{"entity":{"id":"medulloblastoma-wnt","kind":"cancer","name":"WNT-activated medulloblastoma","aka":["WNT medulloblastoma","WNT-subgroup medulloblastoma","CTNNB1-mutant medulloblastoma"],"tldr":"WNT-activated medulloblastoma is the rarest and most curable of the four molecular groups of medulloblastoma, a brain tumour of the cerebellum. It is driven by a mutation in the beta-catenin gene that switches the WNT growth pathway on. Almost every child is cured with standard therapy, so current trials are asking how much radiotherapy and chemotherapy can be taken away.","summary":"Medulloblastoma was split into four molecular groups by gene-expression studies between 2006 and 2012, and the WHO classification adopted them in 2016. WNT-activated tumours carry an activating CTNNB1 (beta-catenin) mutation in about 90 percent, with monosomy 6 in most and germline APC mutations (Turcot syndrome) in some of the rest; nuclear beta-catenin on immunohistochemistry is the practical marker and DNA methylation profiling the reference test. They arise not from the cerebellar granule cell lineage but from the lower rhombic lip of the brainstem, so they sit in the midline against the brainstem and cerebellar peduncle, have classic histology, occur in children over seven and in adolescents, and are almost never metastatic at diagnosis.\n\nWNT patients treated on the average-risk regimens of the 2000s, 23.4 Gy craniospinal radiotherapy with a posterior fossa or tumour-bed boost followed by cisplatin, vincristine and cyclophosphamide or lomustine, almost all survived: pooled analyses of the SIOP PNET3 and HIT-SIOP PNET4 cohorts and the St Jude SJMB03 trial each found WNT tumours to have the best outcome of any group, with few if any relapses. Because the cost of that therapy in a ten-year-old is intellectual decline, hearing loss, growth and hormone failure and second tumours, both cooperative groups opened de-escalation trials: SJMB12 gives WNT patients 15 Gy craniospinal radiotherapy with a reduced boost and four rather than seven cycles of chemotherapy, and COG ACNS1422 gives 18 Gy craniospinal radiotherapy with reduced chemotherapy for non-metastatic WNT tumours with no residual disease. Both are single-arm studies judged against the historical rate.\n\nThe open questions are whether radiotherapy can be cut further, or omitted in favour of chemotherapy alone in the youngest patients; how to treat the rare metastatic or adult WNT tumour, which may not share the excellent prognosis; and whether the mutant beta-catenin pathway itself can be drugged, since no WNT inhibitor has reached the clinic in this disease. Because WNT tumours invade the brainstem, surgeons are advised against chasing the last few millimetres of tumour: residual disease under 1.5 square centimetres does not worsen outcome and brainstem injury does.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Medulloblastoma","links":[{"label":"Wikipedia: Medulloblastoma","url":"https://en.wikipedia.org/wiki/Medulloblastoma"},{"label":"NCI PDQ: Childhood Medulloblastoma Treatment","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}],"tags":["subtype-page","paediatric","cns"],"related":["medulloblastoma-shh","medulloblastoma-group-3-4"],"cancers":[],"sections":[],"technologies":["proton-therapy","methylation-profiling"],"targets":[],"drugs":[],"companies":[],"institutions":["st-jude","childrens-oncology-group","siop-europe"],"pathways":["wnt"],"terms":["late-effects","medulloblastoma-molecular-groups"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"group":"paediatric","burden":"About one medulloblastoma in ten is WNT-activated; it affects older children and adolescents and has the best outlook of the four molecular groups, with almost every child cured in trial cohorts.","subtypes":["WNT-activated medulloblastoma, CTNNB1-mutant with monosomy 6 (about 90 percent)","WNT-activated medulloblastoma with germline APC mutation (Turcot syndrome)","Metastatic WNT-activated medulloblastoma (rare; standard high-risk therapy)","WNT-activated medulloblastoma in adults (uncertain whether the childhood prognosis holds)"],"biomarkers":["Nuclear beta-catenin immunohistochemistry","CTNNB1 exon 3 mutation","Monosomy 6","DNA methylation profiling","APC germline testing","Spinal MRI and CSF cytology staging"],"standardOfCare":[{"setting":"Non-metastatic, standard therapy","approach":"Maximal safe resection, 23.4 Gy craniospinal radiotherapy with tumour-bed boost (protons where available), then cisplatin, vincristine and cyclophosphamide or lomustine.","refs":["proton-therapy","imrt-igrt","cisplatin","vincristine","cyclophosphamide","lomustine","methylation-profiling"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Non-metastatic, de-escalation trials","approach":"15 Gy (SJMB12) or 18 Gy (ACNS1422) craniospinal radiotherapy with reduced boost and fewer chemotherapy cycles, judged against historical survival.","refs":["proton-therapy","cisplatin","vincristine","cyclophosphamide","methylation-profiling","st-jude","childrens-oncology-group"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Metastatic or residual disease","approach":"High-risk therapy: 36 Gy craniospinal radiotherapy with boost and intensified chemotherapy, as for other groups.","refs":["carboplatin","cisplatin","cyclophosphamide","vincristine","imrt-igrt"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}},{"setting":"Survivorship","approach":"Neurocognitive, audiological, endocrine and second-tumour follow-up for life.","refs":["late-effects","survivorship-care-plan"],"guideline":{"version":"NCI PDQ: Childhood Medulloblastoma and Other CNS Embryonal Tumors Treatment (health professional version)","url":"https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq"}}],"stateOfArt":["WNT-activated medulloblastoma has the best outcome of any group, with few relapses on average-risk therapy.","SJMB12 and ACNS1422 are testing reduced craniospinal radiotherapy and chemotherapy specifically for WNT patients.","Nuclear beta-catenin and methylation profiling identify the group reliably at diagnosis."],"history":[{"year":2006,"title":"Gene-expression studies first separate a WNT subgroup of medulloblastoma","refs":[]},{"year":2012,"title":"Consensus on four molecular groups: WNT, SHH, group 3 and group 4","refs":[]},{"year":2013,"title":"SJMB12 opens with reduced therapy for WNT patients","refs":["st-jude"]},{"year":2016,"title":"WHO adopts molecular groups; ACNS1422 opens with 18 Gy craniospinal radiotherapy for WNT tumours","refs":["childrens-oncology-group"]},{"year":2021,"title":"WHO 2021 defines medulloblastoma by molecular group with methylation profiling","refs":["methylation-profiling"]}],"pipeline":["proton-therapy","methylation-profiling","germline-testing"],"openProblems":["How far craniospinal radiotherapy can be reduced without losing cures.","Whether adult and metastatic WNT tumours share the childhood prognosis.","No drug targets the mutant beta-catenin pathway."],"parent":"medulloblastoma"},"route":"/cancers/medulloblastoma-wnt/","neighbours":{"cancer":[{"id":"medulloblastoma-group-3-4","kind":"cancer","name":"Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)","route":"/cancers/medulloblastoma-group-3-4/"},{"id":"medulloblastoma","kind":"cancer","name":"Medulloblastoma","route":"/cancers/medulloblastoma/"},{"id":"medulloblastoma-shh","kind":"cancer","name":"SHH-activated medulloblastoma","route":"/cancers/medulloblastoma-shh/"}],"technology":[{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"germline-testing","kind":"technology","name":"Germline (hereditary) testing","route":"/technologies/germline-testing/"},{"id":"imrt-igrt","kind":"technology","name":"IMRT / IGRT (modern external beam)","route":"/technologies/imrt-igrt/"},{"id":"proton-therapy","kind":"technology","name":"Proton therapy","route":"/technologies/proton-therapy/"},{"id":"survivorship-care-plan","kind":"technology","name":"Survivorship care and late-effects surveillance","route":"/technologies/survivorship-care-plan/"}],"institution":[{"id":"childrens-oncology-group","kind":"institution","name":"Children's Oncology Group (COG)","route":"/institutions/childrens-oncology-group/"},{"id":"siop-europe","kind":"institution","name":"SIOP Europe (European Society for Paediatric Oncology)","route":"/institutions/siop-europe/"},{"id":"st-jude","kind":"institution","name":"St. Jude Children's Research Hospital","route":"/institutions/st-jude/"}],"pathway":[{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"late-effects","kind":"term","name":"Late effects and survivorship toxicity","route":"/terms/late-effects/"},{"id":"medulloblastoma-molecular-groups","kind":"term","name":"Medulloblastoma molecular groups (WNT, SHH, group 3, group 4)","route":"/terms/medulloblastoma-molecular-groups/"}],"drug":[{"id":"carboplatin","kind":"drug","name":"Carboplatin","route":"/drugs/carboplatin/"},{"id":"cisplatin","kind":"drug","name":"Cisplatin","route":"/drugs/cisplatin/"},{"id":"cyclophosphamide","kind":"drug","name":"Cyclophosphamide","route":"/drugs/cyclophosphamide/"},{"id":"lomustine","kind":"drug","name":"Lomustine (CCNU)","route":"/drugs/lomustine/"},{"id":"vincristine","kind":"drug","name":"Vincristine","route":"/drugs/vincristine/"}],"trial":[{"id":"acns0331","kind":"trial","name":"COG ACNS0331","route":"/trials/acns0331/"}]}}