# WNT-activated medulloblastoma

Source: https://onco.cc/cancers/medulloblastoma-wnt/  
OnCo record `medulloblastoma-wnt` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

WNT 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.

The 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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: WNT medulloblastoma; WNT-subgroup medulloblastoma; CTNNB1-mutant medulloblastoma
- Tags: subtype-page; paediatric; cns
- 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

## Standard of care

- Non-metastatic, standard therapy: Maximal safe resection, 23.4 Gy craniospinal radiotherapy with tumour-bed boost (protons where available), then cisplatin, vincristine and cyclophosphamide or lomustine. ([Proton therapy](https://onco.cc/technologies/proton-therapy/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Vincristine](https://onco.cc/drugs/vincristine/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Lomustine (CCNU)](https://onco.cc/drugs/lomustine/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/))
- Non-metastatic, de-escalation trials: 15 Gy (SJMB12) or 18 Gy (ACNS1422) craniospinal radiotherapy with reduced boost and fewer chemotherapy cycles, judged against historical survival. ([Proton therapy](https://onco.cc/technologies/proton-therapy/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Vincristine](https://onco.cc/drugs/vincristine/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [St. Jude Children's Research Hospital](https://onco.cc/institutions/st-jude/), [Children's Oncology Group (COG)](https://onco.cc/institutions/childrens-oncology-group/))
- Metastatic or residual disease: High-risk therapy: 36 Gy craniospinal radiotherapy with boost and intensified chemotherapy, as for other groups. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Vincristine](https://onco.cc/drugs/vincristine/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/))
- Survivorship: Neurocognitive, audiological, endocrine and second-tumour follow-up for life. ([Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Medulloblastoma
- Wikipedia: Medulloblastoma: https://en.wikipedia.org/wiki/Medulloblastoma
- NCI PDQ: Childhood Medulloblastoma Treatment: https://www.cancer.gov/types/brain/hp/child-cns-embryonal-treatment-pdq

## Connected records

- cancers: [Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)](https://onco.cc/cancers/medulloblastoma-group-3-4/), [Medulloblastoma](https://onco.cc/cancers/medulloblastoma/), [SHH-activated medulloblastoma](https://onco.cc/cancers/medulloblastoma-shh/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [IMRT / IGRT (modern external beam)](https://onco.cc/technologies/imrt-igrt/), [Proton therapy](https://onco.cc/technologies/proton-therapy/), [Survivorship care and late-effects surveillance](https://onco.cc/technologies/survivorship-care-plan/)
- institutions: [Children's Oncology Group (COG)](https://onco.cc/institutions/childrens-oncology-group/), [SIOP Europe (European Society for Paediatric Oncology)](https://onco.cc/institutions/siop-europe/), [St. Jude Children's Research Hospital](https://onco.cc/institutions/st-jude/)
- pathways: [Wnt / β-catenin](https://onco.cc/pathways/wnt/)
- terms: [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Medulloblastoma molecular groups (WNT, SHH, group 3, group 4)](https://onco.cc/terms/medulloblastoma-molecular-groups/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Lomustine (CCNU)](https://onco.cc/drugs/lomustine/), [Vincristine](https://onco.cc/drugs/vincristine/)
- trials: [COG ACNS0331](https://onco.cc/trials/acns0331/)

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