Compendium of Cancer Genome Aberrations

CNS5:Medulloblastoma, WNT-activated: Difference between revisions

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{{DISPLAYTITLE:Medulloblastoma, WNT-activated}}
{{DISPLAYTITLE:Medulloblastoma, WNT-activated}}


[[CNS5:Table_of_Contents|Central Nervous System Tumours(WHO Classification, 5th ed.)]]
[[CNS5:Table_of_Contents|Central Nervous System Tumours (WHO Classification, 5th ed.)]]


{{Under Construction}}
{{Under Construction}}
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Midhat Farooqi, MD, Children's Mercy Hospital, University of Missouri–Kansas City
Midhat Farooqi, MD, Children's Mercy Hospital, University of Missouri–Kansas City
==WHO Classification of Disease==
==WHO Classification of Disease==


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|}
|}


==Definition / Description of Disease==
==Related Terminology==
 
Medulloblastoma is the most common malignant pediatric brain tumor, though it can also occur in adults (PMIDs: 29189165; 23175120; 30445539). Recurrent histopathologic, radiologic, and genomic findings have resulted in the establishment of four primary molecularly-defined subgroups: WNT-activated; SHH-activated and ''TP53''-wildtype; SHH-activated and ''TP53''-mutant; and non-WNT/non-SHH (PMID: 22358457). Somatic variants that cause activation of these pathways (e.g., gain-of-function variants in ''CTNNB1'' for the WNT pathway) are considered diagnostic. Of note, a subset of cases can be due to germline loss-of-function variants in the ''APC'' gene (which also result in activation of WNT signaling), which are representative of the spectrum of disorders known as Familial Adenomatous Polyposis (historically referred to as Gardner syndrome; MIM: 175100). In summary, medulloblastoma, WNT-activated, is an embryonal tumour originating in the dorsal brainstem characterized by activation of the WNT signalling pathway.
 
==Synonyms / Terminology==
 
Primitive neuroectodermal tumor of the posterior fossa
 
==Epidemiology / Prevalence==


·      This subtype accounts for approximately 10% of all medulloblastomas (PMIDs: 23175120, 22832581, 22358457, 22134537).
·      Most frequently observed in older children (median age 10 years; PMIDs: 23175120, 22832581) with a balanced male:female ratio (PMID: 22134537); Of note, this medulloblastoma subtype rarely occurs in infants and rarely metastasizes (PMID: 31799776).
·      Excellent prognosis for patients <16 years of age at diagnosis: >95% have a five-year overall survival (PMIDs: 16567768; 17172831; 16258095; 19197950)
·      Accounts for ~15% of all adult medulloblastomas, which may have a worse prognosis than pediatric WNT-activated medulloblastoma (PMID: 28609654, 21632505; 26420814; 27106407)
==Clinical Features==
·      Cranial and spinal MRI are used for diagnosis (PMID: 30765705)
·      Signs and symptoms (listed below) can increase in severity over weeks to months
{| class="wikitable"
{| class="wikitable"
|'''Signs and Symptoms'''
|+
|Headache
|Acceptable
 
|N/A
Clumsiness
 
Fatigue
 
Nausea/vomiting
 
Declining motor skills and/or ataxia
 
Vision problems and/or strabismus
 
Hydrocephalus
|-
|-
|'''Laboratory Findings'''
|Not Recommended
|None
|N/A
|}
 
==Sites of Involvement==
 
·      Cerebellum, cerebellar peduncle or fourth ventricle (PMIDs: 32239782; 26338912)
 
·      Origin: cells in the extracerebellar lower rhombic lip (PMID: 21150899)
 
·      Metastases are much less likely to occur in this subtype relative to other MB subtypes; staging is performed using the Chang classification (PMID: 4983156)
 
==Morphologic Features==
 
·      The WNT-activated subgroup is most commonly observed as an embryonal tumor with classic histology located in the cerebellum and/or fourth ventricle (PMID: 32239782)
 
·      Cases generally show a classical histologic pattern:
 
o  Small round blue cell tumor
 
o   Sheets of densely packed undifferentiated (embryonal) cells
 
o   Individual cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, and salt-and-pepper chromatin
 
o   Presence of mitoses, apoptotic bodies, and Homer Wright rosettes
 
·      High degree of hemorrhage relative to other subtypes
 
·      Rare examples with anaplastic histology have been described (PMIDs: 21267586; 31104222)
 
·      Activated WNT pathway signaling - commonly visualized by immunohistochemical studies showing nuclear beta-catenin staining
 
==Immunophenotype==
 
·      Majority positive for synaptophysin; INI-1 staining should be retained (positive)
 
·      Molecular subtyping may be performed immunohistochemically using Filamin A, YAP1, GAB1 and beta-catenin (PMIDs: 32239782, 21267586)
{| class="wikitable sortable"
|-
!Finding!!Marker
|-
|'''Positive  (universal)'''
|Nuclear beta-catenin, Filamin A, and YAP1
|-
|'''Positive  (subset)'''
|
|-
|'''Negative  (universal)'''
|GAB1
|-
|'''Negative  (subset)'''
|YAP1 (in areas of heavy neuronal differentiation)
|}
|}


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'''Add content below into table above''' -  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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|Unknown
|Unknown
|Unknown
|Unknown
|PMID: 33681213
|<ref name=":0">{{Cite journal|last=Luo|first=Zaili|last2=Dong|first2=Xinran|last3=Yu|first3=Jianzhong|last4=Xia|first4=Yong|last5=Berry|first5=Kalen P.|last6=Rao|first6=Rohit|last7=Xu|first7=Lingli|last8=Xue|first8=Ping|last9=Chen|first9=Tong|date=2021|title=Genomic and Transcriptomic Analyses Reveals ZNF124 as a Critical Regulator in Highly Aggressive Medulloblastomas|url=https://pubmed.ncbi.nlm.nih.gov/33681213|journal=Frontiers in Cell and Developmental Biology|volume=9|pages=634056|doi=10.3389/fcell.2021.634056|issn=2296-634X|pmc=7930499|pmid=33681213}}</ref>
|-
|-
|''ARID1A::PHACTR4''
|''ARID1A::PHACTR4''
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|Unknown
|Unknown
|Unknown
|Unknown
|PMID: 33681213
|<ref name=":0" />
| colspan="8" |
| colspan="8" |
|}
|}
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Chr #!!'''Gain, Loss, Amp, LOH'''!!'''Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]'''!!'''Relevant Gene(s)'''
!Chr #!!Gain, Loss, Amp, LOH!!Minimal Region Cytoband and/or Genomic Coordinates [Genome Build; Size]!!Relevant Gene(s)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>
|<span class="blue-text">EXAMPLE:</span>
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'''Add content below into table above''' -  
·      Monosomy 6 is the most frequently reported genomic alteration, occurring within 80-85% of cases and commonly co-occurring with ''CTNNB1'' somatic mutations<ref name=":6">{{Cite journal|last=Thompson|first=Margaret C.|last2=Fuller|first2=Christine|last3=Hogg|first3=Twala L.|last4=Dalton|first4=James|last5=Finkelstein|first5=David|last6=Lau|first6=Ching C.|last7=Chintagumpala|first7=Murali|last8=Adesina|first8=Adekunle|last9=Ashley|first9=David M.|date=2006-04-20|title=Genomics identifies medulloblastoma subgroups that are enriched for specific genetic alterations|url=https://pubmed.ncbi.nlm.nih.gov/16567768|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=24|issue=12|pages=1924–1931|doi=10.1200/JCO.2005.04.4974|issn=1527-7755|pmid=16567768}}</ref><ref name=":1">{{Cite journal|last=Northcott|first=Paul A.|last2=Buchhalter|first2=Ivo|last3=Morrissy|first3=A. Sorana|last4=Hovestadt|first4=Volker|last5=Weischenfeldt|first5=Joachim|last6=Ehrenberger|first6=Tobias|last7=Gröbner|first7=Susanne|last8=Segura-Wang|first8=Maia|last9=Zichner|first9=Thomas|date=2017-07-19|title=The whole-genome landscape of medulloblastoma subtypes|url=https://pubmed.ncbi.nlm.nih.gov/28726821|journal=Nature|volume=547|issue=7663|pages=311–317|doi=10.1038/nature22973|issn=1476-4687|pmc=5905700|pmid=28726821}}</ref><ref name=":7">{{Cite journal|last=Clifford|first=Steven C.|last2=Lusher|first2=Meryl E.|last3=Lindsey|first3=Janet C.|last4=Langdon|first4=Jacqueline A.|last5=Gilbertson|first5=Richard J.|last6=Straughton|first6=Debbie|last7=Ellison|first7=David W.|date=2006-11|title=Wnt/Wingless pathway activation and chromosome 6 loss characterize a distinct molecular sub-group of medulloblastomas associated with a favorable prognosis|url=https://pubmed.ncbi.nlm.nih.gov/17172831|journal=Cell Cycle (Georgetown, Tex.)|volume=5|issue=22|pages=2666–2670|doi=10.4161/cc.5.22.3446|issn=1551-4005|pmid=17172831}}</ref><ref name=":2">{{Cite journal|last=Northcott|first=Paul A.|last2=Robinson|first2=Giles W.|last3=Kratz|first3=Christian P.|last4=Mabbott|first4=Donald J.|last5=Pomeroy|first5=Scott L.|last6=Clifford|first6=Steven C.|last7=Rutkowski|first7=Stefan|last8=Ellison|first8=David W.|last9=Malkin|first9=David|date=2019-02-14|title=Medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/30765705|journal=Nature Reviews. Disease Primers|volume=5|issue=1|pages=11|doi=10.1038/s41572-019-0063-6|issn=2056-676X|pmid=30765705}}</ref>.


·      Monosomy 6 is the most frequently reported genomic alteration, occurring within 80-85% of cases and commonly co-occurring with ''CTNNB1'' somatic mutations. (PMIDs: 16567768; 28726821; 17172831; 30765705)
·      With the exception of monosomy 6, this medulloblastoma subtype usually has a balanced genome<ref name=":8">{{Cite journal|last=Northcott|first=Paul A.|last2=Shih|first2=David J. H.|last3=Peacock|first3=John|last4=Garzia|first4=Livia|last5=Morrissy|first5=A. Sorana|last6=Zichner|first6=Thomas|last7=Stütz|first7=Adrian M.|last8=Korshunov|first8=Andrey|last9=Reimand|first9=Jüri|date=2012-08-02|title=Subgroup-specific structural variation across 1,000 medulloblastoma genomes|url=https://pubmed.ncbi.nlm.nih.gov/22832581|journal=Nature|volume=488|issue=7409|pages=49–56|doi=10.1038/nature11327|issn=1476-4687|pmc=3683624|pmid=22832581}}</ref>
 
·      With the exception of monosomy 6, this medulloblastoma subtype usually has a balanced genome (PMID: 22832581)
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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|Chr6
|Chr6
|Yes
|Yes
|Yes – Monosomy 6 is associated with very good outcome in pediatric patients (PDQ, PMIDs: 24791927, 21267586, 17012043).
|Yes – Monosomy 6 is associated with very good outcome in pediatric patients (PDQ)<ref>{{Cite journal|last=Pietsch|first=Torsten|last2=Schmidt|first2=Rene|last3=Remke|first3=Marc|last4=Korshunov|first4=Andrey|last5=Hovestadt|first5=Volker|last6=Jones|first6=David T. W.|last7=Felsberg|first7=Jörg|last8=Kaulich|first8=Kerstin|last9=Goschzik|first9=Tobias|date=2014-07|title=Prognostic significance of clinical, histopathological, and molecular characteristics of medulloblastomas in the prospective HIT2000 multicenter clinical trial cohort|url=https://pubmed.ncbi.nlm.nih.gov/24791927|journal=Acta Neuropathologica|volume=128|issue=1|pages=137–149|doi=10.1007/s00401-014-1276-0|issn=1432-0533|pmc=4059991|pmid=24791927}}</ref><ref name=":9">{{Cite journal|last=Ellison|first=David W.|last2=Dalton|first2=James|last3=Kocak|first3=Mehmet|last4=Nicholson|first4=Sarah Leigh|last5=Fraga|first5=Charles|last6=Neale|first6=Geoff|last7=Kenney|first7=Anna M.|last8=Brat|first8=Dan J.|last9=Perry|first9=Arie|date=2011-03|title=Medulloblastoma: clinicopathological correlates of SHH, WNT, and non-SHH/WNT molecular subgroups|url=https://pubmed.ncbi.nlm.nih.gov/21267586|journal=Acta Neuropathologica|volume=121|issue=3|pages=381–396|doi=10.1007/s00401-011-0800-8|issn=1432-0533|pmc=3519926|pmid=21267586}}</ref><ref>{{Cite journal|last=Gajjar|first=Amar|last2=Chintagumpala|first2=Murali|last3=Ashley|first3=David|last4=Kellie|first4=Stewart|last5=Kun|first5=Larry E.|last6=Merchant|first6=Thomas E.|last7=Woo|first7=Shaio|last8=Wheeler|first8=Greg|last9=Ahern|first9=Valerie|date=2006-10|title=Risk-adapted craniospinal radiotherapy followed by high-dose chemotherapy and stem-cell rescue in children with newly diagnosed medulloblastoma (St Jude Medulloblastoma-96): long-term results from a prospective, multicentre trial|url=https://pubmed.ncbi.nlm.nih.gov/17012043|journal=The Lancet. Oncology|volume=7|issue=10|pages=813–820|doi=10.1016/S1470-2045(06)70867-1|issn=1470-2045|pmid=17012043}}</ref>.
|No<span lang="EN-US">Medulloblastomas,
|No<span lang="EN-US">Medulloblastomas,


molecularly defined
molecularly defined
|Presence of monosomy 6 is frequently observed, and present in 80-90% of cases (PMID: 28726821).  This finding is much more common in pediatric patients and has been proposed as a marker for WNT subtype α.  
|Presence of monosomy 6 is frequently observed, and present in 80-90% of cases<ref name=":1" />.  This finding is much more common in pediatric patients and has been proposed as a marker for WNT subtype α.  




However, absence of monosomy 6 does not rule out the possibility of WNT-activated medulloblastoma (PMID: 28726821).  Furthermore, adult patients will be misdiagnosed if monosomy 6 is used alone as a diagnostic factor, as they cluster within WNT subtype β, which characteristically lacks this finding (PMID: 28609654).  
However, absence of monosomy 6 does not rule out the possibility of WNT-activated medulloblastoma<ref name=":1" />.  Furthermore, adult patients will be misdiagnosed if monosomy 6 is used alone as a diagnostic factor, as they cluster within WNT subtype β, which characteristically lacks this finding<ref name=":10">{{Cite journal|last=Cavalli|first=Florence M. G.|last2=Remke|first2=Marc|last3=Rampasek|first3=Ladislav|last4=Peacock|first4=John|last5=Shih|first5=David J. H.|last6=Luu|first6=Betty|last7=Garzia|first7=Livia|last8=Torchia|first8=Jonathon|last9=Nor|first9=Carolina|date=2017-06-12|title=Intertumoral Heterogeneity within Medulloblastoma Subgroups|url=https://pubmed.ncbi.nlm.nih.gov/28609654|journal=Cancer Cell|volume=31|issue=6|pages=737–754.e6|doi=10.1016/j.ccell.2017.05.005|issn=1878-3686|pmc=6163053|pmid=28609654}}</ref>.  




Outside of monosomy 6, other cytogenetic findings are rarely observed in this subtype (PMID: 23175120).
Outside of monosomy 6, other cytogenetic findings are rarely observed in this subtype<ref name=":11">{{Cite journal|last=Northcott|first=Paul A.|last2=Jones|first2=David T. W.|last3=Kool|first3=Marcel|last4=Robinson|first4=Giles W.|last5=Gilbertson|first5=Richard J.|last6=Cho|first6=Yoon-Jae|last7=Pomeroy|first7=Scott L.|last8=Korshunov|first8=Andrey|last9=Lichter|first9=Peter|date=2012-12|title=Medulloblastomics: the end of the beginning|url=https://pubmed.ncbi.nlm.nih.gov/23175120|journal=Nature Reviews. Cancer|volume=12|issue=12|pages=818–834|doi=10.1038/nrc3410|issn=1474-1768|pmc=3889646|pmid=23175120}}</ref>.
|-
|-
| colspan="8" |
| colspan="8" |
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!Chromosomal Pattern
!Chromosomal Pattern
!Molecular Pathogenesis
!Molecular Pathogenesis
!'''Prevalence -'''
!Prevalence -  
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T'''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|
|
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{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene!!'''Genetic Alteration'''!!'''Tumor Suppressor Gene, Oncogene, Other'''!!'''Prevalence -'''
!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -
'''Common >20%, Recurrent 5-20% or Rare <5% (Disease)'''
Common >20%, Recurrent 5-20% or Rare <5% (Disease)
!'''Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  '''
!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  
!'''Established Clinical Significance Per Guidelines - Yes or No (Source)'''
!Established Clinical Significance Per Guidelines - Yes or No (Source)
!'''Clinical Relevance Details/Other Notes'''
!Clinical Relevance Details/Other Notes
|-
|-
|<span class="blue-text">EXAMPLE:</span>''EGFR''
|<span class="blue-text">EXAMPLE:</span>''EGFR''
Line 381: Line 298:




'''Add content below into table above''' -  
·      Characterized by constitutive activation of the WNT signaling pathway. This occurs in approximately 85-90% of WNT-subtype medulloblastomas via somatic, gain-of-function, mutations in exon 3 of the ''CTNNB1'' gene<ref name=":2" />.


·      Characterized by constitutive activation of the WNT signaling pathway. This occurs in approximately 85-90% of WNT-subtype medulloblastomas via somatic, gain-of-function, mutations in exon 3 of the ''CTNNB1'' gene (PMID: 30765705).
·      Patients without activating ''CTNNB1'' somatic mutations often have germline loss-of-function variants in ''APC'', which then also lead to constitutively increased WNT pathway signaling<ref>{{Cite journal|last=Waszak|first=Sebastian M.|last2=Northcott|first2=Paul A.|last3=Buchhalter|first3=Ivo|last4=Robinson|first4=Giles W.|last5=Sutter|first5=Christian|last6=Groebner|first6=Susanne|last7=Grund|first7=Kerstin B.|last8=Brugières|first8=Laurence|last9=Jones|first9=David T. W.|date=2018-06|title=Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort|url=https://pubmed.ncbi.nlm.nih.gov/29753700|journal=The Lancet. Oncology|volume=19|issue=6|pages=785–798|doi=10.1016/S1470-2045(18)30242-0|issn=1474-5488|pmc=5984248|pmid=29753700}}</ref>
 
·      Patients without activating ''CTNNB1'' somatic mutations often have germline loss-of-function variants in ''APC'', which then also lead to constitutively increased WNT pathway signaling (PMID: 29753700)


·      The WNT-subtype has the second highest somatic single nucleotide burden of all subgroups with ~1,800 per genome. ''DDX3X'', ''SMARCA4'', ''TP53'', ''CSNK2B'', ''PIK3CA'', and ''EPHA7'' are among the most recurrently mutated genes (PMIDs: 28726821; 22832583, 22820256, 22722829)
·      The WNT-subtype has the second highest somatic single nucleotide burden of all subgroups with ~1,800 per genome. ''DDX3X'', ''SMARCA4'', ''TP53'', ''CSNK2B'', ''PIK3CA'', and ''EPHA7'' are among the most recurrently mutated genes<ref name=":1" /><ref>{{Cite journal|last=Jones|first=David T. W.|last2=Jäger|first2=Natalie|last3=Kool|first3=Marcel|last4=Zichner|first4=Thomas|last5=Hutter|first5=Barbara|last6=Sultan|first6=Marc|last7=Cho|first7=Yoon-Jae|last8=Pugh|first8=Trevor J.|last9=Hovestadt|first9=Volker|date=2012-08-02|title=Dissecting the genomic complexity underlying medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/22832583|journal=Nature|volume=488|issue=7409|pages=100–105|doi=10.1038/nature11284|issn=1476-4687|pmc=3662966|pmid=22832583}}</ref><ref>{{Cite journal|last=Pugh|first=Trevor J.|last2=Weeraratne|first2=Shyamal Dilhan|last3=Archer|first3=Tenley C.|last4=Pomeranz Krummel|first4=Daniel A.|last5=Auclair|first5=Daniel|last6=Bochicchio|first6=James|last7=Carneiro|first7=Mauricio O.|last8=Carter|first8=Scott L.|last9=Cibulskis|first9=Kristian|date=2012-08-02|title=Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations|url=https://pubmed.ncbi.nlm.nih.gov/22820256|journal=Nature|volume=488|issue=7409|pages=106–110|doi=10.1038/nature11329|issn=1476-4687|pmc=3413789|pmid=22820256}}</ref><ref>{{Cite journal|last=Robinson|first=Giles|last2=Parker|first2=Matthew|last3=Kranenburg|first3=Tanya A.|last4=Lu|first4=Charles|last5=Chen|first5=Xiang|last6=Ding|first6=Li|last7=Phoenix|first7=Timothy N.|last8=Hedlund|first8=Erin|last9=Wei|first9=Lei|date=2012-08-02|title=Novel mutations target distinct subgroups of medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/22722829|journal=Nature|volume=488|issue=7409|pages=43–48|doi=10.1038/nature11213|issn=1476-4687|pmc=3412905|pmid=22722829}}</ref>
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
!Gene; Genetic Alteration!!'''Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)'''!!'''Prevalence (COSMIC /  TCGA / Other)'''!!'''Concomitant Mutations'''!!'''Mutually Exclusive Mutations'''
!Gene; Genetic Alteration!!Presumed Mechanism (Tumor Suppressor Gene [TSG] / Oncogene / Other)!!Prevalence (COSMIC /  TCGA / Other)!!Concomitant Mutations!!Mutually Exclusive Mutations
!'''Diagnostic Significance (Yes, No or Unknown)'''
!Diagnostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Prognostic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
!Therapeutic Significance (Yes, No or Unknown)
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|''APC''
|''APC''
|Yes
|Yes
|Yes – Favorable prognosis (PMID: 31504825)
|Yes – Favorable prognosis<ref name=":3">{{Cite journal|last=Surun|first=Aurore|last2=Varlet|first2=Pascale|last3=Brugières|first3=Laurence|last4=Lacour|first4=Brigitte|last5=Faure-Conter|first5=Cécile|last6=Leblond|first6=Pierre|last7=Bertozzi-Salomon|first7=Anne-Isabelle|last8=Berger|first8=Claire|last9=André|first9=Nicolas|date=2020-01-11|title=Medulloblastomas associated with an APC germline pathogenic variant share the good prognosis of CTNNB1-mutated medulloblastomas|url=https://pubmed.ncbi.nlm.nih.gov/31504825|journal=Neuro-Oncology|volume=22|issue=1|pages=128–138|doi=10.1093/neuonc/noz154|issn=1523-5866|pmc=6954432|pmid=31504825}}</ref>
|No
|No
|~85% of cases (PMID: 28726821); Somatic
|~85% of cases<ref name=":1" />; Somatic
|-
|-
|''APC'';  
|''APC'';  
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Loss of Function
Loss of Function
|Tumor suppressor
|Tumor suppressor
|5-10% (COSMIC; PMID: 28726821)
|5-10% (COSMIC)<ref name=":1" />
|
|
|''CTNNB1''
|''CTNNB1''
|
|
|Yes – Favorable prognosis (PMID: 31504825)
|Yes – Favorable prognosis<ref name=":3" />
|
|
|Warrant germline evaluation if identified (PMID: 32239782, 28726821); LOF of APC  leads to nuclear accumulation of β-catenin, resulting in increased WNT  signaling (PMID: 29189165)
|Warrant germline evaluation if identified<ref name=":1" /><ref name=":4">{{Cite journal|last=Orr|first=Brent A.|date=2020-05|title=Pathology, diagnostics, and classification of medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/32239782|journal=Brain Pathology (Zurich, Switzerland)|volume=30|issue=3|pages=664–678|doi=10.1111/bpa.12837|issn=1750-3639|pmc=7317787|pmid=32239782}}</ref>; LOF of APC  leads to nuclear accumulation of β-catenin, resulting in increased WNT  signaling<ref name=":5">{{Cite journal|last=Khatua|first=Soumen|last2=Song|first2=Anne|last3=Citla Sridhar|first3=Divyaswathi|last4=Mack|first4=Stephen C.|date=2018|title=Childhood Medulloblastoma: Current Therapies, Emerging Molecular Landscape and Newer Therapeutic Insights|url=https://pubmed.ncbi.nlm.nih.gov/29189165|journal=Current Neuropharmacology|volume=16|issue=7|pages=1045–1058|doi=10.2174/1570159X15666171129111324|issn=1875-6190|pmc=6120114|pmid=29189165}}</ref>
|}
|}
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.
Note: A more extensive list of mutations can be found in cBioportal (https://www.cbioportal.org/), COSMIC (https://cancer.sanger.ac.uk/cosmic), ICGC (https://dcc.icgc.org/) and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.


==Epigenomic Alterations==
==Epigenomic Alterations==


Approximately one third of medulloblastomas across all subgroups carry mutations in histone modifier genes, however, they are not unique to the WNT subtype (PMID: 29189165).
Approximately one third of medulloblastomas across all subgroups carry mutations in histone modifier genes, however, they are not unique to the WNT subtype<ref name=":5" />.


==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
·      Canonical WNT-pathway activation (PMID: 31921137)
 
*Canonical WNT-pathway activation<ref>{{Cite journal|last=Patel|first=Sonal|last2=Alam|first2=Aftab|last3=Pant|first3=Richa|last4=Chattopadhyay|first4=Samit|date=2019|title=Wnt Signaling and Its Significance Within the Tumor Microenvironment: Novel Therapeutic Insights|url=https://pubmed.ncbi.nlm.nih.gov/31921137|journal=Frontiers in Immunology|volume=10|pages=2872|doi=10.3389/fimmu.2019.02872|issn=1664-3224|pmc=6927425|pmid=31921137}}</ref>.
 
{| class="wikitable sortable"
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==Genetic Diagnostic Testing Methods==
==Genetic Diagnostic Testing Methods==


·      Chromosomes– assess for monosomy 6 (PMIDs: 32239782, 29027579)
*Chromosomes– assess for monosomy 6<ref name=":4" /><ref>{{Cite journal|last=Korshunov|first=Andrey|last2=Chavez|first2=Lukas|last3=Northcott|first3=Paul A.|last4=Sharma|first4=Tanvi|last5=Ryzhova|first5=Marina|last6=Jones|first6=David T. W.|last7=von Deimling|first7=Andreas|last8=Pfister|first8=Stefan M.|last9=Kool|first9=Marcel|date=2017-12|title=DNA-methylation profiling discloses significant advantages over NanoString method for molecular classification of medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/29027579|journal=Acta Neuropathologica|volume=134|issue=6|pages=965–967|doi=10.1007/s00401-017-1776-9|issn=1432-0533|pmid=29027579}}</ref>
*Chromosomal Microarray – assess for monosomy 6
*Sequence analysis (e.g. NGS) – assess for somatic mutations in ''CTNNB1'' and/or ''APC''
*DNA methylation profiling – tumor type and subtype classification by epigenetic signatures
*Transcriptomics – tumor type and subtype classification by gene expression signatures
 
==Familial Forms==
 
*Germline variants in ''APC'', which most commonly cause Familial Adenomatous Polyposis, may also lead to the development of WNT-activated subtype medulloblastoma<ref name=":4" /><ref name=":2" />.
 
==Additional Information==
 
*DNA methylation profiling is considered to be the current gold-standard for determining MB subgroup and subtype<ref>{{Cite journal|last=Hovestadt|first=Volker|last2=Remke|first2=Marc|last3=Kool|first3=Marcel|last4=Pietsch|first4=Torsten|last5=Northcott|first5=Paul A.|last6=Fischer|first6=Roger|last7=Cavalli|first7=Florence M. G.|last8=Ramaswamy|first8=Vijay|last9=Zapatka|first9=Marc|date=2013-06|title=Robust molecular subgrouping and copy-number profiling of medulloblastoma from small amounts of archival tumour material using high-density DNA methylation arrays|url=https://pubmed.ncbi.nlm.nih.gov/23670100|journal=Acta Neuropathologica|volume=125|issue=6|pages=913–916|doi=10.1007/s00401-013-1126-5|issn=1432-0533|pmc=3661908|pmid=23670100}}</ref><ref>{{Cite journal|last=Schwalbe|first=Edward C.|last2=Williamson|first2=Daniel|last3=Lindsey|first3=Janet C.|last4=Hamilton|first4=Dolores|last5=Ryan|first5=Sarra L.|last6=Megahed|first6=Hisham|last7=Garami|first7=Miklós|last8=Hauser|first8=Peter|last9=Dembowska-Baginska|first9=Bożena|date=2013-03|title=DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies|url=https://pubmed.ncbi.nlm.nih.gov/23291781|journal=Acta Neuropathologica|volume=125|issue=3|pages=359–371|doi=10.1007/s00401-012-1077-2|issn=1432-0533|pmc=4313078|pmid=23291781}}</ref> and is available clinically
*Good prognosis is currently thought to be due to alterations in tumour vasculature and its effects on the blood-brain barrier, making the tumor more accessible to systemic chemotherapies<ref>{{Cite journal|last=Phoenix|first=Timothy N.|last2=Patmore|first2=Deanna M.|last3=Boop|first3=Scott|last4=Boulos|first4=Nidal|last5=Jacus|first5=Megan O.|last6=Patel|first6=Yogesh T.|last7=Roussel|first7=Martine F.|last8=Finkelstein|first8=David|last9=Goumnerova|first9=Liliana|date=2016-04-11|title=Medulloblastoma Genotype Dictates Blood Brain Barrier Phenotype|url=https://pubmed.ncbi.nlm.nih.gov/27050100|journal=Cancer Cell|volume=29|issue=4|pages=508–522|doi=10.1016/j.ccell.2016.03.002|issn=1878-3686|pmc=4829447|pmid=27050100}}</ref>
*Somatic ''TP53'' mutations do not portend a worse prognosis<ref>{{Cite journal|last=Zhukova|first=Nataliya|last2=Ramaswamy|first2=Vijay|last3=Remke|first3=Marc|last4=Pfaff|first4=Elke|last5=Shih|first5=David J. H.|last6=Martin|first6=Dianna C.|last7=Castelo-Branco|first7=Pedro|last8=Baskin|first8=Berivan|last9=Ray|first9=Peter N.|date=2013-08-10|title=Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/23835706|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=31|issue=23|pages=2927–2935|doi=10.1200/JCO.2012.48.5052|issn=1527-7755|pmc=4878050|pmid=23835706}}</ref>
*Recent studies employing single-cell RNA-seq<ref>{{Cite journal|last=Hovestadt|first=Volker|last2=Smith|first2=Kyle S.|last3=Bihannic|first3=Laure|last4=Filbin|first4=Mariella G.|last5=Shaw|first5=McKenzie L.|last6=Baumgartner|first6=Alicia|last7=DeWitt|first7=John C.|last8=Groves|first8=Andrew|last9=Mayr|first9=Lisa|date=2019-08|title=Resolving medulloblastoma cellular architecture by single-cell genomics|url=https://pubmed.ncbi.nlm.nih.gov/31341285|journal=Nature|volume=572|issue=7767|pages=74–79|doi=10.1038/s41586-019-1434-6|issn=1476-4687|pmc=6754173|pmid=31341285}}</ref> are revealing transcriptional and genetic heterogeneity within this and other MB subgroups
 
 
This disease is <u>defined/characterized</u> as detailed below:


·      Chromosomal Microarray – assess for monosomy 6
*Medulloblastoma is the most common malignant pediatric brain tumor, though it can also occur in adults<ref name=":11" /><ref name=":5" /><ref>{{Cite journal|last=Ostrom|first=Quinn T.|last2=Gittleman|first2=Haley|last3=Truitt|first3=Gabrielle|last4=Boscia|first4=Alexander|last5=Kruchko|first5=Carol|last6=Barnholtz-Sloan|first6=Jill S.|date=2018-10-01|title=CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015|url=https://pubmed.ncbi.nlm.nih.gov/30445539|journal=Neuro-Oncology|volume=20|issue=suppl_4|pages=iv1–iv86|doi=10.1093/neuonc/noy131|issn=1523-5866|pmc=6129949|pmid=30445539}}</ref>. Recurrent histopathologic, radiologic, and genomic findings have resulted in the establishment of four primary molecularly-defined subgroups: WNT-activated; SHH-activated and ''TP53''-wildtype; SHH-activated and ''TP53''-mutant; and non-WNT/non-SHH<ref name=":12">{{Cite journal|last=Kool|first=Marcel|last2=Korshunov|first2=Andrey|last3=Remke|first3=Marc|last4=Jones|first4=David T. W.|last5=Schlanstein|first5=Maria|last6=Northcott|first6=Paul A.|last7=Cho|first7=Yoon-Jae|last8=Koster|first8=Jan|last9=Schouten-van Meeteren|first9=Antoinette|date=2012-04|title=Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas|url=https://pubmed.ncbi.nlm.nih.gov/22358457|journal=Acta Neuropathologica|volume=123|issue=4|pages=473–484|doi=10.1007/s00401-012-0958-8|issn=1432-0533|pmc=3306778|pmid=22358457}}</ref>. Somatic variants that cause activation of these pathways (e.g., gain-of-function variants in ''CTNNB1'' for the WNT pathway) are considered diagnostic. Of note, a subset of cases can be due to germline loss-of-function variants in the ''APC'' gene (which also result in activation of WNT signaling), which are representative of the spectrum of disorders known as Familial Adenomatous Polyposis (historically referred to as Gardner syndrome; MIM: 175100). In summary, medulloblastoma, WNT-activated, is an embryonal tumor originating in the dorsal brainstem characterized by activation of the WNT signaling pathway.


·      Sequence analysis (e.g. NGS) – assess for somatic mutations in ''CTNNB1'' and/or ''APC''
The <u>epidemiology/prevalence</u> of this disease is detailed below:


·      DNA methylation profiling – tumor type and subtype classification by epigenetic signatures
*This subtype accounts for approximately 10% of all medulloblastomas<ref name=":8" /><ref name=":11" /><ref name=":12" /><ref name=":13">{{Cite journal|last=Taylor|first=Michael D.|last2=Northcott|first2=Paul A.|last3=Korshunov|first3=Andrey|last4=Remke|first4=Marc|last5=Cho|first5=Yoon-Jae|last6=Clifford|first6=Steven C.|last7=Eberhart|first7=Charles G.|last8=Parsons|first8=D. Williams|last9=Rutkowski|first9=Stefan|date=2012-04|title=Molecular subgroups of medulloblastoma: the current consensus|url=https://pubmed.ncbi.nlm.nih.gov/22134537|journal=Acta Neuropathologica|volume=123|issue=4|pages=465–472|doi=10.1007/s00401-011-0922-z|issn=1432-0533|pmc=3306779|pmid=22134537}}</ref>.
*Most frequently observed in older children (median age 10 years<ref name=":8" /><ref name=":11" />; with a balanced male:female ratio<ref name=":13" />; Of note, this medulloblastoma subtype rarely occurs in infants and rarely metastasizes<ref>{{Cite journal|last=Kumar|first=Rahul|last2=Liu|first2=Anthony P. Y.|last3=Northcott|first3=Paul A.|date=2020-05|title=Medulloblastoma genomics in the modern molecular era|url=https://pubmed.ncbi.nlm.nih.gov/31799776|journal=Brain Pathology (Zurich, Switzerland)|volume=30|issue=3|pages=679–690|doi=10.1111/bpa.12804|issn=1750-3639|pmc=8018047|pmid=31799776}}</ref>
*Excellent prognosis for patients <16 years of age at diagnosis: >95% have a five-year overall survival<ref name=":6" /><ref name=":7" /><ref>{{Cite journal|last=Ellison|first=David W.|last2=Onilude|first2=Olabisi E.|last3=Lindsey|first3=Janet C.|last4=Lusher|first4=Meryl E.|last5=Weston|first5=Claire L.|last6=Taylor|first6=Roger E.|last7=Pearson|first7=Andrew D.|last8=Clifford|first8=Steven C.|last9=United Kingdom Children's Cancer Study Group Brain Tumour Committee|date=2005-11-01|title=beta-Catenin status predicts a favorable outcome in childhood medulloblastoma: the United Kingdom Children's Cancer Study Group Brain Tumour Committee|url=https://pubmed.ncbi.nlm.nih.gov/16258095|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=23|issue=31|pages=7951–7957|doi=10.1200/JCO.2005.01.5479|issn=0732-183X|pmid=16258095}}</ref><ref>{{Cite journal|last=Fattet|first=Sarah|last2=Haberler|first2=Christine|last3=Legoix|first3=Patricia|last4=Varlet|first4=Pascale|last5=Lellouch-Tubiana|first5=Arielle|last6=Lair|first6=Severine|last7=Manie|first7=Elodie|last8=Raquin|first8=Marie-Anne|last9=Bours|first9=Danielle|date=2009-05|title=Beta-catenin status in paediatric medulloblastomas: correlation of immunohistochemical expression with mutational status, genetic profiles, and clinical characteristics|url=https://pubmed.ncbi.nlm.nih.gov/19197950|journal=The Journal of Pathology|volume=218|issue=1|pages=86–94|doi=10.1002/path.2514|issn=1096-9896|pmid=19197950}}</ref>
*Accounts for ~15% of all adult medulloblastomas, which may have a worse prognosis than pediatric WNT-activated medulloblastoma<ref name=":10" /><ref>{{Cite journal|last=Remke|first=Marc|last2=Hielscher|first2=Thomas|last3=Northcott|first3=Paul A.|last4=Witt|first4=Hendrik|last5=Ryzhova|first5=Marina|last6=Wittmann|first6=Andrea|last7=Benner|first7=Axel|last8=von Deimling|first8=Andreas|last9=Scheurlen|first9=Wolfram|date=2011-07-01|title=Adult medulloblastoma comprises three major molecular variants|url=https://pubmed.ncbi.nlm.nih.gov/21632505|journal=Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology|volume=29|issue=19|pages=2717–2723|doi=10.1200/JCO.2011.34.9373|issn=1527-7755|pmid=21632505}}</ref><ref>{{Cite journal|last=Clifford|first=Steven C.|last2=Lannering|first2=Birgitta|last3=Schwalbe|first3=Ed C.|last4=Hicks|first4=Debbie|last5=O'Toole|first5=Kieran|last6=Nicholson|first6=Sarah Leigh|last7=Goschzik|first7=Tobias|last8=Zur Mühlen|first8=Anja|last9=Figarella-Branger|first9=Dominique|date=2015-11-17|title=Biomarker-driven stratification of disease-risk in non-metastatic medulloblastoma: Results from the multi-center HIT-SIOP-PNET4 clinical trial|url=https://pubmed.ncbi.nlm.nih.gov/26420814|journal=Oncotarget|volume=6|issue=36|pages=38827–38839|doi=10.18632/oncotarget.5149|issn=1949-2553|pmc=4770740|pmid=26420814}}</ref><ref>{{Cite journal|last=Zhao|first=Fu|last2=Ohgaki|first2=Hiroko|last3=Xu|first3=Lei|last4=Giangaspero|first4=Felice|last5=Li|first5=Chunde|last6=Li|first6=Peng|last7=Yang|first7=Zhijun|last8=Wang|first8=Bo|last9=Wang|first9=Xingchao|date=2016-07|title=Molecular subgroups of adult medulloblastoma: a long-term single-institution study|url=https://pubmed.ncbi.nlm.nih.gov/27106407|journal=Neuro-Oncology|volume=18|issue=7|pages=982–990|doi=10.1093/neuonc/now050|issn=1523-5866|pmc=4896550|pmid=27106407}}</ref>


·      Transcriptomics – tumor type and subtype classification by gene expression signatures
The <u>clinical features</u> of this disease are detailed below:


==Familial Forms==
*Cranial and spinal MRI are used for diagnosis<ref name=":2" />
*Signs and symptoms (listed below) can increase in severity over weeks to months
*Signs and symptoms - Headache; Clumsiness; Fatigue; Nausea/vomiting; Declining motor skills and/or ataxia; Vision problems and/or strabismus; Hydrocephalus
*Laboratory findings - None
 
The <u>sites of involvement</u> of this disease are detailed below:
 
*Cerebellum, cerebellar peduncle or fourth ventricle<ref name=":4" /><ref>{{Cite journal|last=Patay|first=Z.|last2=DeSain|first2=L. A.|last3=Hwang|first3=S. N.|last4=Coan|first4=A.|last5=Li|first5=Y.|last6=Ellison|first6=D. W.|date=2015-12|title=MR Imaging Characteristics of Wingless-Type-Subgroup Pediatric Medulloblastoma|url=https://pubmed.ncbi.nlm.nih.gov/26338912|journal=AJNR. American journal of neuroradiology|volume=36|issue=12|pages=2386–2393|doi=10.3174/ajnr.A4495|issn=1936-959X|pmc=4827780|pmid=26338912}}</ref>
*Origin: cells in the extracerebellar lower rhombic lip<ref>{{Cite journal|last=Gibson|first=Paul|last2=Tong|first2=Yiai|last3=Robinson|first3=Giles|last4=Thompson|first4=Margaret C.|last5=Currle|first5=D. Spencer|last6=Eden|first6=Christopher|last7=Kranenburg|first7=Tanya A.|last8=Hogg|first8=Twala|last9=Poppleton|first9=Helen|date=2010-12-23|title=Subtypes of medulloblastoma have distinct developmental origins|url=https://pubmed.ncbi.nlm.nih.gov/21150899|journal=Nature|volume=468|issue=7327|pages=1095–1099|doi=10.1038/nature09587|issn=1476-4687|pmc=3059767|pmid=21150899}}</ref>
*Metastases are much less likely to occur in this subtype relative to other MB subtypes; staging is performed using the Chang classification<ref>{{Cite journal|last=Chang|first=C. H.|last2=Housepian|first2=E. M.|last3=Herbert|first3=C.|date=1969-12|title=An operative staging system and a megavoltage radiotherapeutic technic for cerebellar medulloblastomas|url=https://pubmed.ncbi.nlm.nih.gov/4983156|journal=Radiology|volume=93|issue=6|pages=1351–1359|doi=10.1148/93.6.1351|issn=0033-8419|pmid=4983156}}</ref>
 
The <u>morphologic features</u> of this disease are detailed below:
 
*The WNT-activated subgroup is most commonly observed as an embryonal tumor with classic histology located in the cerebellum and/or fourth ventricle<ref name=":4" />
*Cases generally show a classical histologic pattern: Small round blue cell tumor; Sheets of densely packed undifferentiated (embryonal) cells; Individual cells with scant cytoplasm, high nuclear-to-cytoplasmic ratio, and salt-and-pepper chromatin; Presence of mitoses, apoptotic bodies, and Homer Wright rosettes


·      Germline variants in ''APC'', which most commonly cause Familial Adenomatous Polyposis, may also lead to the development of WNT-activated subtype medulloblastoma (PMIDs: 32239782, 30765705)
*High degree of hemorrhage relative to other subtypes
*Rare examples with anaplastic histology have been described<ref name=":9" /><ref>{{Cite journal|last=Kaur|first=Kavneet|last2=Jha|first2=Prerana|last3=Pathak|first3=Pankaj|last4=Suri|first4=Vaishali|last5=Sharma|first5=Mehar Chand|last6=Garg|first6=Ajay|last7=Suri|first7=Ashish|last8=Sarkar|first8=Chitra|date=2019-07|title=Approach to molecular subgrouping of medulloblastomas: Comparison of NanoString nCounter assay versus combination of immunohistochemistry and fluorescence in-situ hybridization in resource constrained centres|url=https://pubmed.ncbi.nlm.nih.gov/31104222|journal=Journal of Neuro-Oncology|volume=143|issue=3|pages=393–403|doi=10.1007/s11060-019-03187-y|issn=1573-7373|pmid=31104222}}</ref>
*Activated WNT pathway signaling - commonly visualized by immunohistochemical studies showing nuclear beta-catenin staining


==Additional Information==
The <u>immunophenotype</u> of this disease is detailed below:


·      DNA methylation profiling is considered to be the current gold-standard for determining MB subgroup and subtype (PMIDs: 23670100; 23291781) and is available clinically
*Majority positive for synaptophysin; INI-1 staining should be retained (positive)
*Molecular subtyping may be performed immunohistochemically using Filamin A, YAP1, GAB1 and beta-catenin<ref name=":9" /><ref name=":4" />


·      Good prognosis is currently thought to be due to alterations in tumour vasculature and its effects on the blood-brain barrier, making the tumor more accessible to systemic chemotherapies (PMID: 27050100)
Positive (universal) - Nuclear beta-catenin, Filamin A, and YAP1


·      Somatic ''TP53'' mutations do not portend a worse prognosis (PMID: 23835706)
Negative (universal) - GAB1


·      Recent studies employing single-cell RNA-seq (PMID: 31341285) are revealing transcriptional and genetic heterogeneity within this and other MB subgroups
Negative (subset) - YAP1 (in areas of heavy neuronal differentiation)


==Links==
==Links==
Line 471: Line 427:
*''[https://pecan.stjude.cloud/proteinpaint/ctnnb1 CTNNB1 entry in PeCAN]''
*''[https://pecan.stjude.cloud/proteinpaint/ctnnb1 CTNNB1 entry in PeCAN]''
*''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?coords=AA%3AAA&sn=central_nervous_system&ss=brain&hn=primitive_neuroectodermal_tumour-medulloblastoma&sh=WNT_subtype&wgs=off&id=141847&ln=CTNNB1&start=1&end=782 CTNNB1 entry in COSMIC (WNT-activated medulloblastoma)]''
*''[https://cancer.sanger.ac.uk/cosmic/gene/analysis?coords=AA%3AAA&sn=central_nervous_system&ss=brain&hn=primitive_neuroectodermal_tumour-medulloblastoma&sh=WNT_subtype&wgs=off&id=141847&ln=CTNNB1&start=1&end=782 CTNNB1 entry in COSMIC (WNT-activated medulloblastoma)]''
<br />


==References==
==References==
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