CNS5:Medulloblastoma, WNT-activated

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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

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

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)

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)

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

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)

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). NoMedulloblastomas,

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).

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)

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)

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

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


References

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Notes

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