Medulloblastoma, WNT-activated

WNT tumors are medulloblastomas with aberrations in the WNT signaling pathway and represent approximately 10% of all medulloblastomas.[112] WNT medulloblastomas show a WNT signaling gene expression signature and beta-catenin nuclear staining by immunohistochemistry.[116] They are usually histologically classified as classic medulloblastoma tumors and rarely have a large cell/anaplastic appearance. WNT medulloblastomas generally occur in older patients (median age, 10 years) and are infrequently metastasized at diagnosis. Recent studies have demonstrated the value of methylation profiling in identifying WNT-activated medulloblastomas. These studies included cases that would not be detected using other current testing methods (e.g., beta-catenin immunohistochemistry, CTNNB1 variant analysis, and evaluation for monosomy 6).[117]

CTNNB1 variants are observed in 85% to 90% of WNT medulloblastoma cases, with APC variants detected in many of the cases that lack CTNNB1 variants. Patients with WNT medulloblastoma whose tumors have APC variants often have Turcot syndrome (i.e., germline APC pathogenic variants).[113] In addition to CTNNB1 variants, WNT medulloblastoma tumors show 6q loss (monosomy 6) in 80% to 90% of cases. While monosomy 6 is observed in most medulloblastoma patients younger than 18 years at diagnosis, it appears to be much less common (approximately 25% of cases) in patients older than 18 years.[112,116]

The WNT subset is primarily observed in older children, adolescents, and adults and does not show a male predominance. The subset is believed to have brain stem origin, from the embryonal rhombic lip region.[118] WNT medulloblastomas are associated with a very good outcome in children, especially in individuals whose tumors have beta-catenin nuclear staining and proven 6q loss and/or CTNNB1 variants.[107,119-121] Retrospective studies have suggested that additional TP53 variants and OTX2 copy number gains may be associated with a worse prognosis for patients with WNT medulloblastoma.[122] These latter associations need to be verified in prospective studies.[123]