Compendium of Cancer Genome Aberrations

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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.)]]


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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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|Subtype(s)
|Subtype(s)
|Medulloblastoma, WNT-activated
|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)
|}
|}


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'''Add content below into table above''' -  
{| class="wikitable sortable"
{| class="wikitable sortable"
|-
|-
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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. (PMIDs: 16567768; 28726821; 17172831; 30765705)
·      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)


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'''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 (PMID: 30765705).
·      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).


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==Genes and Main Pathways Involved==
==Genes and Main Pathways Involved==
·      Canonical WNT-pathway activation (PMID: 31921137)
 
* Canonical WNT-pathway activation (PMID: 31921137)
 
{| class="wikitable sortable"
{| 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 (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


·      Chromosomal Microarray – assess for monosomy 6
==Familial Forms==


·      Sequence analysis (e.g. NGS) – assess for somatic mutations in ''CTNNB1'' and/or ''APC''
* 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)


·      DNA methylation profiling – tumor type and subtype classification by epigenetic signatures
==Additional Information==


·      Transcriptomics – tumor type and subtype classification by gene expression signatures
* 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


==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)
This disease is <u>defined/characterized</u> as detailed below:
 
* 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 tumor originating in the dorsal brainstem characterized by activation of the WNT signaling pathway.
 
The <u>epidemiology/prevalence</u> of this disease is detailed below:
 
* 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)
 
The <u>clinical features</u> of this disease are detailed below:
 
* Cranial and spinal MRI are used for diagnosis (PMID: 30765705)
* 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 (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)
 
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 (PMID: 32239782)
* 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
 
* 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


==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 (PMIDs: 32239782, 21267586)


·      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==
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*''[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==
Retrieved from "https://test.ccga.io/index.php/CNS5:Medulloblastoma,_WNT-activated"