Difference between revisions of "CNS5:Diffuse astrocytoma, MYB- or MYBL1-altered"

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==Primary Author(s)*==
 
==Primary Author(s)*==
  
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Scott C. Smith, PhD, FACMG; SUNY Upstate Medical University
  
 
__TOC__
 
__TOC__
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==Cancer Category/Type==
 
==Cancer Category/Type==
  
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WHO Classification of Tumours of the Central Nervous System (5th Edition)
  
 
==Cancer Sub-Classification / Subtype==
 
==Cancer Sub-Classification / Subtype==
  
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Put your text here
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Diffuse Astrocytoma, MYB- or MYBL1-Altered
  
 
==Definition / Description of Disease==
 
==Definition / Description of Disease==
  
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Put your text here
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Diffuse astrocytoma, ''MYB'' or ''MYBL1''-altered is one of several newly recognized tumor types in the 5<sup>th</sup> edition of the ''WHO Classification of Tumors of the Central Nervous System''. The newly recognized classifications were in response to advances in understanding of paediatric-type gliomas, facilitated by an increased molecular characterisation of these tumours. Diffuse astrocytoma, MYB or MYBL1-altered is a subset of diffuse low-grade glioma with amplifications, structural variants, and fusions involving the ''MYB'' and ''MYBL1'' protooncogenes. Diffuse astrocytoma, MYB or MYBL1-altered subtypes are without characteristic histological features of angiocentric glioma<ref>{{Cite journal|last=Slegers|first=Rutger Juriaan|last2=Blumcke|first2=Ingmar|date=2020-03-09|title=Low-grade developmental and epilepsy associated brain tumors: a critical update 2020|url=https://pubmed.ncbi.nlm.nih.gov/32151273|journal=Acta Neuropathologica Communications|volume=8|issue=1|pages=27|doi=10.1186/s40478-020-00904-x|issn=2051-5960|pmc=7063704|pmid=32151273}}</ref><ref>{{Cite journal|last=Bandopadhayay|first=Pratiti|last2=Ramkissoon|first2=Lori A.|last3=Jain|first3=Payal|last4=Bergthold|first4=Guillaume|last5=Wala|first5=Jeremiah|last6=Zeid|first6=Rhamy|last7=Schumacher|first7=Steven E.|last8=Urbanski|first8=Laura|last9=O'Rourke|first9=Ryan|date=2016-03|title=MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism|url=https://pubmed.ncbi.nlm.nih.gov/26829751|journal=Nature Genetics|volume=48|issue=3|pages=273–282|doi=10.1038/ng.3500|issn=1546-1718|pmc=4767685|pmid=26829751}}</ref>. A related group of diffuse gliomas, the isomorphic glioma, occur predominantly in adults and are typically well-differentiated, low to moderately cellular, comprised of astrocytes with rounded nuclei and regular chromatin structures, and have low proliferative indices<ref>{{Cite journal|last=Wefers|first=Annika K.|last2=Stichel|first2=Damian|last3=Schrimpf|first3=Daniel|last4=Coras|first4=Roland|last5=Pages|first5=Mélanie|last6=Tauziède-Espariat|first6=Arnault|last7=Varlet|first7=Pascale|last8=Schwarz|first8=Daniel|last9=Söylemezoglu|first9=Figen|date=2020-01|title=Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course|url=https://pubmed.ncbi.nlm.nih.gov/31563982|journal=Acta Neuropathologica|volume=139|issue=1|pages=193–209|doi=10.1007/s00401-019-02078-w|issn=1432-0533|pmc=7477753|pmid=31563982}}</ref><ref>{{Cite journal|last=Chiang|first=Jason|last2=Harreld|first2=Julie H.|last3=Tinkle|first3=Christopher L.|last4=Moreira|first4=Daniel C.|last5=Li|first5=Xiaoyu|last6=Acharya|first6=Sahaja|last7=Qaddoumi|first7=Ibrahim|last8=Ellison|first8=David W.|date=2019-12|title=A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration|url=https://pubmed.ncbi.nlm.nih.gov/31595312|journal=Acta Neuropathologica|volume=138|issue=6|pages=1091–1092|doi=10.1007/s00401-019-02081-1|issn=1432-0533|pmc=7467132|pmid=31595312}}</ref>. These adult diffuse gliomas exhibit alterations of ''MYBL1'' rather than ''MYB'' . Gene fusions with multiple partners characterize the pediatric ''MYB'' or ''MYBL1-''altered gliomas<ref>{{Cite journal|last=Ramkissoon|first=Lori A.|last2=Horowitz|first2=Peleg M.|last3=Craig|first3=Justin M.|last4=Ramkissoon|first4=Shakti H.|last5=Rich|first5=Benjamin E.|last6=Schumacher|first6=Steven E.|last7=McKenna|first7=Aaron|last8=Lawrence|first8=Michael S.|last9=Bergthold|first9=Guillaume|date=2013-05-14|title=Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1|url=https://pubmed.ncbi.nlm.nih.gov/23633565|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=20|pages=8188–8193|doi=10.1073/pnas.1300252110|issn=1091-6490|pmc=3657784|pmid=23633565}}</ref><ref>{{Cite journal|last=Barinfeld|first=Orit|last2=Zahavi|first2=Alon|last3=Weiss|first3=Shirel|last4=Toledano|first4=Helen|last5=Michowiz|first5=Shalom|last6=Goldenberg-Cohen|first6=Nitza|date=2022|title=Genetic Alteration Analysis of IDH1, IDH2, CDKN2A, MYB and MYBL1 in Pediatric Low-Grade Gliomas|url=https://pubmed.ncbi.nlm.nih.gov/35574540|journal=Frontiers in Surgery|volume=9|pages=880048|doi=10.3389/fsurg.2022.880048|issn=2296-875X|pmc=9096721|pmid=35574540}}</ref>. The most frequently identified fusion is with ''QKI''<ref>{{Cite journal|last=Suh|first=Ye Yoon|last2=Lee|first2=Kwanghoon|last3=Shim|first3=Yu-Mi|last4=Phi|first4=Ji Hoon|last5=Park|first5=Chul-Kee|last6=Kim|first6=Seung-Ki|last7=Choi|first7=Seung Hong|last8=Yun|first8=Hongseok|last9=Park|first9=Sung-Hye|date=2023-02-21|title=MYB/MYBL1::QKI fusion-positive diffuse glioma|url=https://pubmed.ncbi.nlm.nih.gov/36592415|journal=Journal of Neuropathology and Experimental Neurology|volume=82|issue=3|pages=250–260|doi=10.1093/jnen/nlac123|issn=1554-6578|pmc=9941827|pmid=36592415}}</ref><ref>{{Cite journal|last=Jain|first=Payal|last2=Resnick|first2=Adam C.|date=2017-03-04|title=MYB-QKI drives childhood brain tumors via tripartite mechanism|url=https://pubmed.ncbi.nlm.nih.gov/27973981|journal=Cell Cycle (Georgetown, Tex.)|volume=16|issue=5|pages=390–391|doi=10.1080/15384101.2016.1260990|issn=1551-4005|pmc=5351923|pmid=27973981}}</ref>''.'' The ''MYB'' or ''MYBL1-''altered diffuse gliomas in both children and adults are generally indolent and behave in a WHO grade 1 fashion.
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==Synonyms / Terminology==
 
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==Epidemiology / Prevalence==
 
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==Clinical Features==
 
==Clinical Features==
  
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Medically refractory epilepsy since childhood.
 
{| class="wikitable"
 
{| class="wikitable"
 
|'''Signs and Symptoms'''
 
|'''Signs and Symptoms'''
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|EXAMPLE Asymptomatic (incidental finding on complete blood counts)
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|History of epilepsy or seizure
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+
Magnetic resonance imaging (MRI): well-delineated, occasionally infiltrative-appearing, non-enhancing T1-hypointense, T2-fluid attenuated inversion recovery-hyperintense lesion without restricted diffusion<ref>{{Cite journal|last=Fabbri|first=Viscardo Paolo|last2=Caporalini|first2=Chiara|last3=Asioli|first3=Sofia|last4=Buccoliero|first4=Annamaria|date=2022-12|title=Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome|url=https://pubmed.ncbi.nlm.nih.gov/36534420|journal=Pathologica|volume=114|issue=6|pages=410–421|doi=10.32074/1591-951X-828|issn=1591-951X|pmc=9763978|pmid=36534420}}</ref>
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EXAMPLE B-symptoms (weight loss, fever, night sweats)
 
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EXAMPLE Fatigue
 
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EXAMPLE Lymphadenopathy (uncommon)
 
 
|-
 
|-
 
|'''Laboratory Findings'''
 
|'''Laboratory Findings'''
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|EXAMPLE Cytopenias
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|Genetics: Negative for ''IDH1'' p.R132H, ''BRAF'' p.V600E; positive for ''MYBL1'' or ''MYB'' rearrangement, amplification, or copy number change
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−
EXAMPLE Lymphocytosis (low level)
 
 
|}
 
|}
  
 
==Sites of Involvement==
 
==Sites of Involvement==
  
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Put your text here
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Supratentorial (adult), cortical and subcortical regions of the cerebral cortex (pediatric)<ref>{{Cite journal|last=Fabbri|first=Viscardo Paolo|last2=Caporalini|first2=Chiara|last3=Asioli|first3=Sofia|last4=Buccoliero|first4=Annamaria|date=2022-12|title=Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome|url=https://pubmed.ncbi.nlm.nih.gov/36534420|journal=Pathologica|volume=114|issue=6|pages=410–421|doi=10.32074/1591-951X-828|issn=1591-951X|pmc=9763978|pmid=36534420}}</ref>
  
 
==Morphologic Features==
 
==Morphologic Features==
  
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Put your text here
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Histomorphology: minimally to moderately hypercellular tumor; diffuse infiltration by monomorphic cells with ovoid to elongated nuclei, scant cytoplasm, fibrillary background<ref>{{Cite journal|last=Fabbri|first=Viscardo Paolo|last2=Caporalini|first2=Chiara|last3=Asioli|first3=Sofia|last4=Buccoliero|first4=Annamaria|date=2022-12|title=Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome|url=https://pubmed.ncbi.nlm.nih.gov/36534420|journal=Pathologica|volume=114|issue=6|pages=410–421|doi=10.32074/1591-951X-828|issn=1591-951X|pmc=9763978|pmid=36534420}}</ref><ref>{{Cite journal|last=Suh|first=Ye Yoon|last2=Lee|first2=Kwanghoon|last3=Shim|first3=Yu-Mi|last4=Phi|first4=Ji Hoon|last5=Park|first5=Chul-Kee|last6=Kim|first6=Seung-Ki|last7=Choi|first7=Seung Hong|last8=Yun|first8=Hongseok|last9=Park|first9=Sung-Hye|date=2023-02-21|title=MYB/MYBL1::QKI fusion-positive diffuse glioma|url=https://pubmed.ncbi.nlm.nih.gov/36592415|journal=Journal of Neuropathology and Experimental Neurology|volume=82|issue=3|pages=250–260|doi=10.1093/jnen/nlac123|issn=1554-6578|pmc=9941827|pmid=36592415}}</ref>
  
 
==Immunophenotype==
 
==Immunophenotype==
  
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Put your text here and fill in the table
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Positivity for GFAP, below 1% Ki-67 index, negative for OLIG2 and IDH1 R132H<ref>{{Cite journal|last=Wefers|first=Annika K.|last2=Stichel|first2=Damian|last3=Schrimpf|first3=Daniel|last4=Coras|first4=Roland|last5=Pages|first5=Mélanie|last6=Tauziède-Espariat|first6=Arnault|last7=Varlet|first7=Pascale|last8=Schwarz|first8=Daniel|last9=Söylemezoglu|first9=Figen|date=2020-01|title=Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course|url=https://pubmed.ncbi.nlm.nih.gov/31563982|journal=Acta Neuropathologica|volume=139|issue=1|pages=193–209|doi=10.1007/s00401-019-02078-w|issn=1432-0533|pmc=7477753|pmid=31563982}}</ref>
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Finding!!Marker
 
!Finding!!Marker
 
|-
 
|-
−
|Positive (universal)||EXAMPLE CD1
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|Positive (universal)||GFAP<span lang="EN-US">Scott C. Smith,
 +
PhD, FACMG; SUNY Upstate Medical University</span>
 
|-
 
|-
−
|Positive (subset)||EXAMPLE CD2
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|Positive (subset)||Ki-67 index below 1%
 
|-
 
|-
−
|Negative (universal)||EXAMPLE CD3
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|Negative (universal)||OLIG2, IDH1 R132H
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|-
 
−
|Negative (subset)||EXAMPLE CD4
 
 
|}
 
|}
  
 
==Chromosomal Rearrangements (Gene Fusions)==
 
==Chromosomal Rearrangements (Gene Fusions)==
  
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Put your text here and fill in the table
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''MYB'' or ''MYBL1'' rearrangement
  
 +
''MYB'' or ''MYBL1'' amplification
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
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!Notes
 
!Notes
 
|-
 
|-
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|EXAMPLE t(9;22)(q34;q11.2)||EXAMPLE 3'ABL1 / 5'BCR||EXAMPLE der(22)||EXAMPLE 20% (COSMIC)
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|6q23.3 rearrangement
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EXAMPLE 30% (add reference)
+
|
 +
|
 +
|
 +
|Yes
 +
|Yes
 +
|
 +
|Multiple potential  partners
 +
|-
 +
|8q13.1 rearrangement
 +
|
 +
|
 +
|
 +
|Yes
 +
|Yes
 +
|
 +
|Multiple potential  partners
 +
|-
 +
|del(6)(q23.3q26); t(6;6)(q23.3;q26)
 +
|''MYB::QKI''
 +
|
 +
|
 
|Yes
 
|Yes
−
|No
 
 
|Yes
 
|Yes
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|EXAMPLE
+
|
−
 
+
|Creates fusion oncogenic protein
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The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference).
 
 
|}
 
|}
 
 
 
==Individual Region Genomic Gain/Loss/LOH==
 
==Individual Region Genomic Gain/Loss/LOH==
  
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Put your text here and fill in the table
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''MYB'' or ''MYBL1'' copy number variation as identified by chromosomal microarray or FISH
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
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|EXAMPLE
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|6
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+
|Amp/Loss/Gain
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7
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|135502446-135540310 [GRCh37]
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|EXAMPLE Loss
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|6q23.3
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|EXAMPLE
 
−
 
 
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chr7:1- 159,335,973 [hg38]
 
−
|EXAMPLE
 
−
 
 
−
chr7
 
 
|Yes
 
|Yes
 
|Yes
 
|Yes
−
|No
+
|Yes<ref>{{Cite journal|last=Trkova|first=Katerina|last2=Sumerauer|first2=David|last3=Krskova|first3=Lenka|last4=Vicha|first4=Ales|last5=Koblizek|first5=Miroslav|last6=Votava|first6=Tomas|last7=Priban|first7=Vladimir|last8=Zapotocky|first8=Michal|date=2023-09|title=DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy|url=https://pubmed.ncbi.nlm.nih.gov/37165121|journal=Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery|volume=39|issue=9|pages=2509–2513|doi=10.1007/s00381-023-05976-3|issn=1433-0350|pmc=PMC10432314|pmid=37165121}}</ref>
−
|EXAMPLE
+
|<ref>{{Cite journal|last=Ramkissoon|first=Lori A.|last2=Horowitz|first2=Peleg M.|last3=Craig|first3=Justin M.|last4=Ramkissoon|first4=Shakti H.|last5=Rich|first5=Benjamin E.|last6=Schumacher|first6=Steven E.|last7=McKenna|first7=Aaron|last8=Lawrence|first8=Michael S.|last9=Bergthold|first9=Guillaume|date=2013-05-14|title=Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1|url=https://pubmed.ncbi.nlm.nih.gov/23633565|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=20|pages=8188–8193|doi=10.1073/pnas.1300252110|issn=1091-6490|pmc=3657784|pmid=23633565}}</ref><ref>{{Cite journal|last=Bale|first=Tejus A.|last2=Rosenblum|first2=Marc K.|date=2022-07|title=The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors|url=https://pubmed.ncbi.nlm.nih.gov/35218102|journal=Brain Pathology (Zurich, Switzerland)|volume=32|issue=4|pages=e13060|doi=10.1111/bpa.13060|issn=1750-3639|pmc=9245930|pmid=35218102}}</ref><ref>{{Cite journal|last=Trkova|first=Katerina|last2=Sumerauer|first2=David|last3=Krskova|first3=Lenka|last4=Vicha|first4=Ales|last5=Koblizek|first5=Miroslav|last6=Votava|first6=Tomas|last7=Priban|first7=Vladimir|last8=Zapotocky|first8=Michal|date=2023-09|title=DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy|url=https://pubmed.ncbi.nlm.nih.gov/37165121|journal=Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery|volume=39|issue=9|pages=2509–2513|doi=10.1007/s00381-023-05976-3|issn=1433-0350|pmc=PMC10432314|pmid=37165121}}</ref>
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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).
 
 
|-
 
|-
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|EXAMPLE
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|8
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+
|Amp/Loss/Gain
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8
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|67474410-67525453 [GRCh37]  
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|EXAMPLE Gain
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|8q13.1
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|EXAMPLE
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|Yes
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+
|Yes
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chr8:1-145,138,636 [hg38]
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|Unknown
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|EXAMPLE
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|<ref>{{Cite journal|last=Ramkissoon|first=Lori A.|last2=Horowitz|first2=Peleg M.|last3=Craig|first3=Justin M.|last4=Ramkissoon|first4=Shakti H.|last5=Rich|first5=Benjamin E.|last6=Schumacher|first6=Steven E.|last7=McKenna|first7=Aaron|last8=Lawrence|first8=Michael S.|last9=Bergthold|first9=Guillaume|date=2013-05-14|title=Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1|url=https://pubmed.ncbi.nlm.nih.gov/23633565|journal=Proceedings of the National Academy of Sciences of the United States of America|volume=110|issue=20|pages=8188–8193|doi=10.1073/pnas.1300252110|issn=1091-6490|pmc=3657784|pmid=23633565}}</ref><ref>{{Cite journal|last=Bale|first=Tejus A.|last2=Rosenblum|first2=Marc K.|date=2022-07|title=The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors|url=https://pubmed.ncbi.nlm.nih.gov/35218102|journal=Brain Pathology (Zurich, Switzerland)|volume=32|issue=4|pages=e13060|doi=10.1111/bpa.13060|issn=1750-3639|pmc=9245930|pmid=35218102}}</ref>
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chr8
 
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|No
 
−
|No
 
−
|No
 
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|EXAMPLE
 
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Common recurrent secondary finding for t(8;21) (add reference).
 
 
|}
 
|}
 
==Characteristic Chromosomal Patterns==
 
==Characteristic Chromosomal Patterns==
  
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Put your text here
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Possible detection of double minutes or homogeneously stained regions by G-banding for amplification; will require confirmation of being associated with MYB or MYBL (likely by chromosomal microarray)
  
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
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!Notes
 
!Notes
 
|-
 
|-
−
|EXAMPLE
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|6q23.3 hsr; '' MYB'' amplification <span lang="EN-US">Scott C. Smith,
−
 
+
PhD, FACMG; SUNY Upstate Medical University</span>
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Co-deletion of 1p and 18q
 
−
|Yes
 
 
|No
 
|No
 +
|Unknown
 +
|Unknown
 +
|
 +
|-
 +
|8q13.1 hsr; ''MYBL1'' amplification<span lang="EN-US">Scott C. Smith,
 +
PhD, FACMG; SUNY Upstate Medical University</span>
 
|No
 
|No
−
|EXAMPLE:
+
|Unknown
−
 
+
|Unknown
−
See chromosomal rearrangements table as this pattern is due to an unbalanced derivative translocation associated with oligodendroglioma (add reference).
 
−
|}
 
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==Gene Mutations (SNV/INDEL)==
 
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Put your text here and fill in the table
 
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{| class="wikitable sortable"
 
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|-
 
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!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
 
−
|-
 
−
|EXAMPLE: TP53; Variable LOF mutations
 
−
 
 
−
EXAMPLE:
 
−
 
 
−
EGFR; Exon 20 mutations
 
−
 
 
−
EXAMPLE: BRAF; Activating mutations
 
−
|EXAMPLE: TSG
 
−
|EXAMPLE: 20% (COSMIC)
 
−
 
 
−
EXAMPLE: 30% (add Reference)
 
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|EXAMPLE: IDH1 R123H
 
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|EXAMPLE: EGFR amplification
 
 
|
 
|
−
|
 
−
|
 
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|EXAMPLE:  Excludes hairy cell leukemia (HCL) (add reference).
 
−
<br />
 
 
|}
 
|}
−
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.
 
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==Epigenomic Alterations==
 
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−
Put your text here
 
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==Genes and Main Pathways Involved==
 
==Genes and Main Pathways Involved==
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Put your text here and fill in the table
 
 
{| class="wikitable sortable"
 
{| class="wikitable sortable"
 
|-
 
|-
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
 
|-
 
|-
−
|EXAMPLE: BRAF and MAP2K1; Activating mutations
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|''MYB/MYBL1'' 3’-deletion
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|EXAMPLE: MAPK signaling
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|MYB/MYBL1 protooncogene
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|EXAMPLE: Increased cell growth and proliferation
+
|Deregulation  of MYB/MYBL1
−
|-
 
−
|EXAMPLE: CDKN2A; Inactivating mutations
 
−
|EXAMPLE: Cell cycle regulation
 
−
|EXAMPLE: Unregulated cell division
 
 
|-
 
|-
−
|EXAMPLE:  KMT2C and ARID1A; Inactivating mutations
+
|''MYB/MYBL1'' amplification
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|EXAMPLE: Histone modification, chromatin remodeling
+
|MYB/MYBL1 protooncogene
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|EXAMPLE: Abnormal gene expression program
+
|Overexpression of MYB/MYBL1
 
|}
 
|}
 
==Genetic Diagnostic Testing Methods==
 
==Genetic Diagnostic Testing Methods==
  
−
Put your text here
+
Sequencing, PCR, RT-PCR, chromosomal microarray, FISH, possibly detection of double minutes or homogenously stained regions by G-banding
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==Familial Forms==
 
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−
Put your text here
 
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==Additional Information==
 
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Put your text here
 
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==Links==
 
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==References==
 
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#Arber DA, et al., (2017). Acute myeloid leukaemia with recurrent genetic abnormalities, in World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues, Revised 4th edition. Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J, Arber DA, Hasserjian RP, Le Beau MM, Orazi A, and Siebert R, Editors. IARC Press: Lyon, France, p129-171.
 
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==Notes==
 
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<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.
 
<nowiki>*</nowiki>Primary authors will typically be those that initially create and complete the content of a page.  If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage).  Additional global feedback or concerns are also welcome.

Latest revision as of 16:04, 30 July 2024

Primary Author(s)*

Scott C. Smith, PhD, FACMG; SUNY Upstate Medical University

Cancer Category/Type

WHO Classification of Tumours of the Central Nervous System (5th Edition)

Cancer Sub-Classification / Subtype

Diffuse Astrocytoma, MYB- or MYBL1-Altered

Definition / Description of Disease

Diffuse astrocytoma, MYB or MYBL1-altered is one of several newly recognized tumor types in the 5th edition of the WHO Classification of Tumors of the Central Nervous System. The newly recognized classifications were in response to advances in understanding of paediatric-type gliomas, facilitated by an increased molecular characterisation of these tumours. Diffuse astrocytoma, MYB or MYBL1-altered is a subset of diffuse low-grade glioma with amplifications, structural variants, and fusions involving the MYB and MYBL1 protooncogenes. Diffuse astrocytoma, MYB or MYBL1-altered subtypes are without characteristic histological features of angiocentric glioma[1][2]. A related group of diffuse gliomas, the isomorphic glioma, occur predominantly in adults and are typically well-differentiated, low to moderately cellular, comprised of astrocytes with rounded nuclei and regular chromatin structures, and have low proliferative indices[3][4]. These adult diffuse gliomas exhibit alterations of MYBL1 rather than MYB . Gene fusions with multiple partners characterize the pediatric MYB or MYBL1-altered gliomas[5][6]. The most frequently identified fusion is with QKI[7][8]. The MYB or MYBL1-altered diffuse gliomas in both children and adults are generally indolent and behave in a WHO grade 1 fashion.

Clinical Features

Medically refractory epilepsy since childhood.

Signs and Symptoms History of epilepsy or seizure

Magnetic resonance imaging (MRI): well-delineated, occasionally infiltrative-appearing, non-enhancing T1-hypointense, T2-fluid attenuated inversion recovery-hyperintense lesion without restricted diffusion[9]

Laboratory Findings Genetics: Negative for IDH1 p.R132H, BRAF p.V600E; positive for MYBL1 or MYB rearrangement, amplification, or copy number change

Sites of Involvement

Supratentorial (adult), cortical and subcortical regions of the cerebral cortex (pediatric)[10]

Morphologic Features

Histomorphology: minimally to moderately hypercellular tumor; diffuse infiltration by monomorphic cells with ovoid to elongated nuclei, scant cytoplasm, fibrillary background[11][12]

Immunophenotype

Positivity for GFAP, below 1% Ki-67 index, negative for OLIG2 and IDH1 R132H[13]

Finding Marker
Positive (universal) GFAPScott C. Smith,

PhD, FACMG; SUNY Upstate Medical University

Positive (subset) Ki-67 index below 1%
Negative (universal) OLIG2, IDH1 R132H

Chromosomal Rearrangements (Gene Fusions)

MYB or MYBL1 rearrangement

MYB or MYBL1 amplification

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
6q23.3 rearrangement Yes Yes Multiple potential  partners
8q13.1 rearrangement Yes Yes Multiple potential  partners
del(6)(q23.3q26); t(6;6)(q23.3;q26) MYB::QKI Yes Yes Creates fusion oncogenic protein

Individual Region Genomic Gain/Loss/LOH

MYB or MYBL1 copy number variation as identified by chromosomal microarray or FISH

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
6 Amp/Loss/Gain 135502446-135540310 [GRCh37] 6q23.3 Yes Yes Yes[14] [15][16][17]
8 Amp/Loss/Gain 67474410-67525453 [GRCh37] 8q13.1 Yes Yes Unknown [18][19]

Characteristic Chromosomal Patterns

Possible detection of double minutes or homogeneously stained regions by G-banding for amplification; will require confirmation of being associated with MYB or MYBL (likely by chromosomal microarray)

Chromosomal Pattern Diagnostic Significance (Yes, No or Unknown) Prognostic Significance (Yes, No or Unknown) Therapeutic Significance (Yes, No or Unknown) Notes
6q23.3 hsr;  MYB amplification Scott C. Smith,

PhD, FACMG; SUNY Upstate Medical University

No Unknown Unknown
8q13.1 hsr; MYBL1 amplificationScott C. Smith,

PhD, FACMG; SUNY Upstate Medical University

No Unknown Unknown

Genes and Main Pathways Involved

Gene; Genetic Alteration Pathway Pathophysiologic Outcome
MYB/MYBL1 3’-deletion MYB/MYBL1 protooncogene Deregulation of MYB/MYBL1
MYB/MYBL1 amplification MYB/MYBL1 protooncogene Overexpression of MYB/MYBL1

Genetic Diagnostic Testing Methods

Sequencing, PCR, RT-PCR, chromosomal microarray, FISH, possibly detection of double minutes or homogenously stained regions by G-banding

References

  1. ↑ Slegers, Rutger Juriaan; et al. (2020-03-09). "Low-grade developmental and epilepsy associated brain tumors: a critical update 2020". Acta Neuropathologica Communications. 8 (1): 27. doi:10.1186/s40478-020-00904-x. ISSN 2051-5960. PMC 7063704 Check |pmc= value (help). PMID 32151273 Check |pmid= value (help).
  2. ↑ Bandopadhayay, Pratiti; et al. (2016-03). "MYB-QKI rearrangements in angiocentric glioma drive tumorigenicity through a tripartite mechanism". Nature Genetics. 48 (3): 273–282. doi:10.1038/ng.3500. ISSN 1546-1718. PMC 4767685. PMID 26829751. Check date values in: |date= (help)
  3. ↑ Wefers, Annika K.; et al. (2020-01). "Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course". Acta Neuropathologica. 139 (1): 193–209. doi:10.1007/s00401-019-02078-w. ISSN 1432-0533. PMC 7477753 Check |pmc= value (help). PMID 31563982. Check date values in: |date= (help)
  4. ↑ Chiang, Jason; et al. (2019-12). "A single-center study of the clinicopathologic correlates of gliomas with a MYB or MYBL1 alteration". Acta Neuropathologica. 138 (6): 1091–1092. doi:10.1007/s00401-019-02081-1. ISSN 1432-0533. PMC 7467132 Check |pmc= value (help). PMID 31595312. Check date values in: |date= (help)
  5. ↑ Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  6. ↑ Barinfeld, Orit; et al. (2022). "Genetic Alteration Analysis of IDH1, IDH2, CDKN2A, MYB and MYBL1 in Pediatric Low-Grade Gliomas". Frontiers in Surgery. 9: 880048. doi:10.3389/fsurg.2022.880048. ISSN 2296-875X. PMC 9096721 Check |pmc= value (help). PMID 35574540 Check |pmid= value (help).
  7. ↑ Suh, Ye Yoon; et al. (2023-02-21). "MYB/MYBL1::QKI fusion-positive diffuse glioma". Journal of Neuropathology and Experimental Neurology. 82 (3): 250–260. doi:10.1093/jnen/nlac123. ISSN 1554-6578. PMC 9941827 Check |pmc= value (help). PMID 36592415 Check |pmid= value (help).
  8. ↑ Jain, Payal; et al. (2017-03-04). "MYB-QKI drives childhood brain tumors via tripartite mechanism". Cell Cycle (Georgetown, Tex.). 16 (5): 390–391. doi:10.1080/15384101.2016.1260990. ISSN 1551-4005. PMC 5351923. PMID 27973981.
  9. ↑ Fabbri, Viscardo Paolo; et al. (2022-12). "Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome". Pathologica. 114 (6): 410–421. doi:10.32074/1591-951X-828. ISSN 1591-951X. PMC 9763978 Check |pmc= value (help). PMID 36534420 Check |pmid= value (help). Check date values in: |date= (help)
  10. ↑ Fabbri, Viscardo Paolo; et al. (2022-12). "Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome". Pathologica. 114 (6): 410–421. doi:10.32074/1591-951X-828. ISSN 1591-951X. PMC 9763978 Check |pmc= value (help). PMID 36534420 Check |pmid= value (help). Check date values in: |date= (help)
  11. ↑ Fabbri, Viscardo Paolo; et al. (2022-12). "Paediatric-type diffuse low-grade gliomas: a clinically and biologically distinct group of tumours with a favourable outcome". Pathologica. 114 (6): 410–421. doi:10.32074/1591-951X-828. ISSN 1591-951X. PMC 9763978 Check |pmc= value (help). PMID 36534420 Check |pmid= value (help). Check date values in: |date= (help)
  12. ↑ Suh, Ye Yoon; et al. (2023-02-21). "MYB/MYBL1::QKI fusion-positive diffuse glioma". Journal of Neuropathology and Experimental Neurology. 82 (3): 250–260. doi:10.1093/jnen/nlac123. ISSN 1554-6578. PMC 9941827 Check |pmc= value (help). PMID 36592415 Check |pmid= value (help).
  13. ↑ Wefers, Annika K.; et al. (2020-01). "Isomorphic diffuse glioma is a morphologically and molecularly distinct tumour entity with recurrent gene fusions of MYBL1 or MYB and a benign disease course". Acta Neuropathologica. 139 (1): 193–209. doi:10.1007/s00401-019-02078-w. ISSN 1432-0533. PMC 7477753 Check |pmc= value (help). PMID 31563982. Check date values in: |date= (help)
  14. ↑ Trkova, Katerina; et al. (2023-09). "DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy". Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery. 39 (9): 2509–2513. doi:10.1007/s00381-023-05976-3. ISSN 1433-0350. PMC PMC10432314 Check |pmc= value (help). PMID 37165121 Check |pmid= value (help). Check date values in: |date= (help)CS1 maint: PMC format (link)
  15. ↑ Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  16. ↑ Bale, Tejus A.; et al. (2022-07). "The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors". Brain Pathology (Zurich, Switzerland). 32 (4): e13060. doi:10.1111/bpa.13060. ISSN 1750-3639. PMC 9245930 Check |pmc= value (help). PMID 35218102 Check |pmid= value (help). Check date values in: |date= (help)
  17. ↑ Trkova, Katerina; et al. (2023-09). "DIPG-like MYB-altered diffuse astrocytoma with durable response to intensive chemotherapy". Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery. 39 (9): 2509–2513. doi:10.1007/s00381-023-05976-3. ISSN 1433-0350. PMC PMC10432314 Check |pmc= value (help). PMID 37165121 Check |pmid= value (help). Check date values in: |date= (help)CS1 maint: PMC format (link)
  18. ↑ Ramkissoon, Lori A.; et al. (2013-05-14). "Genomic analysis of diffuse pediatric low-grade gliomas identifies recurrent oncogenic truncating rearrangements in the transcription factor MYBL1". Proceedings of the National Academy of Sciences of the United States of America. 110 (20): 8188–8193. doi:10.1073/pnas.1300252110. ISSN 1091-6490. PMC 3657784. PMID 23633565.
  19. ↑ Bale, Tejus A.; et al. (2022-07). "The 2021 WHO Classification of Tumors of the Central Nervous System: An update on pediatric low-grade gliomas and glioneuronal tumors". Brain Pathology (Zurich, Switzerland). 32 (4): e13060. doi:10.1111/bpa.13060. ISSN 1750-3639. PMC 9245930 Check |pmc= value (help). PMID 35218102 Check |pmid= value (help). Check date values in: |date= (help)

Notes

*Primary authors will typically be those that initially create and complete the content of a page. If a subsequent user modifies the content and feels the effort put forth is of high enough significance to warrant listing in the authorship section, please contact the CCGA coordinators (contact information provided on the homepage). Additional global feedback or concerns are also welcome.

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