View source for CNS5:Diffuse paediatric-type high-grade glioma, H3-wildtype and IDH-wildtype

<br />
==Primary Author(s)*==

Madina Sukhanova, PhD FACMG Northwestern University

__TOC__

==Cancer Category/Type==

Glioma

==Cancer Sub-Classification / Subtype==

Paediatric-type diffuse high-grade gliomas with three molecular subtypes: RTK2, RTK1, and MYCN

==Definition / Description of Disease==

This is a distinct entity in the World Health Organization (WHO) classification system within the section of paediatric-type diffuse high-grade gliomas. Distinct methylation profiles and molecular alterations define three subtypes: dpHGG RTK1, dpHGG RTK2, and dpHGG MYCN. Gliomas arising after therapeutic radiation are predominantly of the pHGG RTK1 subtype. Known tumorigenic drivers include TP53, MYCN, ID2, and genes from RAS/MAPK and PI3K pathways.<ref>{{Cite journal|last=Buczkowicz|first=Pawel|last2=Hoeman|first2=Christine|last3=Rakopoulos|first3=Patricia|last4=Pajovic|first4=Sanja|last5=Letourneau|first5=Louis|last6=Dzamba|first6=Misko|last7=Morrison|first7=Andrew|last8=Lewis|first8=Peter|last9=Bouffet|first9=Eric|date=2014-05|title=Genomic analysis of diffuse intrinsic pontine gliomas identifies three molecular subgroups and recurrent activating ACVR1 mutations|url=https://pubmed.ncbi.nlm.nih.gov/24705254|journal=Nature Genetics|volume=46|issue=5|pages=451–456|doi=10.1038/ng.2936|issn=1546-1718|pmc=3997489|pmid=24705254}}</ref> <ref>{{Cite journal|last=Sturm|first=Dominik|last2=Orr|first2=Brent A.|last3=Toprak|first3=Umut H.|last4=Hovestadt|first4=Volker|last5=Jones|first5=David T. W.|last6=Capper|first6=David|last7=Sill|first7=Martin|last8=Buchhalter|first8=Ivo|last9=Northcott|first9=Paul A.|date=2016-02-25|title=New Brain Tumor Entities Emerge from Molecular Classification of CNS-PNETs|url=https://pubmed.ncbi.nlm.nih.gov/26919435|journal=Cell|volume=164|issue=5|pages=1060–1072|doi=10.1016/j.cell.2016.01.015|issn=1097-4172|pmc=5139621|pmid=26919435}}</ref> <ref name=":0">{{Cite journal|last=Korshunov|first=Andrey|last2=Ryzhova|first2=Marina|last3=Hovestadt|first3=Volker|last4=Bender|first4=Sebastian|last5=Sturm|first5=Dominik|last6=Capper|first6=David|last7=Meyer|first7=Jochen|last8=Schrimpf|first8=Daniel|last9=Kool|first9=Marcel|date=2015-05|title=Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers|url=https://pubmed.ncbi.nlm.nih.gov/25752754|journal=Acta Neuropathologica|volume=129|issue=5|pages=669–678|doi=10.1007/s00401-015-1405-4|issn=1432-0533|pmid=25752754}}</ref> <ref name=":1">{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Carvalho|first3=Diana|last4=Izquierdo|first4=Elisa|last5=Fazal-Salom|first5=Janat|last6=Taylor|first6=Kathryn R.|last7=Bjerke|first7=Lynn|last8=Clarke|first8=Matthew|last9=Vinci|first9=Mara|date=2017-10-09|title=Integrated Molecular Meta-Analysis of 1,000 Pediatric High-Grade and Diffuse Intrinsic Pontine Glioma|url=https://pubmed.ncbi.nlm.nih.gov/28966033|journal=Cancer Cell|volume=32|issue=4|pages=520–537.e5|doi=10.1016/j.ccell.2017.08.017|issn=1878-3686|pmc=5637314|pmid=28966033}}</ref>

==Synonyms / Terminology==

None

==Epidemiology / Prevalence==

The 2021 WHO classified this entity as pediatric-type, based on well defined studies focusing on a pediatric population with gliomas characterised by IDH-/H3-wildtype status<ref name=":1" /><ref>{{Cite journal|last=Mackay|first=Alan|last2=Burford|first2=Anna|last3=Molinari|first3=Valeria|last4=Jones|first4=David T. W.|last5=Izquierdo|first5=Elisa|last6=Brouwer-Visser|first6=Jurriaan|last7=Giangaspero|first7=Felice|last8=Haberler|first8=Christine|last9=Pietsch|first9=Torsten|date=2018-05-14|title=Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial|url=https://pubmed.ncbi.nlm.nih.gov/29763623|journal=Cancer Cell|volume=33|issue=5|pages=829–842.e5|doi=10.1016/j.ccell.2018.04.004|issn=1878-3686|pmc=5956280|pmid=29763623}}</ref><ref name=":2">{{Cite journal|last=Korshunov|first=Andrey|last2=Schrimpf|first2=Daniel|last3=Ryzhova|first3=Marina|last4=Sturm|first4=Dominik|last5=Chavez|first5=Lukas|last6=Hovestadt|first6=Volker|last7=Sharma|first7=Tanvi|last8=Habel|first8=Antje|last9=Burford|first9=Anna|date=2017-09|title=H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers|url=https://pubmed.ncbi.nlm.nih.gov/28401334|journal=Acta Neuropathologica|volume=134|issue=3|pages=507–516|doi=10.1007/s00401-017-1710-1|issn=1432-0533|pmid=28401334}}</ref>. Therefore, the frequency of this tumor type in adults in unknown. The median reported age of patients at the time of diagnosis was 9.8 years. One study reported male prevalence.<ref name=":2" />

==Clinical Features==

The clinical features are dependent on the tumour location. Symptoms can include seizures and motor or sensory deficits. 
{| class="wikitable"
|'''Signs and Symptoms'''
|Seizures and motor or sensory deficits.
|-
|'''Imaging Findings'''
|MRI characteristics are comparable to other high-grade glioma tumour types. MRI typically reveals well-defined margins and homogeneous contrast-enhancement and mild perilesional edema.<ref name=":3">{{Cite journal|last=Tauziède-Espariat|first=A.|last2=Debily|first2=M.-A.|last3=Castel|first3=D.|last4=Grill|first4=J.|last5=Puget|first5=S.|last6=Roux|first6=A.|last7=Saffroy|first7=R.|last8=Pagès|first8=M.|last9=Gareton|first9=A.|date=2020-07-09|title=The pediatric supratentorial MYCN-amplified high-grade gliomas methylation class presents the same radiological, histopathological and molecular features as their pontine counterparts|url=https://pubmed.ncbi.nlm.nih.gov/32646492|journal=Acta Neuropathologica Communications|volume=8|issue=1|pages=104|doi=10.1186/s40478-020-00974-x|issn=2051-5960|pmc=7346460|pmid=32646492}}</ref><ref>{{Cite journal|last=Tauziède-Espariat|first=A.|last2=Debily|first2=M.-A.|last3=Castel|first3=D.|last4=Grill|first4=J.|last5=Puget|first5=S.|last6=Sabel|first6=M.|last7=Blomgren|first7=K.|last8=Gareton|first8=A.|last9=Dangouloff-Ros|first9=V.|date=2019-06-10|title=An integrative radiological, histopathological and molecular analysis of pediatric pontine histone-wildtype glioma with MYCN amplification (HGG-MYCN)|url=https://pubmed.ncbi.nlm.nih.gov/31177990|journal=Acta Neuropathologica Communications|volume=7|issue=1|pages=87|doi=10.1186/s40478-019-0738-y|issn=2051-5960|pmc=6556947|pmid=31177990}}</ref>
|}

==Sites of Involvement==

Main site: supratentorial brain.

Other sites: brainstem, and cerebellum.<ref name=":2" />

Although most of molecular subtypes of dpHGG involve the supratentorial compartment (96% of dpHGG RTK2; 86% of dpHGG MYCN; 82% of dpHGG RTK1 tumors),  a lesser proporton can involve infratentorial/brainstem sites (4% of dpHGG RTK2;14% of dpHGG MYCN; 18% of dpHGG RTK1 cases).<ref name=":2" />

==Morphologic Features==

The morphology of dHGGs, H3-/IDH-wildtype, shows glioblastoma-like features with high cellularity, mitotic activity, microvascular proliferation, and necrosis; however, undifferentiated, primitive morphology and areas of glial differentiation can also be noted within the same case. The pHGG MYCN molecular subtype often consists of large cells with distinct nucleoli admixed with spindle-shaped and epithelioid cells; the architecture of these tumours can show areas of diffuse infiltration, in combinaiton with circumscribed nodules.<ref name=":3" /> 

==Immunophenotype==

{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|Positive (universal)||Neoplastic glial component – GFAP, and/or OLIG2<ref name=":0" /><ref name=":1" />
|-
|Positive (subset)||dpHGG MYCN molecular subtype can be positive for neuronal markers
|-
|Negative (universal)|| IDH1 R132H
H3 p.K28me3 (K27me3) (preserved expression)<ref name=":3" />
|-
|Negative (subset)||dpHGG MYCN molecular subtype can be negative for glial marker GFAP, and/or OLIG2
|}

==Chromosomal Rearrangements (Gene Fusions)==
Fusions listed in the table below were identified in a single study, thus, frequencies in dpHGG H3/IGH-wt should be interpreted with caution.<ref name=":4">{{Cite journal|last=Deng|first=Maximilian Y.|last2=Sturm|first2=Dominik|last3=Pfaff|first3=Elke|last4=Sill|first4=Martin|last5=Stichel|first5=Damian|last6=Balasubramanian|first6=Gnana Prakash|last7=Tippelt|first7=Stephan|last8=Kramm|first8=Christof|last9=Donson|first9=Andrew M.|date=2021-09-20|title=Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B|url=https://pubmed.ncbi.nlm.nih.gov/34545083|journal=Nature Communications|volume=12|issue=1|pages=5530|doi=10.1038/s41467-021-25708-y|issn=2041-1723|pmc=8452680|pmid=34545083}}</ref>
{| class="wikitable sortable"
|-
!Chromosomal Rearrangement!!Genes in Fusion (5’ or 3’ Segments)!!Structural  variation!!Prevalence
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|t(3;3)(p21.31;p25.2)
|FYCO1::RAF1
|deletion
|11%<ref name=":4" />
|Unknown
|Unknown
|Unknown
|Results in constitutive activation of kinase domain<ref name=":4" />
|-
|t(7;7)(q31.2;q31.32)||PTPRZ1::MET||deletion||22%<ref name=":4" />
|Unknown
|Unknown
|Unknown
|Concurrent MET amp is frequently noted<ref name=":4" />
|-
|t(7;7)(q31.2;q31.32)
|CAPZA2::MET
|deletion
|11%<ref name=":4" />
|Unknown
|Unknown
|Unknown
|Concurrent MET amp is frequently noted<ref name=":4" />
|-
|t(9;9)(p31.32;p21.33)
|GKAP1::NTRK2
|deletion
|11%<ref name=":4" />
|Unknown
|Unknown
|Unknown
|Results in constitutive dimerization of receptor<ref name=":4" />
|}		
			
==Individual Region Genomic Gain/Loss/LOH==

{| class="wikitable sortable"
|-
!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
|-
|2
|Amplification
|chr2:15,940,550-15,947,004 [GRCh38]
|2p24.3
|Yes [50% dpHGG MYCN subtype]
|Worse OS<ref name=":1" /><ref name=":2" />
|Unknown
|MYCN amplification<ref name=":2" /><ref name=":5">{{Cite journal|last=Capper|first=David|last2=Jones|first2=David T. W.|last3=Sill|first3=Martin|last4=Hovestadt|first4=Volker|last5=Schrimpf|first5=Daniel|last6=Sturm|first6=Dominik|last7=Koelsche|first7=Christian|last8=Sahm|first8=Felix|last9=Chavez|first9=Lukas|date=2018-03-22|title=DNA methylation-based classification of central nervous system tumours|url=https://pubmed.ncbi.nlm.nih.gov/29539639|journal=Nature|volume=555|issue=7697|pages=469–474|doi=10.1038/nature26000|issn=1476-4687|pmc=6093218|pmid=29539639}}</ref>
|-
|2
|Amplification
|chr2:8,682,056-8,684,461 [GRCh38]
|2p25.1
|No, but recurrent secondary finding [66% of dpHGG MYCN subtype]
|Unknown
|Unknown
|ID2 amplification is often (66%) co-amplified with MYCN<ref name=":2" /><ref name=":5" />
|-
|4
|Amplification/Mutation
|chr4:51819533-54425718 [GRCh38]
|4q12
|Yes [33% of dpHGG RTK1 subtype]
|No<ref name=":2" />
|Unknown
|PDGFRA alterations<ref name=":2" /><ref name=":6">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>
|-
|7
|Amplification
|chr7:55,019,017-55,211,628 [GRCh38]
|7p11.2
|Yes [50% of dpHGG RTK2 subtype]
|No<ref name=":2" />
|Unknown
|EGFR amplification<ref name=":2" />
|-
|8
|Amplification
|chr8:127,736,231-127,742,951 [GRCh38]
|8q24.21
|No, but recurrent in dpHGG MYCN subtype [8%]
|Unknown
|Unknown
|MYC amplification<ref name=":2" />
|-
|9
|Homozygous loss
|CDKN2A - chr9:21,967,752-21,995,324 [GRCh38]
CDKN2B - chr9: ''9:''22,002,903-22,009,313  [GRCh38]
|9p21.3
|No
|Worse outcome<ref name=":2" />
|Unknown
|Deletions result in bi-allelic loss of CDKN2A/B seen in 6% MYCN subtype, 27% RTK1 subtype; 72% RTK2 subtype.<ref name=":2" /><ref name=":4" />
|-
|12 / 7
|Amplification
|CDK4 - chr12:57,747,727-57,752,310 [GRCh38]
CDK6 - chr7:92,604,921-92,836,573 [GRCh38]
|12q14.1 / 7q21.2
|No
|Unknown
|Unknown
|Ampifications of CDK4/6 seen in 22% MYCN subtype, 9% RTK1 subtype; 17% RTK2 subtype.<ref name=":2" />
|}
==Characteristic Chromosomal Patterns==

{| class="wikitable sortable"
|-
!Chromosomal Pattern
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Notes
|-
|Chromosome 7 gain
|No
|Yes
|No
|Recurrent finding in 47% MYCN subtype; 12% RTK1 subtype; 28% RTK2 subtype.<ref name=":2" />
|-
|Chromosome 10q loss
|No
|No
|No
|Recurrent finding in 42% MYCN subtype; 12% RTK1 subtype; 50% RTK2 subtype.<ref name=":2" />
|}
==Gene Mutations (SNV/INDEL)==

{| class="wikitable sortable"
|-
!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
|-
|PDGFRA
|Receptor
|Not stated in literature; referred to in the WHO Classification<ref name=":6" />
|unclear
|IDH1/2, H3<br />
|Unknown
|Unknown
|Unknown
|
|-
|TERT promoter
|Enzyme/ acts as TCG
|26% MYCN subtype; 64% RTK2 subtype<ref name=":2" />
|unclear
|IDH1/2, H3
|Unknown
|Unknown
|Unknown
|
|-
|TP53
|TSG
|67% MYCN subtype; 48% RTK1 subtype; 50% RTK2 subtype<ref name=":2" /><ref name=":4" />
|unclear
|IDH1/2, H3
|Unknown
|Unknown
|Unknown
|
|}
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==

Methylation profiling can be used in the diagnosis of this tumor entity and can help to differentiate between three molecular profiles, pHGG RTK1, pHGG RTK2, and pHGG MYCN. Methylation of MGMT has been noted in 11% of pHGG MYCN cases and 18% of RTK1 cases.<ref name=":2" /> ''MGMT'' promoter methylation can be seen in 18% of the RTK1 subtype, 11% in the MYCN subtype and is rare in the RTK2 subtype.

==Genes and Main Pathways Involved==

The pHGG, H3/IDH-wildtype frequently reveals variants in genes encoding members of the TAS/MAPK and PI3K pathways.<ref name=":4" /> 
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|MET; activating alterations
|MAPK/ERK pathway activation
|Increased cell growth and proliferation
|-
|RAF1; activating alterations
|MAPK/ERK pathway activation
|Increased cell growth and proliferation
|-
|NTRK2; activating alterations
|MAPK/ERK pathway activation
|Increased cell growth and proliferation
|}
==Genetic Diagnostic Testing Methods==

*Chromosome microarray  
*Next generation sequencing  
*DNA methylation profiling

==Familial Forms==

Germline mutations of genes involved in the mismatch repair (MMR) system can be associated with a proportion of pHGG cases,<ref>{{Cite journal|last=Dodgshun|first=Andrew J.|last2=Fukuoka|first2=Kohei|last3=Edwards|first3=Melissa|last4=Bianchi|first4=Vanessa J.|last5=Das|first5=Anirban|last6=Sexton-Oates|first6=Alexandra|last7=Larouche|first7=Valérie|last8=Vanan|first8=Magimairajan I.|last9=Lindhorst|first9=Scott|date=2020-11|title=Germline-driven replication repair-deficient high-grade gliomas exhibit unique hypomethylation patterns|url=https://pubmed.ncbi.nlm.nih.gov/32895736|journal=Acta Neuropathologica|volume=140|issue=5|pages=765–776|doi=10.1007/s00401-020-02209-8|issn=1432-0533|pmid=32895736}}</ref><ref>{{Cite journal|last=Alphones|first=Sheena|last2=Chatterjee|first2=Uttara|last3=Singh|first3=Angad|last4=Das|first4=Anirban|last5=Zameer|first5=Lateef|last6=Achari|first6=Rimpa|last7=Bhattacharya|first7=Arpita|last8=Roy|first8=Paromita|date=2021-08|title=Immunohistochemical screening for mismatch repair protein deficiency in paediatric high-grade gliomas - institutional experience and review of literature|url=https://pubmed.ncbi.nlm.nih.gov/34097097|journal=Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery|volume=37|issue=8|pages=2521–2530|doi=10.1007/s00381-021-05229-1|issn=1433-0350|pmid=34097097}}</ref><ref>{{Cite journal|last=Amayiri|first=Nisreen|last2=Tabori|first2=Uri|last3=Campbell|first3=Brittany|last4=Bakry|first4=Doua|last5=Aronson|first5=Melyssa|last6=Durno|first6=Carol|last7=Rakopoulos|first7=Patricia|last8=Malkin|first8=David|last9=Qaddoumi|first9=Ibrahim|date=2016-01-15|title=High frequency of mismatch repair deficiency among pediatric high grade gliomas in Jordan|url=https://pubmed.ncbi.nlm.nih.gov/26293621|journal=International Journal of Cancer|volume=138|issue=2|pages=380–385|doi=10.1002/ijc.29724|issn=1097-0215|pmid=26293621}}</ref> typically of the pHGG RTK1 subtype.

==References==
<references />
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==Notes==
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