View source for CNS5:Medulloblastoma, WNT-activated

==Primary Author(s)*==

Lisa Lansdon, PhD, Children's Mercy Hospital, University of Missouri–Kansas City

Midhat Farooqi, MD, Children's Mercy Hospital, University of Missouri–Kansas City

__TOC__

==Cancer Category/Type==

Medulloblastomas, molecularly defined

==Cancer Sub-Classification / Subtype==

Medulloblastoma, WNT-activated

==Definition / Description of Disease==

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"
|'''Signs and Symptoms'''
|Headache

Clumsiness

Fatigue

Nausea/vomiting

Declining motor skills and/or ataxia

Vision problems and/or strabismus

Hydrocephalus
|-
|'''Laboratory Findings'''
|None
|}

==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)
|}

==Chromosomal Rearrangements (Gene Fusions)==

{| class="wikitable sortable"
|-
!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
|-
|RAP1A-TMIGD3

1p13.2; 1p13.2
|Unknown
|Unknown
|Rare (estimated ≤5% of medulloblastoma)
|Unknown
|Unknown
|Unknown
|PMID: 33681213
|-
|ARID1A-PHACTR4

1p36.11; 1p35.3
|ARID1A (5’); PHACTR4 (3’)
|Exons 1-4 ARID1A; Exons 11-15 PHACTR4
|Rare (estimated ≤2% of medulloblastoma)
|Unknown
|Unknown
|Unknown
|PMID: 33681213
|-
| colspan="8" |
|}		
			
==Individual Region Genomic Gain/Loss/LOH==

·      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 (PMID: 22832581)
{| 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
|-
|6
|Loss
|Chr6:1-170,805,979- [hg38]
|Chr6
|Yes
|Yes – Monosomy 6 is associated with very good outcome in pediatric  patients (PDQ, PMIDs: 24791927, 21267586, 17012043).
|No<span lang="EN-US">Medulloblastomas,

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. 


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). 


Outside of monosomy 6, other cytogenetic findings are rarely  observed in this subtype (PMID: 23175120).
|-
| colspan="8" |
|}
==Characteristic Chromosomal Patterns==

N/A
==Gene Mutations (SNV/INDEL)==

·      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 (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)
{| 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
|-
|''CTNNB1''; Activating;  Exon 3
|Oncogene
|85% (WNT-subtype medulloblastoma cases in COSMIC)
|Often observed with monosomy 6
|''APC''
|Yes
|Yes – Favorable prognosis (PMID: 31504825)
|No
|~85% of cases (PMID: 28726821);  Somatic
|-
|''APC''; 

Loss of Function
|Tumor suppressor
|5-10% (COSMIC; PMID: 28726821)
|
|''CTNNB1''
|
|Yes – Favorable prognosis (PMID: 31504825)
|
|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)
|}
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==

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).

==Genes and Main Pathways Involved==

·      Canonical WNT-pathway activation (PMID: 31921137)
{| class="wikitable sortable"
|-
!Gene; Genetic Alteration!!Pathway!!Pathophysiologic Outcome
|-
|''CTNNB1''; Activating  mutations in exon 3 (especially at amino acid residues p.D32, p.S33, p.G34,  and p.S37; COSMIC, PeCAN)
|Canonical WNT-signaling
|Promotes cell proliferation and differentiation

Promotes immune tolerance

Promotes epithelial-mesenchymal transition 
|-
| colspan="3" |
|}
==Genetic Diagnostic Testing Methods==

·      Chromosomes– assess for monosomy 6 (PMIDs: 32239782, 29027579)

·      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 (PMIDs: 32239782, 30765705)

==Additional Information==

·      DNA methylation profiling is considered to be the current gold-standard for determining MB subgroup and subtype (PMIDs: 23670100; 23291781) 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 (PMID: 27050100)

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

·      Recent studies employing single-cell RNA-seq (PMID: 31341285) are revealing transcriptional and genetic heterogeneity within this and other MB subgroups

==Links==

*''[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)]''

<br />

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<references />
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==Notes==
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