Changes

==Definition / Description of Disease==

==Definition / Description of Disease==

Diffuse hemispheric glioma, H3 G34–mutant (G34-DHG) is a newly recognized tumor entity that is characterized by point mutations in the ''H3-3A'' (''H3F3A'') 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" />. The distinct tumor entity is featured with aggressive glioma that arises from cerebral hemispheres and DHG is included in WHO 5th edition as CNS grade 4 tumor type.

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==

==Synonyms / Terminology==

==Epidemiology / Prevalence==

==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>{{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>{{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>.

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==

==Clinical Features==

|-

|-

|'''Laboratory Findings'''

|'''Laboratory Findings'''

|MRI in T2 hyperintense shows 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>.

|Not applicable

|}

|}

*Usually involves cerebral hemispheres

*Usually involves cerebral hemispheres

*Occasionally across the midline and disseminate to leptomeningeal structures.

*Occasionally across the midline and disseminate to leptomeningeal structures.

==Morphologic Features==

==Morphologic Features==

* Grossly, grey/tan solid mass within cortical and subcortical region with soft consistence, necrotic and hemorrhagic features.

*Grossly, grey/tan solid mass within cortical and subcortical region with soft consistency, necrotic and hemorrhagic features.

* Microscopically, heterogenous histological appearance including glioblastoma (GBM) and central nervous system embryonal tumor. GBM typically presents with highly cellularity, infiltrative astrocytic tumor. High mitotic activity and microvascular proliferation and necrosis are frequently seen. Embryonal tumors show hyperchromatic nuclei and scant cytoplasm with occasionally Homer-Wright rosettes appearance.

*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==

==Immunophenotype==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Finding!!Marker

!Finding!!Marker

|-

|-

|Positive (universal)||EXAMPLE CD1

|Positive (universal)||MAP2, FOXG1, p53

|-

|-

|Positive (subset)||EXAMPLE CD2

|Positive (subset)||GFAP (GBM-like morphology), synaptophysin (embryonal-like morphology)

|-

|-

|Negative (universal)||EXAMPLE CD3

|Negative (universal)||ATRX, Olig2

|-

|-

|Negative (subset)||EXAMPLE CD4

|Negative (subset)||

|}

|}

==Chromosomal Rearrangements (Gene Fusions)==

==Chromosomal Rearrangements (Gene Fusions)==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

|-

|-

|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)

|N/A||N/A

|N/A

|Yes

|N/A

|No

|N/A

|Yes

|N/A

|EXAMPLE

|N/A

 

|N/A

|}

|}

==Individual Region Genomic Gain/Loss/LOH==

==Individual Region Genomic Gain/Loss/LOH==

 

Oncogenic amplifications in G34-DHG have been shown to be negative prognostic markers, as documented below <ref name=":4" />.

Put your text here and fill in the table

 

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Notes

!Notes

|-

|-

|EXAMPLE

|''PDGFRA''

 

|EXAMPLE Loss

|EXAMPLE

|Unk

 

|Yes

chr7:1- 159,335,973 [hg38]

|EXAMPLE

|27% cases of G34-DHG; overrepresented in cases with GBM-like  morph <ref name=":5">{{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>

 

|-

|12:4,273,762-4,305,353

|12p13.32

|Yes

|Yes

|Yes

|Yes

|No

|Unk

|EXAMPLE

|10% cases of G34-DHG; overrepresented in cases with GBM-like morph <ref name=":5" />

 

Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference). Monosomy 7/7q deletion is associated with a poor prognosis in AML (add reference).

|-

|-

|EXAMPLE

|''CDKN2A''

 

|Homoz del

|9:21,967,752-21,995,324

|EXAMPLE Gain

|9p21.3

|EXAMPLE

|Unk

 

|Unk

chr8:1-145,138,636 [hg38]

|Unk

|EXAMPLE

|14% case of G34-DHG <ref name=":5" />

 

|No

|No

|No

|EXAMPLE

 

|}

|}

==Characteristic Chromosomal Patterns==

==Characteristic Chromosomal Patterns==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

|-

|-

|EXAMPLE

|4q loss

 

Co-deletion of 1p and 18q

|-

|Found in 48% of cases of G34-DHG <ref name=":5" />

|Yes

|Yes

|No

|No

|No

|No

|EXAMPLE:

|Found in 44% of cases of G34-DHG <ref name=":5" />

 

|}

|}

==Gene Mutations (SNV/INDEL)==

==Gene Mutations (SNV/INDEL/Methylation)==

{| class="wikitable sortable"

{| class="wikitable sortable"

!Notes

!Notes

|-

|-

|EXAMPLE: TP53; Variable LOF mutations

|''H3-3A'' p.G35R/V

p.G35V 6% <ref name=":3" />

|TP53 mutations 90%;

ATRX mutations 95%

EXAMPLE:

MGMT promoter methylation 70%-74% <ref name=":1" /><ref name=":4" />

EGFR; Exon 20 mutations

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>

EXAMPLE: BRAF; Activating mutations

H3 p.K28M/I <ref name=":2">{{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>

|EXAMPLE: TSG

|EXAMPLE: 20% (COSMIC)

|EXAMPLE: IDH1 R123H

|Yes

|

|

|

|

|

|

|EXAMPLE: Excludes hairy cell leukemia (HCL) (add reference).

|-

|70%-74% of G34-DHG <ref name=":1" /><ref name=":4" />

|Yes (longer overall survival)

|}

|}

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==

==Genes and Main Pathways Involved==

==Genes and Main Pathways Involved==

{| class="wikitable sortable"

{| class="wikitable sortable"

|-

|-

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome

|-

|-

|EXAMPLE: BRAF and MAP2K1; Activating mutations

|''H3-3A''; p.G35/R/V

|EXAMPLE: MAPK signaling

|EXAMPLE: Increased cell growth and proliferation

|Altered methylation and gene expression

|''MGMT''; promoter methylation

|DNA repair

|Sensitize tumor cells to chemo-  or radiotherapy.

|-

|-

|EXAMPLE: CDKN2A; Inactivating mutations

|''TP53''; mutation

|EXAMPLE: Cell cycle regulation

|Genome guardian, apoptosis

|EXAMPLE: Unregulated cell division

|Apoptosis resistance

|-

|-

|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations

|''ATRX''; mutation

|EXAMPLE: Histone modification, chromatin remodeling

|Chromatin remodeling, alternative telomeres lengthening repression

|EXAMPLE: Abnormal gene expression program

|Facilitate alternative lengthening of telomeres

|}

|}

==Genetic Diagnostic Testing Methods==

==Genetic Diagnostic Testing Methods==

 

 

*''MGMT'' promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (bisulfite treated DNA undergoes real-time PCR)<br />

 

 

 

 

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

==References==

==References==