Medulloblastoma, WNT-activated

Central Nervous System Tumours(WHO Classification, 5th ed.)

(General Instructions – The focus of these pages is the clinically significant genetic alterations in each disease type. This is based on up-to-date knowledge from multiple resources such as PubMed and the WHO classification books. The CCGA is meant to be a supplemental resource to the WHO classification books; the CCGA captures in a continually updated wiki-stye manner the current genetics/genomics knowledge of each disease, which evolves more rapidly than books can be revised and published. If the same disease is described in multiple WHO classification books, the genetics-related information for that disease will be consolidated into a single main page that has this template (other pages would only contain a link to this main page). Use HUGO-approved gene names and symbols (italicized when appropriate), HGVS-based nomenclature for variants, as well as generic names of drugs and testing platforms or assays if applicable. Please complete tables whenever possible and do not delete them (add N/A if not applicable in the table and delete the examples); to add (or move) a row or column in a table, click nearby within the table and select the > symbol that appears. Please do not delete or alter the section headings. The use of bullet points alongside short blocks of text rather than only large paragraphs is encouraged. Additional instructions below in italicized blue text should not be included in the final page content. Please also see Author_Instructions and FAQs as well as contact your Associate Editor or Technical Support.)

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

WHO Classification of Disease

Structure	Disease
Book	Central Nervous System Tumours (5th ed.)
Category	Embryonal tumours
Family	Medulloblastoma
Type	Medulloblastomas, molecularly defined
Subtype(s)	Medulloblastoma, WNT-activated

WHO Essential and Desirable Genetic Diagnostic Criteria

(Instructions: The table will have the diagnostic criteria from the WHO book autocompleted; remove any non-genetics related criteria. If applicable, add text about other classification systems that define this entity and specify how the genetics-related criteria differ.)

WHO Essential Criteria (Genetics)*
WHO Desirable Criteria (Genetics)*
Other Classification

*Note: These are only the genetic/genomic criteria. Additional diagnostic criteria can be found in the WHO Classification of Tumours.

Related Terminology

(Instructions: The table will have the related terminology from the WHO autocompleted.)

Acceptable
Not Recommended

Gene Rearrangements

Put your text here and fill in the table (Instructions: Details on clinical significance such as prognosis and other important information can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

Driver Gene	Fusion(s) and Common Partner Genes	Molecular Pathogenesis	Typical Chromosomal Alteration(s)	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
EXAMPLE: ABL1	EXAMPLE: BCR::ABL1	EXAMPLE: The pathogenic derivative is the der(22) resulting in fusion of 5’ BCR and 3’ABL1.	EXAMPLE: t(9;22)(q34;q11.2)	EXAMPLE: Common (CML)	EXAMPLE: D, P, T	EXAMPLE: Yes (WHO, NCCN)	EXAMPLE: The t(9;22) is diagnostic of CML in the appropriate morphology and clinical context (add reference). This fusion is responsive to targeted therapy such as Imatinib (Gleevec) (add reference). BCR::ABL1 is generally favorable in CML (add reference).
EXAMPLE: CIC	EXAMPLE: CIC::DUX4	EXAMPLE: Typically, the last exon of CIC is fused to DUX4. The fusion breakpoint in CIC is usually intra-exonic and removes an inhibitory sequence, upregulating PEA3 genes downstream of CIC including ETV1, ETV4, and ETV5.	EXAMPLE: t(4;19)(q25;q13)	EXAMPLE: Common (CIC-rearranged sarcoma)	EXAMPLE: D		EXAMPLE: DUX4 has many homologous genes; an alternate translocation in a minority of cases is t(10;19), but this is usually indistinguishable from t(4;19) by short-read sequencing (add references).
EXAMPLE: ALK	EXAMPLE: ELM4::ALK Other fusion partners include KIF5B, NPM1, STRN, TFG, TPM3, CLTC, KLC1	EXAMPLE: Fusions result in constitutive activation of the ALK tyrosine kinase. The most common ALK fusion is EML4::ALK, with breakpoints in intron 19 of ALK. At the transcript level, a variable (5’) partner gene is fused to 3’ ALK at exon 20. Rarely, ALK fusions contain exon 19 due to breakpoints in intron 18.	EXAMPLE: N/A	EXAMPLE: Rare (Lung adenocarcinoma)	EXAMPLE: T		EXAMPLE: Both balanced and unbalanced forms are observed by FISH (add references).
EXAMPLE: ABL1	EXAMPLE: N/A	EXAMPLE: Intragenic deletion of exons 2–7 in EGFR removes the ligand-binding domain, resulting in a constitutively active tyrosine kinase with downstream activation of multiple oncogenic pathways.	EXAMPLE: N/A	EXAMPLE: Recurrent (IDH-wildtype Glioblastoma)	EXAMPLE: D, P, T

Add content below into table above -  

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
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

Individual Region Genomic Gain/Loss/LOH

Put your text here and fill in the table (Instructions: Includes aberrations not involving gene rearrangements. Details on clinical significance such as prognosis and other important information can be provided in the notes section. Can refer to CGC workgroup tables as linked on the homepage if applicable. Please include references throughout the table. Do not delete the table.)

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
EXAMPLE: 7	EXAMPLE: Loss	EXAMPLE: chr7	EXAMPLE: Unknown	EXAMPLE: D, P	EXAMPLE: No	EXAMPLE: Presence of monosomy 7 (or 7q deletion) is sufficient for a diagnosis of AML with MDS-related changes when there is ≥20% blasts and no prior therapy (add reference).  Monosomy 7/7q deletion is associated with a poor prognosis in AML (add references).
EXAMPLE: 8	EXAMPLE: Gain	EXAMPLE: chr8	EXAMPLE: Unknown	EXAMPLE: D, P		EXAMPLE: Common recurrent secondary finding for t(8;21) (add references).
EXAMPLE: 17	EXAMPLE: Amp	EXAMPLE: 17q12; chr17:39,700,064-39,728,658 [hg38; 28.6 kb]	EXAMPLE: ERBB2	EXAMPLE: D, P, T		EXAMPLE: Amplification of ERBB2 is associated with HER2 overexpression in HER2 positive breast cancer (add references). Add criteria for how amplification is defined.

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.

·      With the exception of monosomy 6, this medulloblastoma subtype usually has a balanced genome

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).	NoMedulloblastomas, molecularly defined	Presence of monosomy 6 is frequently observed, and present in 80-90% of cases. 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. 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. Outside of monosomy 6, other cytogenetic findings are rarely observed in this subtype.

Characteristic Chromosomal or Other Global Mutational Patterns

Chromosomal Pattern	Molecular Pathogenesis	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 Mutations (SNV/INDEL)

Put your text here and fill in the table (Instructions: This table is not meant to be an exhaustive list; please include only genes/alterations that are recurrent or common as well either disease defining and/or clinically significant. If a gene has multiple mechanisms depending on the type or site of the alteration, add multiple entries in the table. For clinical significance, denote associations with FDA-approved therapy (not an extensive list of applicable drugs) and NCCN or other national guidelines if applicable; Can also refer to CGC workgroup tables as linked on the homepage if applicable as well as any high impact papers or reviews of gene mutations in this entity. Details on clinical significance such as prognosis and other important information such as concomitant and mutually exclusive mutations can be provided in the notes section. Please include references throughout the table. Do not delete the table.)

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
EXAMPLE:EGFR	EXAMPLE: Exon 18-21 activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (lung cancer)	EXAMPLE: T	EXAMPLE: Yes (NCCN)	EXAMPLE: Exons 18, 19, and 21 mutations are targetable for therapy. Exon 20 T790M variants cause resistance to first generation TKI therapy and are targetable by second and third generation TKIs (add references).
EXAMPLE: TP53; Variable LOF mutations	EXAMPLE: Variable LOF mutations	EXAMPLE: Tumor Supressor Gene	EXAMPLE: Common (breast cancer)	EXAMPLE: P		EXAMPLE: >90% are somatic; rare germline alterations associated with Li-Fraumeni syndrome (add reference). Denotes a poor prognosis in breast cancer.
EXAMPLE: BRAF; Activating mutations	EXAMPLE: Activating mutations	EXAMPLE: Oncogene	EXAMPLE: Common (melanoma)	EXAMPLE: T

Note: A more extensive list of mutations can be found in cBioportal, COSMIC, and/or other databases. When applicable, gene-specific pages within the CCGA site directly link to pertinent external content.

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.

·      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

·      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

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	No	~85% of cases; Somatic
APC; Loss of Function	Tumor suppressor	5-10% (COSMIC)		CTNNB1		Yes – Favorable prognosis		Warrant germline evaluation if identified; LOF of APC leads to nuclear accumulation of β-catenin, resulting in increased WNT signaling

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.

Genes and Main Pathways Involved

• Canonical WNT-pathway activation.

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
• 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.

Additional Information

• DNA methylation profiling is considered to be the current gold-standard for determining MB subgroup and subtype 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
• Somatic TP53 mutations do not portend a worse prognosis
• Recent studies employing single-cell RNA-seq are revealing transcriptional and genetic heterogeneity within this and other MB subgroups

This disease is defined/characterized as detailed below:

• Medulloblastoma is the most common malignant pediatric brain tumor, though it can also occur in adults. 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. 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 epidemiology/prevalence of this disease is detailed below:

• This subtype accounts for approximately 10% of all medulloblastomas.
• Most frequently observed in older children (median age 10 years; with a balanced male:female ratio; Of note, this medulloblastoma subtype rarely occurs in infants and rarely metastasizes
• Excellent prognosis for patients <16 years of age at diagnosis: >95% have a five-year overall survival
• Accounts for ~15% of all adult medulloblastomas, which may have a worse prognosis than pediatric WNT-activated medulloblastoma

The clinical features of this disease are detailed below:

• Cranial and spinal MRI are used for diagnosis
• 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 sites of involvement of this disease are detailed below:

• Cerebellum, cerebellar peduncle or fourth ventricle
• Origin: cells in the extracerebellar lower rhombic lip
• Metastases are much less likely to occur in this subtype relative to other MB subtypes; staging is performed using the Chang classification

The morphologic features 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
• 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
• Activated WNT pathway signaling - commonly visualized by immunohistochemical studies showing nuclear beta-catenin staining

The immunophenotype of this disease is detailed below:

• 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

Positive (universal) - Nuclear beta-catenin, Filamin A, and YAP1

Negative (universal) - GAB1

Negative (subset) - YAP1 (in areas of heavy neuronal differentiation)

Links

• CTNNB1 entry in PeCAN
• CTNNB1 entry in COSMIC (WNT-activated medulloblastoma)

References

1.      Ellison, DW, Korshunov A, Northcott PA, Taylor MD, Kaur K, Clifford SC. Medulloblastoma, WNT-activated. In: WHO Classification of Tumours Editorial Board. Central nervous system tumours. Lyon (France): International Agency for Research on Cancer; 2021. (WHO classification of tumours series, 5th ed.; vol. 6). https://publications.iarc.fr/601.

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4.      Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2011-2015. Neuro Oncol. 2018 Oct 1;20(suppl_4):iv1-iv86. doi: 10.1093/neuonc/noy131. Erratum in: Neuro Oncol. 2018 Nov 17. PMID: 30445539

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7.      Kool M, Korshunov A, Remke M, Jones DT, Schlanstein M, Northcott PA, Cho YJ, Koster J, Schouten-van Meeteren A, van Vuurden D, Clifford SC, Pietsch T, von Bueren AO, Rutkowski S, McCabe M, Collins VP, Bäcklund ML, Haberler C, Bourdeaut F, Delattre O, Doz F, Ellison DW, Gilbertson RJ, Pomeroy SL, Taylor MD, Lichter P, Pfister SM. Molecular subgroups of medulloblastoma: an international meta-analysis of transcriptome, genetic aberrations, and clinical data of WNT, SHH, Group 3, and Group 4 medulloblastomas. Acta Neuropathol. 2012 Apr;123(4):473-84. doi: 10.1007/s00401-012-0958-8. Epub 2012 Feb 23. PMID: 22358457

8.      Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM. Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol. 2012 Apr;123(4):465-72. doi: 10.1007/s00401-011-0922-z. Epub 2011 Dec 2. PMID: 22134537

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Notes

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Prior Author(s): *Citation of this Page: “Medulloblastoma, WNT-activated”. Compendium of Cancer Genome Aberrations (CCGA), Cancer Genomics Consortium (CGC), updated 03/27/2025, https://ccga.io/index.php/CNS5:Medulloblastoma, WNT-activated.