schittenhelm|first9=Jens|date=2018-12|title=Characterization of Diffuse Gliomas With Histone H3-G34 Mutation by MRI and Dynamic 18F-FET PET|url=https://pubmed.ncbi.nlm.nih.gov/30358620|journal=Clinical Nuclear Medicine|volume=43|issue=12|pages=895–898|doi=10.1097/RLU.0000000000002300|issn=1536-0229|pmid=30358620}}</ref>.
 
==Morphologic Features==
 
*Grossly, grey/tan solid mass within cortical and subcortical region with soft consistency, necrotic and hemorrhagic features.
*Microscopically, heterogenous histological appearance, with two main histological appearances: glioblastoma-like and primitive embryonal-like. GBM-like morphology typically shows a highly cellular, infiltrative, astrocytic tumor. High mitotic activity, microvascular proliferation and necrosis are frequently seen. Embryonal-like morphology shows hyperchromatic nuclei with scant cytoplasm, and occasional Homer-Wright rosettes.
 
==Immunophenotype==
 
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||MAP2, FOXG1, p53
|-
|-
|Positive (subset)||GFAP (GBM-like morphology), synaptophysin (embryonal-like morphology)
|Not Recommended
|-
|Paediatric glioblastoma, H3.3 G34–mutant
|Negative (universal)||ATRX, Olig2
|-
|Negative (subset)||
|}
|}


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|
|}
|}
Not applicable
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Pathogenic Derivative!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|N/A||N/A
|N/A
|N/A
|N/A
|N/A
|N/A
|N/A
|}




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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!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'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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'''Add content below into table above''' -      


Oncogenic amplifications in G34-DHG have been shown to be negative prognostic markers, as documented below <ref name=":4" />.
Oncogenic amplifications in G34-DHG have been shown to be negative prognostic markers, as documented below <ref name=":4">{{Cite journal|last=Korshunov|first=Andrey|last2=Capper|first2=David|last3=Reuss|first3=David|last4=Schrimpf|first4=Daniel|last5=Ryzhova|first5=Marina|last6=Hovestadt|first6=Volker|last7=Sturm|first7=Dominik|last8=Meyer|first8=Jochen|last9=Jones|first9=Chris|date=2016-01|title=Histologically distinct neuroepithelial tumors with histone 3 G34  mutation are molecularly similar and comprise a single nosologic  entity|url=https://pubmed.ncbi.nlm.nih.gov/26482474|journal=Acta Neuropathologica|volume=131|issue=1|pages=137–146|doi=10.1007/s00401-015-1493-1|issn=1432-0533|pmid=26482474}}</ref>.
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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|14% case of G34-DHG <ref name=":5" />
|14% case of G34-DHG <ref name=":5" />
|}
|}
==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>
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>
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!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Molecular Pathogenesis
!'''Prevalence -'''
!Prevalence -  
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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|}


 
'''Add content below into table above''' -      
 
 
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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|Found in 44% of cases of G34-DHG <ref name=":5" />
|Found in 44% of cases of G34-DHG <ref name=":5" />
|}
|}
==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"
|-
!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
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''


<br />
|<span class="blue-text">EXAMPLE:</span> Exon 18-21 activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (lung cancer)
|<span class="blue-text">EXAMPLE:</span> T
|<span class="blue-text">EXAMPLE:</span> Yes (NCCN)
|<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
<br />
|<span class="blue-text">EXAMPLE:</span> Variable LOF mutations
|<span class="blue-text">EXAMPLE:</span> Tumor Supressor Gene
|<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.
|-
|<span class="blue-text">EXAMPLE:</span> ''BRAF''; Activating mutations
|<span class="blue-text">EXAMPLE:</span> Activating mutations
|<span class="blue-text">EXAMPLE:</span> Oncogene
|<span class="blue-text">EXAMPLE:</span> Common (melanoma)
|<span class="blue-text">EXAMPLE:</span> T
|
|
|-
|
|
|
|
|
|
|
|}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.


==Gene Mutations (SNV/INDEL/Methylation)==
<br />


'''Add content below into table above''' -      
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!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)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
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|chromosome modification
|chromosome modification
|p.G35R 94%
|p.G35R 94%
p.G35V 6% <ref name=":3" />
p.G35V 6% <ref name=":3">Ellison, DW, Korshunov A, Northcott PA, Taylor MD, Kaur K, Clifford SC. Medulloblastoma, WNT-activated. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). <nowiki>https://publications.iarc.fr/601</nowiki>.</ref>
|TP53 mutations 90%;
|TP53 mutations 90%;
ATRX mutations 95%
ATRX mutations 95%


MGMT promoter methylation 70%-74% <ref name=":1" /><ref name=":4" />
MGMT promoter methylation 70%-74% <ref name=":1">{{Cite journal|last=Crowell|first=Cameron|last2=Mata-Mbemba|first2=Daddy|last3=Bennett|first3=Julie|last4=Matheson|first4=Kara|last5=Mackley|first5=Michael|last6=Perreault|first6=Sébastien|last7=Erker|first7=Craig|date=2022-01|title=Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors|url=https://pubmed.ncbi.nlm.nih.gov/36105387|journal=Neuro-Oncology Advances|volume=4|issue=1|pages=vdac133|doi=10.1093/noajnl/vdac133|issn=2632-2498|pmc=9466272|pmid=36105387}}</ref><ref name=":4" />


PDGFRA mutations 50-70%<ref>{{Cite journal|last=Chen|first=Carol C. L.|last2=Deshmukh|first2=Shriya|last3=Jessa|first3=Selin|last4=Hadjadj|first4=Djihad|last5=Lisi|first5=Véronique|last6=Andrade|first6=Augusto Faria|last7=Faury|first7=Damien|last8=Jawhar|first8=Wajih|last9=Dali|first9=Rola|date=2020-12-10|title=Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis|url=https://pubmed.ncbi.nlm.nih.gov/33259802|journal=Cell|volume=183|issue=6|pages=1617–1633.e22|doi=10.1016/j.cell.2020.11.012|issn=1097-4172|pmc=7791404|pmid=33259802}}</ref> <ref>{{Cite journal|last=Lucas|first=Calixto-Hope G.|last2=Mueller|first2=Sabine|last3=Reddy|first3=Alyssa|last4=Taylor|first4=Jennie W.|last5=Oberheim Bush|first5=Nancy Ann|last6=Clarke|first6=Jennifer L.|last7=Chang|first7=Susan M.|last8=Gupta|first8=Nalin|last9=Berger|first9=Mitchel S.|date=2021-11-02|title=Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy|url=https://pubmed.ncbi.nlm.nih.gov/34519829|journal=Neuro-Oncology|volume=23|issue=11|pages=1974–1976|doi=10.1093/neuonc/noab184|issn=1523-5866|pmc=8628364|pmid=34519829}}</ref>
PDGFRA mutations 50-70%<ref>{{Cite journal|last=Chen|first=Carol C. L.|last2=Deshmukh|first2=Shriya|last3=Jessa|first3=Selin|last4=Hadjadj|first4=Djihad|last5=Lisi|first5=Véronique|last6=Andrade|first6=Augusto Faria|last7=Faury|first7=Damien|last8=Jawhar|first8=Wajih|last9=Dali|first9=Rola|date=2020-12-10|title=Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis|url=https://pubmed.ncbi.nlm.nih.gov/33259802|journal=Cell|volume=183|issue=6|pages=1617–1633.e22|doi=10.1016/j.cell.2020.11.012|issn=1097-4172|pmc=7791404|pmid=33259802}}</ref> <ref>{{Cite journal|last=Lucas|first=Calixto-Hope G.|last2=Mueller|first2=Sabine|last3=Reddy|first3=Alyssa|last4=Taylor|first4=Jennie W.|last5=Oberheim Bush|first5=Nancy Ann|last6=Clarke|first6=Jennifer L.|last7=Chang|first7=Susan M.|last8=Gupta|first8=Nalin|last9=Berger|first9=Mitchel S.|date=2021-11-02|title=Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy|url=https://pubmed.ncbi.nlm.nih.gov/34519829|journal=Neuro-Oncology|volume=23|issue=11|pages=1974–1976|doi=10.1093/neuonc/noab184|issn=1523-5866|pmc=8628364|pmid=34519829}}</ref>
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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.
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==
==Epigenomic Alterations==
 
Put your text here
*H3.3 G34R/V/D mutations impair di- or tri- methylation of lysine 36 by blocking the access to its lysine methyltransferase SETD2 and lysine demethylase KDM2A <ref>{{Cite journal|last=Shi|first=Leilei|last2=Shi|first2=Jiejun|last3=Shi|first3=Xiaobing|last4=Li|first4=Wei|last5=Wen|first5=Hong|date=2018-05-25|title=Histone H3.3 G34 Mutations Alter Histone H3K36 and H3K27 Methylation In Cis|url=https://pubmed.ncbi.nlm.nih.gov/29689253|journal=Journal of Molecular Biology|volume=430|issue=11|pages=1562–1565|doi=10.1016/j.jmb.2018.04.014|issn=1089-8638|pmc=6450091|pmid=29689253}}</ref><ref>{{Cite journal|last=Cheng|first=Zhongjun|last2=Cheung|first2=Peggie|last3=Kuo|first3=Alex J.|last4=Yukl|first4=Erik T.|last5=Wilmot|first5=Carrie M.|last6=Gozani|first6=Or|last7=Patel|first7=Dinshaw J.|date=2014-08-15|title=A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36|url=https://pubmed.ncbi.nlm.nih.gov/25128496|journal=Genes & Development|volume=28|issue=16|pages=1758–1771|doi=10.1101/gad.246561.114|issn=1549-5477|pmc=4197961|pmid=25128496}}</ref>. This attenuated interaction alters genome wide methylation level and promote tumorigenesis.
*G34-DHG demonstrates global hypomethylation pattern but MGMT promoter is frequently methylated <ref>{{Cite journal|last=Sturm|first=Dominik|last2=Witt|first2=Hendrik|last3=Hovestadt|first3=Volker|last4=Khuong-Quang|first4=Dong-Anh|last5=Jones|first5=David T. W.|last6=Konermann|first6=Carolin|last7=Pfaff|first7=Elke|last8=Tönjes|first8=Martje|last9=Sill|first9=Martin|date=2012-10-16|title=Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma|url=https://pubmed.ncbi.nlm.nih.gov/23079654|journal=Cancer Cell|volume=22|issue=4|pages=425–437|doi=10.1016/j.ccr.2012.08.024|issn=1878-3686|pmid=23079654}}</ref><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><ref>{{Cite journal|last=Wan|first=Yi Ching Esther|last2=Liu|first2=Jiaxian|last3=Chan|first3=Kui Ming|date=2018|title=Histone H3 Mutations in Cancer|url=https://pubmed.ncbi.nlm.nih.gov/30101054|journal=Current Pharmacology Reports|volume=4|issue=4|pages=292–300|doi=10.1007/s40495-018-0141-6|issn=2198-641X|pmc=6061380|pmid=30101054}}</ref>
*''MGMT'' promoter methylation is seen between 70 and 74% of cases (ref 4, 5) and is associated with significantly longer overall survival <ref name=":1" /><ref name=":4" />.
 
==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
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>
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>
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==Epigenomic Alterations==
*H3.3 G34R/V/D mutations impair di- or tri- methylation of lysine 36 by blocking the access to its lysine methyltransferase SETD2 and lysine demethylase KDM2A <ref>{{Cite journal|last=Shi|first=Leilei|last2=Shi|first2=Jiejun|last3=Shi|first3=Xiaobing|last4=Li|first4=Wei|last5=Wen|first5=Hong|date=2018-05-25|title=Histone H3.3 G34 Mutations Alter Histone H3K36 and H3K27 Methylation In Cis|url=https://pubmed.ncbi.nlm.nih.gov/29689253|journal=Journal of Molecular Biology|volume=430|issue=11|pages=1562–1565|doi=10.1016/j.jmb.2018.04.014|issn=1089-8638|pmc=6450091|pmid=29689253}}</ref><ref>{{Cite journal|last=Cheng|first=Zhongjun|last2=Cheung|first2=Peggie|last3=Kuo|first3=Alex J.|last4=Yukl|first4=Erik T.|last5=Wilmot|first5=Carrie M.|last6=Gozani|first6=Or|last7=Patel|first7=Dinshaw J.|date=2014-08-15|title=A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36|url=https://pubmed.ncbi.nlm.nih.gov/25128496|journal=Genes & Development|volume=28|issue=16|pages=1758–1771|doi=10.1101/gad.246561.114|issn=1549-5477|pmc=4197961|pmid=25128496}}</ref>. This attenuated interaction alters genome wide methylation level and promote tumorigenesis.
*G34-DHG demonstrates global hypomethylation pattern but MGMT promoter is frequently methylated <ref>{{Cite journal|last=Sturm|first=Dominik|last2=Witt|first2=Hendrik|last3=Hovestadt|first3=Volker|last4=Khuong-Quang|first4=Dong-Anh|last5=Jones|first5=David T. W.|last6=Konermann|first6=Carolin|last7=Pfaff|first7=Elke|last8=Tönjes|first8=Martje|last9=Sill|first9=Martin|date=2012-10-16|title=Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma|url=https://pubmed.ncbi.nlm.nih.gov/23079654|journal=Cancer Cell|volume=22|issue=4|pages=425–437|doi=10.1016/j.ccr.2012.08.024|issn=1878-3686|pmid=23079654}}</ref><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><ref>{{Cite journal|last=Wan|first=Yi Ching Esther|last2=Liu|first2=Jiaxian|last3=Chan|first3=Kui Ming|date=2018|title=Histone H3 Mutations in Cancer|url=https://pubmed.ncbi.nlm.nih.gov/30101054|journal=Current Pharmacology Reports|volume=4|issue=4|pages=292–300|doi=10.1007/s40495-018-0141-6|issn=2198-641X|pmc=6061380|pmid=30101054}}</ref>
*''MGMT'' promoter methylation is seen between 70 and 74% of cases (ref 4, 5) and is associated with significantly longer overall survival <ref name=":1" /><ref name=":4" />.


==Genes and Main Pathways Involved==


{| class="wikitable sortable"
{| class="wikitable sortable"
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|Facilitate alternative  lengthening of telomeres
|Facilitate alternative  lengthening of telomeres
|}
|}


==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==
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*Pan-cancer sequencing will likely detect concurrent mutations in ''TP53, ATRX, PDGFRA'' etc.
*Pan-cancer sequencing will likely detect concurrent mutations in ''TP53, ATRX, PDGFRA'' etc.
*DNA methylation and gene expression profiling can be used to differentiate G34-DHG with other glioma subgroups.
*DNA methylation and gene expression profiling can be used to differentiate G34-DHG with other glioma subgroups.
*''MGMT'' promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (bisulfite treated DNA undergoes real-time PCR)<br />
*''MGMT'' promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (bisulfite treated DNA undergoes real-time PCR)
 
==Familial Forms==
N/A
 
==Additional Information==
This disease is <u>defined/characterized</u> as detailed below:
 
*Diffuse hemispheric glioma, H3 G34–mutant (G34-DHG) is a newly recognized tumor entity that is characterized by point mutations in the ''H3-3A'' (''H3-3A'') gene, encoding for histone variant H3.3  <ref name=":0">{{Cite journal|last=Schwartzentruber|first=Jeremy|last2=Korshunov|first2=Andrey|last3=Liu|first3=Xiao-Yang|last4=Jones|first4=David T. W.|last5=Pfaff|first5=Elke|last6=Jacob|first6=Karine|last7=Sturm|first7=Dominik|last8=Fontebasso|first8=Adam M.|last9=Quang|first9=Dong-Anh Khuong|date=2012-01-29|title=Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma|url=https://pubmed.ncbi.nlm.nih.gov/22286061|journal=Nature|volume=482|issue=7384|pages=226–231|doi=10.1038/nature10833|issn=1476-4687|pmid=22286061}}</ref><ref>{{Cite journal|last=Wu|first=Gang|last2=Broniscer|first2=Alberto|last3=McEachron|first3=Troy A.|last4=Lu|first4=Charles|last5=Paugh|first5=Barbara S.|last6=Becksfort|first6=Jared|last7=Qu|first7=Chunxu|last8=Ding|first8=Li|last9=Huether|first9=Robert|date=2012-01-29|title=Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas|url=https://pubmed.ncbi.nlm.nih.gov/22286216|journal=Nature Genetics|volume=44|issue=3|pages=251–253|doi=10.1038/ng.1102|issn=1546-1718|pmc=3288377|pmid=22286216}}</ref>. Point mutations tend to be clustered at codon 34 including c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or rarely c.104G>T p.G35V (G34V) <ref name=":0" />. This distinct tumor entity is an aggressive glioma arising from the cerebral hemispheres. G34-DHG is designated as CNS WHO grade 4 in in the WHO 5th edition <ref name=":3" />.
 
*Please note that historically, numbering of the amino acid sequences of histone genes has begun at the second codon, as the amino acid encoded by the first codon (methionine) is cleaved post-translationally. Therefore, H3.3 G34 represents the legacy nomenclature of what is now referred to as H3.3 G35 <ref>{{Cite journal|last=Leske|first=Henning|last2=Dalgleish|first2=Raymond|last3=Lazar|first3=Alexander J.|last4=Reifenberger|first4=Guido|last5=Cree|first5=Ian A.|date=2021-06|title=A common classification framework for histone sequence alterations in tumours: an expert consensus proposal|url=https://pubmed.ncbi.nlm.nih.gov/33779999|journal=The Journal of Pathology|volume=254|issue=2|pages=109–120|doi=10.1002/path.5666|issn=1096-9896|pmid=33779999}}</ref>.
 
The <u>epidemiology/prevalence</u> of this disease is detailed below:
 
*G34-DHG is reported to account for approximately 15% of high grade gliomas (HGSs) and typically affect adolescents and young adults with a median age at diagnosis of 15.8 years old <ref>{{Cite journal|last=Picart|first=Thiébaud|last2=Barritault|first2=Marc|last3=Poncet|first3=Delphine|last4=Berner|first4=Lise-Prune|last5=Izquierdo|first5=Cristina|last6=Tabouret|first6=Emeline|last7=Figarella-Branger|first7=Dominique|last8=Idbaïh|first8=Ahmed|last9=Bielle|first9=Franck|date=2021-01|title=Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults|url=https://pubmed.ncbi.nlm.nih.gov/34056608|journal=Neuro-Oncology Advances|volume=3|issue=1|pages=vdab061|doi=10.1093/noajnl/vdab061|issn=2632-2498|pmc=8156974|pmid=34056608}}</ref><ref name=":1" />. Studies have shown that there is a gender difference with male to female ratio of 1.4:1 <ref name=":4" /><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>.
 
The <u>clinical features</u> of this disease are detailed below:
 
*Site dependent neurological symptoms including epileptic seizure, focal deficit, increased intracranial hypertension (headache, nausea and vomiting) <ref>{{Cite journal|last=Picart|first=Thiébaud|last2=Barritault|first2=Marc|last3=Poncet|first3=Delphine|last4=Berner|first4=Lise-Prune|last5=Izquierdo|first5=Cristina|last6=Tabouret|first6=Emeline|last7=Figarella-Branger|first7=Dominique|last8=Idbaïh|first8=Ahmed|last9=Bielle|first9=Franck|date=2021|title=Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults|url=https://pubmed.ncbi.nlm.nih.gov/34056608|journal=Neuro-Oncology Advances|volume=3|issue=1|pages=vdab061|doi=10.1093/noajnl/vdab061|issn=2632-2498|pmc=8156974|pmid=34056608}}</ref>.
*Signs and symptoms - epileptic seizure, focal deficit, increased intracranial hypertension
 
The <u>sites of involvement</u> of this disease are detailed below:
 
*sually involves cerebral hemispheres
 
*Occasionally across the midline and disseminate to leptomeningeal structures.
 
*MRI typically shows a bulky cortical mass, most commonly seen in the parietal or temporal lobe. Multifocal lesions and/or leptomeningeal dissemination can be seen along with necrosis, cysts, hemorrhage and calcification <ref name=":6">{{Cite journal|last=Vettermann|first=Franziska J.|last2=Felsberg|first2=Jörg|last3=Reifenberger|first3=Guido|last4=Hasselblatt|first4=Martin|last5=Forbrig|first5=Robert|last6=Berding|first6=Georg|last7=la Fougère|first7=Christian|last8=Galldiks|first8=Norbert|last9=Schittenhelm|first9=Jens|date=2018-12|title=Characterization of Diffuse Gliomas With Histone H3-G34 Mutation by MRI and Dynamic 18F-FET PET|url=https://pubmed.ncbi.nlm.nih.gov/30358620|journal=Clinical Nuclear Medicine|volume=43|issue=12|pages=895–898|doi=10.1097/RLU.0000000000002300|issn=1536-0229|pmid=30358620}}</ref>.
 
The <u>morphologic features</u> of this disease are detailed below:
 
*Usually involves cerebral hemispheres
 
*Occasionally across the midline and disseminate to leptomeningeal structures.
 
*MRI typically shows a bulky cortical mass, most commonly seen in the parietal or temporal lobe. Multifocal lesions and/or leptomeningeal dissemination can be seen along with necrosis, cysts, hemorrhage and calcification <ref name=":6" />
 
The <u>immunophenotype</u> of this disease is detailed below:
 
Positive (universal) - MAP2, FOXG1, p53
 
Positive (subset) - GFAP (GBM-like morphology), synaptophysin (embryonal-like morphology)
 
Negative (universal) - ATRX, Olig2
 
==Links==
None


==References==
==References==




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(use the "Cite" icon at the top of the page) <span style="color:#0070C0">(''Instructions: Add each reference into the text above by clicking where you want to insert the reference, selecting the “Cite” icon at the top of the wiki page, and using the “Automatic” tab option to search by PMID to select the reference to insert. If a PMID is not available, such as for a book, please use the “Cite” icon, select “Manual” and then “Basic Form”, and include the entire reference. To insert the same reference again later in the page, select the “Cite” icon and “Re-use” to find the reference; DO NOT insert the same reference twice using the “Automatic” tab as it will be treated as two separate references. The reference list in this section will be automatically generated and sorted''</span><span style="color:#0070C0">''.''</span><span style="color:#0070C0">)</span><references />
 
==Notes==
==Notes==


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Prior Author(s):
Prior Author(s):
<nowiki>*</nowiki>''Citation of this Page'': “Diffuse hemispheric glioma, H3 G34-mutant”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/CNS5:Diffuse hemispheric glioma, H3 G34-mutant</nowiki>.
<nowiki>*</nowiki>''Citation of this Page'': “Diffuse hemispheric glioma, H3 G34-mutant”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated {{REVISIONMONTH}}/{{REVISIONDAY}}/{{REVISIONYEAR}}, <nowiki>https://ccga.io/index.php/CNS5:Diffuse hemispheric glioma, H3 G34-mutant</nowiki>.
[[Category:CNS5]][[Category:DISEASE]][[Category:Diseases D]]
[[Category:CNS5]]
[[Category:DISEASE]]
[[Category:Diseases D]]
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