# SHH-activated medulloblastoma

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

## TL;DR

SHH-activated medulloblastoma is driven by the sonic hedgehog growth pathway, the signal that normally tells the developing cerebellum to grow. In infants it is often cured with chemotherapy alone and no radiotherapy; in adults it responds for a time to hedgehog-blocking pills such as vismodegib; and when it carries a TP53 mutation in an older child, often inherited, it resists everything.

## Summary

The SHH group arises from cerebellar granule neuron precursors and is defined by activation of the sonic hedgehog pathway: loss of PTCH1 or SUFU, activating SMO mutations, or amplification of GLI2 or MYCN downstream. Age fixes the biology. Infants have PTCH1 or SUFU alterations (germline in a fifth, including Gorlin syndrome), desmoplastic/nodular or extensive-nodularity histology and a good prognosis; adults have PTCH1 and SMO mutations and an intermediate outcome; children aged around eight to seventeen carry TP53 mutations, half of them germline (Li-Fraumeni syndrome), with GLI2 and MYCN amplification and chromothripsis, and do very badly. WHO 2021 therefore splits SHH-activated tumours into TP53-wildtype and TP53-mutant.

The German HIT-SKK'92 trial, reported in the New England Journal of Medicine in 2005, treated infants with cyclophosphamide, vincristine, methotrexate, carboplatin, etoposide and intraventricular methotrexate without radiotherapy and found that desmoplastic histology, which is nearly all SHH, predicted a high cure rate, so radiotherapy-sparing chemotherapy became the infant standard; ACNS1221, which tried to reproduce this without the intraventricular methotrexate, closed early for excess relapses, showing the intraventricular drug matters. For children over three, SHH tumours receive the same craniospinal radiotherapy and chemotherapy as other groups, and TP53-mutant SHH disease relapses despite it: a 2013 pooled analysis found five-year overall survival of 41 percent with a TP53 mutation against 81 percent without in the SHH group. Smoothened inhibitors developed for basal cell carcinoma were tested by the Pediatric Brain Tumor Consortium: vismodegib produced responses only in SHH tumours with upstream PTCH1 or SMO lesions, mostly in adults, that lasted months, and it fuses growth plates in growing children, so it is limited to skeletally mature patients.

Nothing yet helps TP53-mutant SHH disease, which resists radiotherapy and chemotherapy and cannot use SMO inhibitors because its pathway activation is downstream; CDK4/6 inhibitors, bromodomain inhibitors aimed at GLI and MYCN, and immunotherapy are in early trials, and germline TP53 testing at diagnosis matters for the family and for avoiding radiotherapy-induced second tumours. For infants the question is which SHH tumours can be cured with less: SJYC07 and the current SIOP and COG trials stratify by methylation subtype, with high-dose chemotherapy and stem cell rescue kept for the poorer subgroups. Adult SHH medulloblastoma is treated with craniospinal radiotherapy and, increasingly, chemotherapy, with SMO inhibitors reserved for relapse in patients whose tumours carry an upstream mutation.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: SHH medulloblastoma; Sonic hedgehog medulloblastoma; Desmoplastic/nodular medulloblastoma; SHH-activated TP53-mutant medulloblastoma
- Tags: subtype-page; paediatric; cns
- Group: paediatric
- Burden: About three medulloblastomas in ten are SHH-activated; they cluster in infants under three and in adults, and the TP53-mutant form in older children is among the childhood brain tumours with the lowest survival.
- Subtypes: SHH-activated medulloblastoma, TP53-wildtype, in infants (PTCH1 or SUFU; desmoplastic/nodular or extensive nodularity; chemotherapy without radiotherapy); SHH-activated medulloblastoma, TP53-wildtype, in children and adults (PTCH1, SMO); SHH-activated medulloblastoma, TP53-mutant (children 8 to 17; often germline Li-Fraumeni; GLI2 and MYCN amplification; very poor); SHH-activated medulloblastoma in Gorlin syndrome (germline PTCH1 or SUFU; radiotherapy causes field basal cell carcinomas); Adult SHH medulloblastoma with upstream PTCH1 or SMO mutation (smoothened inhibitor-responsive)
- Biomarkers: GAB1, YAP1 and filamin A immunohistochemistry for SHH; PTCH1, SUFU and SMO mutations; TP53 mutation, somatic and germline; GLI2 and MYCN amplification; DNA methylation subtype (SHH infant, child, adult); Germline PTCH1, SUFU and TP53 testing; Chromosome 9q loss

## Sections of this record

The page is a hub with ten sections in reading order; large sections have their own page. The same plan as JSON: https://onco.cc/api/v1/cancers/medulloblastoma-shh/sections.json

- Overview (on the hub): The TL;DR, the family this cancer belongs to, the organ, who gets it and what the state of the art is. https://onco.cc/cancers/medulloblastoma-shh/#overview [3 state-of-the-art points]
- Types and stages (on the hub): Anatomy, the subtypes and how they differ, how it is staged, and where advanced disease spreads. https://onco.cc/cancers/medulloblastoma-shh/#what-it-is [5 subtypes]
- Symptoms and diagnosis (on the hub): How this cancer shows itself, how the diagnosis is confirmed, and the biomarkers clinicians test for. https://onco.cc/cancers/medulloblastoma-shh/#finding-it [7 biomarkers]
- Treatment (on the hub): The standard of care by setting, the medicines, surgery and radiotherapy named in it, and the regimens behind them. https://onco.cc/cancers/medulloblastoma-shh/#treating-it [5 settings, 4 decisions with options]
- Trials and papers (on the hub): Trials recruiting now, the landmark trials, the trials held by this cancer's subtypes, the key papers and what they mean, the latest literature, and the milestones year by year. https://onco.cc/cancers/medulloblastoma-shh/#evidence [1 trial, 5 key papers, 7 milestones]
- Biology and targets (on the hub): The molecular landscape: the targets and how often each appears, the pathways, the mechanics stages and the preclinical models. https://onco.cc/cancers/medulloblastoma-shh/#science [4 targets, 1 pathway]
- Countries and centres (own page): Cases by country, the UK and NHS pathway and other country lenses, the expert centres with trials on record, and the centres named on this cancer's subtypes. https://onco.cc/cancers/medulloblastoma-shh/where-you-are/ [2 centres]
- Decisions and support (on the hub): The decisions you may face, the aids that walk through them, the warnings on record, the first sixty days and the questions to ask. https://onco.cc/cancers/medulloblastoma-shh/#living-with-it [18 questions, 6 red cards]
- Pipeline and open problems (own page): Everything in development, the medicines held by this cancer's subtypes, the open problems and what is being done about them, the roadmaps, and what changed on this record. https://onco.cc/cancers/medulloblastoma-shh/coming/ [11 medicines, 1 trial, 3 open problems]
- Data (own page): Every connected record, the notes, the JSON, Markdown and RDF twins, and where the record came from and when it was checked. https://onco.cc/cancers/medulloblastoma-shh/data/ [51 connected records]

## Standard of care

- Infants under three, TP53-wildtype: HIT-SKK-type chemotherapy with intraventricular methotrexate and no radiotherapy; high-dose chemotherapy with stem cell rescue for poorer methylation subtypes. ([Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Vincristine](https://onco.cc/drugs/vincristine/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Carboplatin](https://onco.cc/drugs/carboplatin/), [Etoposide](https://onco.cc/drugs/etoposide/), [Thiotepa](https://onco.cc/drugs/thiotepa/), [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/))
- Children over three and adults, TP53-wildtype: Maximal safe resection, craniospinal radiotherapy (23.4 Gy average risk, 36 Gy high risk) with boost, 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/))
- TP53-mutant: High-risk therapy with germline testing of the child and family; trials of novel agents; radiotherapy weighed against second-tumour risk in Li-Fraumeni syndrome. ([Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Vincristine](https://onco.cc/drugs/vincristine/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [TP53](https://onco.cc/targets/tp53/), [Li-Fraumeni syndrome (germline TP53)](https://onco.cc/terms/li-fraumeni/))
- Relapsed, skeletally mature, upstream PTCH1 or SMO lesion: Vismodegib or sonidegib for temporary control; other relapses receive temozolomide-based chemotherapy or re-irradiation. ([Vismodegib](https://onco.cc/drugs/vismodegib/), [Sonidegib](https://onco.cc/drugs/sonidegib/), [Smoothened (hedgehog pathway)](https://onco.cc/targets/smoothened/), [Hedgehog signalling](https://onco.cc/pathways/hedgehog/), [Temozolomide](https://onco.cc/drugs/temozolomide/))
- Survivorship: Neurocognitive, endocrine and hearing follow-up; skin surveillance for basal cell carcinoma in Gorlin syndrome after radiotherapy. ([Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Secondary malignancy (therapy-related cancer)](https://onco.cc/terms/secondary-malignancy/))

## State of the art

- Infants with desmoplastic SHH tumours are cured with chemotherapy including intraventricular methotrexate and no radiotherapy.
- TP53 status splits SHH medulloblastoma into a curable disease and one that is rarely cured; germline testing is part of diagnosis.
- Smoothened inhibitors work only in upstream-mutant tumours in skeletally mature patients and for months rather than years.

## Open problems

- No therapy improves TP53-mutant SHH medulloblastoma.
- Smoothened inhibitors fuse growth plates and fail against downstream activation.
- Which infant SHH tumours can safely receive less chemotherapy.

## 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: [Basal cell carcinoma](https://onco.cc/cancers/basal-cell-carcinoma/), [Group 3 and group 4 medulloblastoma (non-WNT/non-SHH)](https://onco.cc/cancers/medulloblastoma-group-3-4/), [Medulloblastoma](https://onco.cc/cancers/medulloblastoma/), [WNT-activated medulloblastoma](https://onco.cc/cancers/medulloblastoma-wnt/)
- technologies: [Autologous stem cell transplant (high-dose therapy)](https://onco.cc/technologies/autologous-stem-cell-transplant/), [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/)
- targets: [PTCH1 (Patched 1)](https://onco.cc/targets/ptch1/), [Smoothened (hedgehog pathway)](https://onco.cc/targets/smoothened/), [TP53](https://onco.cc/targets/tp53/)
- companies: [Children's Oncology Group (COG)](https://onco.cc/companies/childrens-oncology-group/)
- institutions: [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: [Hedgehog signalling](https://onco.cc/pathways/hedgehog/)
- terms: [Late effects and survivorship toxicity](https://onco.cc/terms/late-effects/), [Li-Fraumeni syndrome (germline TP53)](https://onco.cc/terms/li-fraumeni/), [Medulloblastoma molecular groups (WNT, SHH, group 3, group 4)](https://onco.cc/terms/medulloblastoma-molecular-groups/), [Secondary malignancy (therapy-related cancer)](https://onco.cc/terms/secondary-malignancy/)
- key papers: [Intertumoural heterogeneity within medulloblastoma subgroups](https://onco.cc/key-papers/paper-cavalli-medulloblastoma-subtypes-cancer-cell-2017/), [Molecular subgroups of medulloblastoma: the current consensus](https://onco.cc/key-papers/paper-taylor-medulloblastoma-consensus-acta-neuropathol-2012/), [Subgroup-specific prognostic implications of TP53 mutation in medulloblastoma](https://onco.cc/key-papers/paper-zhukova-tp53-medulloblastoma-jco-2013/), [The 2021 WHO classification of tumours of the central nervous system: a summary](https://onco.cc/key-papers/paper-who-2021-cns-louis-neuro-oncology-2021/), [Vismodegib in recurrent sonic hedgehog-subgroup medulloblastoma (PBTC-025B and PBTC-032)](https://onco.cc/key-papers/paper-robinson-vismodegib-shh-medulloblastoma-jco-2015/)
- drugs: [Carboplatin](https://onco.cc/drugs/carboplatin/), [Cisplatin](https://onco.cc/drugs/cisplatin/), [Cyclophosphamide](https://onco.cc/drugs/cyclophosphamide/), [Etoposide](https://onco.cc/drugs/etoposide/), [Lomustine (CCNU)](https://onco.cc/drugs/lomustine/), [Methotrexate](https://onco.cc/drugs/methotrexate/), [Sonidegib](https://onco.cc/drugs/sonidegib/), [Temozolomide](https://onco.cc/drugs/temozolomide/), [Thiotepa](https://onco.cc/drugs/thiotepa/), [Vincristine](https://onco.cc/drugs/vincristine/), [Vismodegib](https://onco.cc/drugs/vismodegib/)
- people: [Giles W. Robinson](https://onco.cc/people/giles-robinson/)
- trials: [SJMB12](https://onco.cc/trials/sjmb12/)

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JSON: https://onco.cc/api/v1/entities/medulloblastoma-shh.json