Medulloblastoma, WNT-activated

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Done

Parent item

Medulloblastoma

Definition

• Essential:
• A medulloblastoma AND
• WNT pathway activation OR
• A DNA methylation profile aligned with medulloblastoma, WNT-activated

Numbers

• 10% of all medulloblastomas

• Tend to occur in older children and not in infants
• 4 years of age to early adulthood (median age of diagnosis ~11 years)

• 15% of adult medulloblastomas

CNS WHO grading

• Grade 4 but good prognosis

Origin

• Cells in the dorsal brain stem that originate from the lower rhombic lip
• Mossy fibre neuron lineage

• DNA methylation profile show that WNT-activated medulloblastoma has a profile distinct from those of other medulloblastoma subgroups → probably explains why their prognosis is so good

Localization

• Cerebellar midline +/- close association with the Foramen of Luschka, often forming broad contact with the brainstem

Mechanism

1. Canonical (Normal) Wnt signalling
• LEFT inactive Wnt signalling: Absence of Wnt ligands (Wnt signalling inactive state) → Phosphorylation of β-catenin by the destruction complex, which contains the scaffold protein Axin, APC and the kinases GSK3β and casein kinase (CK1α) → β-catenin is phosphorylated by GSK3β + ubiquitinated by β-TrCP200 + targeted for proteasomal degradation → without nuclear β-catenin, a repressive complex containing TCF/LEF and transducing-like enhancer protein (TLE/Groucho) recruits HDACs to repress target genes
• RIGHT active Wnt signalling: Binding of secreted Wnt ligands (for example, Wnt3a and Wnt1) to Frizzled receptors and LRP co-receptors → LRP receptors are then phosphorylated by CK1α and GSK3β → which recruits Dishevelled (Dvl) proteins to the plasma membrane where they polymerize and are activated. → Dvl polymers inactivate the destruction complex, for example, by sequestration in multivesicular bodies → Accumulation of β-catenin → β-catenin translocates into the nucleus → β-catenin forms an active complex with LEF (lymphoid enhancer factor) and TCF (T-cell factor) proteins by displacing TLE/Groucho complexes and recruitment of histone modifying co-activators such as CBP/p300, BRG1, BCL9 and Pygo (reviewed in Lien and Fuchs) → This transcriptional switch leads to a change of multiple cellular processes.

2. Non-canonical Wnt signalling
• Defined by β-catenin-independent mechanisms of signal transduction.
• Wnt ligands bind to the ROR-Frizzled receptor complex to recruit and activate Dvl → Dvl binds to the small GTPase Rho by de-inhibition of the cytoplasmic protein DAAM1 (Dvl associated activator of morphogenesis 1) → The small GTPase Rac1 and Rho together trigger ROCK (Rho kinase) and JNK. → causes rearrangements of the cytoskeleton and/or transcriptional responses via for example, ATF2 (activating transcription factor 2).
• Vangl, a key member of Wnt/PCP signalling is activated by phosphorylation in a Wnt5a-dependent manner.
• Wnt/Ca2+ signalling is initiated by G-protein triggered phospholipase C activity leading to intracellular calcium fluxes and downstream calcium dependent cytoskeletal and/or transcriptional responses.

Histological subtype

• Classic (nearly all)
• Low-risk tumour; classic morphology found in almost all WNT-activated tumours

• Large cell / anaplastic (very rare)
• Tumour of uncertain clinicopathological significance

Molecular subtype

• WNT-α
• Median age at diagnosis: 10
• Frequency of monosomy 6: high (almost 100%)

• WNT-β
• Median age at diagnosis: 20
• Frequency of monosomy 6: low (almost 0%)
• More inconsistent survival outcomes

Genetic profile

• Somatic mutation in exon 3 of CTNNB1 (90%)
• CTNNB1 encodes beta-catenin

• DDX3X (in 50% of cases)

• SMARCA4 (in 26.3%)

• KMT2D (in 12.5%)

• TP53 (in 12.5%).

• Monosomy of Chr 6 (85%)

• Association between APC (Adenomatous polyposis coli) germline mutation and WNT-activated medulloblastoma

Radiology

• Tumours located in
• Cerebellar midline
• Cerebellopontine angle

• Many in close contact with the brainstem

• WNT-activated medulloblastomas have a relatively porous blood-brain barrier when compared with other types of medulloblastoma, and therefore enhance very brightly

Immunophenotype

• Nuclear beta-catenin immunoreactivity

• YAP1 antibody labelled tumour cells in both WNT-activated and SHH-activated medulloblastomas, but not non-WNT/ non-SHH medulloblastomas.

• Same for all medulloblastoma

Prognosis

• Good
• Surgical approaches and adjuvant therapy regimens,
• Overall survival is close to 100%
• 5-year survival of 95% or better
• Infrequently metastatic at diagnosis

• Adult patients with WNT-activated medulloblastoma do not have such a favourable outcome