CNS5:Medulloblastoma, WNT-activated: Difference between revisions

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

 

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!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

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

!Prevalence -  

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

!Gene!!Genetic Alteration!!Tumor Suppressor Gene, Oncogene, Other!!Prevalence -

Common >20%, Recurrent 5-20% or Rare <5% (Disease)

!Diagnostic, Prognostic, and Therapeutic Significance - D, P, T  

!Established Clinical Significance Per Guidelines - Yes or No (Source)

!Clinical Relevance Details/Other Notes

·      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" />.

·      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>

·      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>

!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)

|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>