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

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==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==
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==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 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>{{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==
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|-
 
|-
 
|'''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
 
|}
 
|}
  
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*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.
 +
 +
*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==
 
==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==
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!Finding!!Marker
 
!Finding!!Marker
 
|-
 
|-
−
|Positive (universal)||MAP2, FOXG1, Ki-67, H3.3 p.G35R or p. G35V
+
|Positive (universal)||MAP2, FOXG1, p53
 
|-
 
|-
−
|Positive (subset)||GFAP (GBM), synaptophysin (embryonal tumor), p53
+
|Positive (subset)||GFAP (GBM-like morphology), synaptophysin (embryonal-like morphology)
 
|-
 
|-
 
|Negative (universal)||ATRX, Olig2
 
|Negative (universal)||ATRX, Olig2
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==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" />.
−
<br />
 
−
 
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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!Notes
 
!Notes
 
|-
 
|-
−
|N/A
+
|''PDGFRA''
−
|N/A
+
|Amp
−
|N/A
+
|chr4:54,229,293-54,298,245 [hg38]
−
|N/A
+
|4q12
−
|N/A
+
|Unk
−
|N/A
+
|Yes
−
|N/A
+
|Unk
−
|N/A
+
|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>
 +
|-
 +
|''CCND2''
 +
|Amp
 +
|12:4,273,762-4,305,353
 +
|12p13.32
 +
|Unk
 +
|Yes
 +
|Unk
 +
|10% cases of G34-DHG; overrepresented in cases with  embryonal-like morph <ref name=":5" />
 +
|-
 +
|''CDK6''
 +
|Amp
 +
|7:92,604,921-92,836,573
 +
|7q21.2
 +
|Unk
 +
|Yes
 +
|Unk
 +
|10% cases of G34-DHG; overrepresented in cases with GBM-like  morph <ref name=":5" />
 
|-
 
|-
−
|
+
|''CDKN2A''
−
|
+
|Homoz del
−
|
+
|9:21,967,752-21,995,324
−
|
+
|9p21.3
−
|
+
|Unk
−
|
+
|Unk
−
|
+
|Unk
−
|
+
|14% case of G34-DHG <ref name=":5" />
 
|}
 
|}
 
==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
−
 
−
Put your text here
 
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
 +
|4q loss
 +
|Yes
 
|N/A
 
|N/A
 
|N/A
 
|N/A
−
|N/A
+
|Found in 70% of cases of G34-DHG <ref name=":5" />
−
|N/A
+
|-
−
|N/A
+
|3q loss
 +
|Yes
 +
|No
 +
|No
 +
|Found in 67% of cases of G34-DHG<ref name=":5" />
 +
|-
 +
|13q loss
 +
|Yes
 +
|No
 +
|No
 +
|Found in 57% of cases of G34-DHG <ref name=":5" />
 +
|-
 +
|7q gain
 +
|Yes
 +
|No
 +
|No
 +
|Found in 48% of cases of G34-DHG <ref name=":5" />
 +
|-
 +
|1q gain
 +
|Yes
 +
|No
 +
|No
 +
|Found in 44% of cases of G34-DHG <ref name=":5" />
 
|}
 
|}
−
==Gene Mutations (SNV/INDEL)==
+
==Gene Mutations (SNV/INDEL/Methylation)==
  
−
Put your text here and fill in the table
+
<br />
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
Line 142: Line 185:
 
!Notes
 
!Notes
 
|-
 
|-
−
|H3F3A
+
|''H3-3A'' p.G35R/V
−
|p.G34R/V
+
|chromosome modification
−
|all of this cateogory
+
|p.G35R 94%
−
|TP53 inactivation mutations 83%;
+
p.G35V 6% <ref name=":3" />
−
ATRX mutations 93%
+
|TP53 mutations 90%;
 +
ATRX mutations 95%
  
−
MGMT promoter methylation 70% <ref name=":1" />
+
MGMT promoter methylation 70%-74% <ref name=":1" /><ref name=":4" />
−
|IDH
+
 
−
TERT
+
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>
 +
|IDH1
 +
IDH2
 +
 
 +
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>
 +
 
 +
TERT promoter
 
|Yes
 
|Yes
 
|
 
|
 +
|
 +
|
 +
|-
 +
|''MGMT''
 +
|promoter methylation
 +
|70%-74% of G34-DHG <ref name=":1" /><ref name=":4" />
 +
|
 +
|
 +
|
 +
|Yes (longer overall survival)
 
|
 
|
 
|
 
|
Line 160: Line 220:
 
==Epigenomic Alterations==
 
==Epigenomic Alterations==
  
−
H3.3 G34R/V/D mutations impair di- or tri- methylation of lysine 36 by blocking the access to its lysine methyltransferase (e.g. SETD2) <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>. This attenuated interaction between SETD2 and H3 K36 alters genome wide methylation level and promote tumorigenesis.  
+
*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==
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{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
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!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
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|-
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|EXAMPLE: BRAF and MAP2K1; Activating mutations
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|''H3-3A''; p.G35/R/V
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|EXAMPLE: MAPK signaling
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|Histone modification, chromatin  remodeling
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|EXAMPLE: Increased cell growth and proliferation
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|Altered methylation and gene expression
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|-
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|''MGMT''; promoter methylation
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|DNA repair
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|Sensitize tumor cells to chemo-  or radiotherapy.
 
|-
 
|-
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|EXAMPLE: CDKN2A; Inactivating mutations
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|''TP53''; mutation
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|EXAMPLE: Cell cycle regulation
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|Genome guardian, apoptosis
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|EXAMPLE: Unregulated cell division
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|Apoptosis resistance
 
|-
 
|-
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|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
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|''ATRX''; mutation
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|EXAMPLE: Histone modification, chromatin remodeling
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|Chromatin remodeling, alternative telomeres lengthening repression
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|EXAMPLE: Abnormal gene expression program
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|Facilitate alternative lengthening of telomeres
 
|}
 
|}
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
  
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Put your text here
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*Targeted sequencing to identify c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or c.104G>T p.G35V (G34V) is diagnostic for G34-DHG.
−
 
+
*Pan-cancer sequencing will likely detect concurrent mutations in ''TP53, ATRX, PDGFRA'' etc.
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==Familial Forms==
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*DNA methylation and gene expression profiling can be used to differentiate G34-DHG with other glioma subgroups.
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*''MGMT'' promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (bisulfite treated DNA undergoes real-time PCR)<br />
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Put your text here
 
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==Additional Information==
 
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==Links==
 
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Put your text placeholder here (use "Link" icon at top of page)
 
  
 
==References==
 
==References==

Latest revision as of 13:51, 25 February 2024

Primary Author(s)*

Xiaolin Hu, PhD, Sema4 OpCo Inc.

Cancer Category/Type

Gliomas, glioneuronal tumors, and neuronal tumors / Pediatric-type diffuse high-grade gliomas

Cancer Sub-Classification / Subtype

Diffuse hemispheric glioma, H3 G34–mutant

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 (H3-3A) gene, encoding for histone variant H3.3 [1][2]. 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) [1]. 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 [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 [4].

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 [5][6]. Studies have shown that there is a gender difference with male to female ratio of 1.4:1 [7][8].

Clinical Features

Site dependent neurological symptoms including epileptic seizure, focal deficit, increased intracranial hypertension (headache, nausea and vomiting) [9].

Signs and Symptoms epileptic seizure, focal deficit, increased intracranial hypertension
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 [10].

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

Finding Marker
Positive (universal) MAP2, FOXG1, p53
Positive (subset) GFAP (GBM-like morphology), synaptophysin (embryonal-like morphology)
Negative (universal) ATRX, Olig2
Negative (subset)

Chromosomal Rearrangements (Gene Fusions)

Not applicable

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

Individual Region Genomic Gain/Loss/LOH

Oncogenic amplifications in G34-DHG have been shown to be negative prognostic markers, as documented below [7].

Chr # Gain / Loss / Amp / LOH Minimal Region Genomic Coordinates [Genome Build] Minimal Region Cytoband Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
PDGFRA Amp chr4:54,229,293-54,298,245 [hg38] 4q12 Unk Yes Unk 27% cases of G34-DHG; overrepresented in cases with GBM-like morph [11]
CCND2 Amp 12:4,273,762-4,305,353 12p13.32 Unk Yes Unk 10% cases of G34-DHG; overrepresented in cases with embryonal-like morph [11]
CDK6 Amp 7:92,604,921-92,836,573 7q21.2 Unk Yes Unk 10% cases of G34-DHG; overrepresented in cases with GBM-like morph [11]
CDKN2A Homoz del 9:21,967,752-21,995,324 9p21.3 Unk Unk Unk 14% case of G34-DHG [11]

Characteristic Chromosomal Patterns

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
4q loss Yes N/A N/A Found in 70% of cases of G34-DHG [11]
3q loss Yes No No Found in 67% of cases of G34-DHG[11]
13q loss Yes No No Found in 57% of cases of G34-DHG [11]
7q gain Yes No No Found in 48% of cases of G34-DHG [11]
1q gain Yes No No Found in 44% of cases of G34-DHG [11]

Gene Mutations (SNV/INDEL/Methylation)


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) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
H3-3A p.G35R/V chromosome modification p.G35R 94%

p.G35V 6% [3]

TP53 mutations 90%;

ATRX mutations 95%

MGMT promoter methylation 70%-74% [6][7]

PDGFRA mutations 50-70%[12] [13]

IDH1

IDH2

H3 p.K28M/I [14]

TERT promoter

Yes
MGMT promoter methylation 70%-74% of G34-DHG [6][7] 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.

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 [15][16]. This attenuated interaction alters genome wide methylation level and promote tumorigenesis.
  • G34-DHG demonstrates global hypomethylation pattern but MGMT promoter is frequently methylated [17][18][19]
  • MGMT promoter methylation is seen between 70 and 74% of cases (ref 4, 5) and is associated with significantly longer overall survival [6][7].

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
H3-3A; p.G35/R/V Histone modification, chromatin remodeling Altered methylation and gene expression
MGMT; promoter methylation DNA repair Sensitize tumor cells to chemo- or radiotherapy.
TP53; mutation Genome guardian, apoptosis Apoptosis resistance
ATRX; mutation Chromatin remodeling, alternative telomeres lengthening repression Facilitate alternative lengthening of telomeres

Genetic Diagnostic Testing Methods

  • Targeted sequencing to identify c.103G>A p.G35R (G34R), c.103G>C p.G35R (G34R), or c.104G>T p.G35V (G34V) is diagnostic for G34-DHG.
  • 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.
  • MGMT promoter methylation can be assessed by methylation specific polymerase chain reaction analysis (bisulfite treated DNA undergoes real-time PCR)

References

  1. ↑ 1.0 1.1 Schwartzentruber, Jeremy; et al. (2012-01-29). "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma". Nature. 482 (7384): 226–231. doi:10.1038/nature10833. ISSN 1476-4687. PMID 22286061.
  2. ↑ Wu, Gang; et al. (2012-01-29). "Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas". Nature Genetics. 44 (3): 251–253. doi:10.1038/ng.1102. ISSN 1546-1718. PMC 3288377. PMID 22286216.
  3. ↑ 3.0 3.1 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). https://publications.iarc.fr/601.
  4. ↑ Leske, Henning; et al. (2021-06). "A common classification framework for histone sequence alterations in tumours: an expert consensus proposal". The Journal of Pathology. 254 (2): 109–120. doi:10.1002/path.5666. ISSN 1096-9896. PMID 33779999 Check |pmid= value (help). Check date values in: |date= (help)
  5. ↑ Picart, Thiébaud; et al. (2021-01). "Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults". Neuro-Oncology Advances. 3 (1): vdab061. doi:10.1093/noajnl/vdab061. ISSN 2632-2498. PMC 8156974 Check |pmc= value (help). PMID 34056608 Check |pmid= value (help). Check date values in: |date= (help)
  6. ↑ 6.0 6.1 6.2 6.3 Crowell, Cameron; et al. (2022-01). "Systematic review of diffuse hemispheric glioma, H3 G34-mutant: Outcomes and associated clinical factors". Neuro-Oncology Advances. 4 (1): vdac133. doi:10.1093/noajnl/vdac133. ISSN 2632-2498. PMC 9466272 Check |pmc= value (help). PMID 36105387 Check |pmid= value (help). Check date values in: |date= (help)
  7. ↑ 7.0 7.1 7.2 7.3 7.4 Korshunov, Andrey; et al. (2016-01). "Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity". Acta Neuropathologica. 131 (1): 137–146. doi:10.1007/s00401-015-1493-1. ISSN 1432-0533. PMID 26482474. Check date values in: |date= (help)
  8. ↑ Mackay, Alan; et al. (2017-10-09). "Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma". Cancer Cell. 32 (4): 520–537.e5. doi:10.1016/j.ccell.2017.08.017. ISSN 1878-3686. PMC 5637314. PMID 28966033.
  9. ↑ Picart, Thiébaud; et al. (2021). "Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults". Neuro-Oncology Advances. 3 (1): vdab061. doi:10.1093/noajnl/vdab061. ISSN 2632-2498. PMC 8156974 Check |pmc= value (help). PMID 34056608 Check |pmid= value (help).
  10. ↑ Vettermann, Franziska J.; et al. (2018-12). "Characterization of Diffuse Gliomas With Histone H3-G34 Mutation by MRI and Dynamic 18F-FET PET". Clinical Nuclear Medicine. 43 (12): 895–898. doi:10.1097/RLU.0000000000002300. ISSN 1536-0229. PMID 30358620. Check date values in: |date= (help)
  11. ↑ 11.0 11.1 11.2 11.3 11.4 11.5 11.6 11.7 11.8 Korshunov, Andrey; et al. (2016-01). "Histologically distinct neuroepithelial tumors with histone 3 G34 mutation are molecularly similar and comprise a single nosologic entity". Acta Neuropathologica. 131 (1): 137–146. doi:10.1007/s00401-015-1493-1. ISSN 1432-0533. PMID 26482474. Check date values in: |date= (help)
  12. ↑ Chen, Carol C. L.; et al. (2020-12-10). "Histone H3.3G34-Mutant Interneuron Progenitors Co-opt PDGFRA for Gliomagenesis". Cell. 183 (6): 1617–1633.e22. doi:10.1016/j.cell.2020.11.012. ISSN 1097-4172. PMC 7791404 Check |pmc= value (help). PMID 33259802 Check |pmid= value (help).
  13. ↑ Lucas, Calixto-Hope G.; et al. (2021-11-02). "Diffuse hemispheric glioma, H3 G34-mutant: Genomic landscape of a new tumor entity and prospects for targeted therapy". Neuro-Oncology. 23 (11): 1974–1976. doi:10.1093/neuonc/noab184. ISSN 1523-5866. PMC 8628364 Check |pmc= value (help). PMID 34519829 Check |pmid= value (help).
  14. ↑ Sturm, Dominik; et al. (2012-10-16). "Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma". Cancer Cell. 22 (4): 425–437. doi:10.1016/j.ccr.2012.08.024. ISSN 1878-3686. PMID 23079654.
  15. ↑ Shi, Leilei; et al. (2018-05-25). "Histone H3.3 G34 Mutations Alter Histone H3K36 and H3K27 Methylation In Cis". Journal of Molecular Biology. 430 (11): 1562–1565. doi:10.1016/j.jmb.2018.04.014. ISSN 1089-8638. PMC 6450091. PMID 29689253.
  16. ↑ Cheng, Zhongjun; et al. (2014-08-15). "A molecular threading mechanism underlies Jumonji lysine demethylase KDM2A regulation of methylated H3K36". Genes & Development. 28 (16): 1758–1771. doi:10.1101/gad.246561.114. ISSN 1549-5477. PMC 4197961. PMID 25128496.
  17. ↑ Sturm, Dominik; et al. (2012-10-16). "Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma". Cancer Cell. 22 (4): 425–437. doi:10.1016/j.ccr.2012.08.024. ISSN 1878-3686. PMID 23079654.
  18. ↑ Mackay, Alan; et al. (2017-10-09). "Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma". Cancer Cell. 32 (4): 520–537.e5. doi:10.1016/j.ccell.2017.08.017. ISSN 1878-3686. PMC 5637314. PMID 28966033.
  19. ↑ Wan, Yi Ching Esther; et al. (2018). "Histone H3 Mutations in Cancer". Current Pharmacology Reports. 4 (4): 292–300. doi:10.1007/s40495-018-0141-6. ISSN 2198-641X. PMC 6061380. PMID 30101054.

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