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Lookup NU author(s): Dr Stacey RichardsonORCiD, Dr Debbie HicksORCiD, Melissa Gough, Ellie Butler, Dr Dean Thompson, Dr Jemma CastleORCiD, Dr Stephen Crosier, Dr Ed Schwalbe, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© 2026 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Background: Infant medulloblastoma (age <3–5 years at diagnosis) is a major challenge in paediatric oncology. Clinical studies of molecularly defined non-WNT/non-SHH infant medulloblastoma (~60% of cases) have not been done, and this group is currently considered to have uniformly high risk. Understanding the potential for its biological subclassification and clinical stratification is an essential goal towards improved outcomes. This study therefore aimed to directly compare different therapeutic approaches in non-WNT/non-SHH infant medulloblastoma and assess the relationships between outcomes and clinicomolecular features. Methods: We assembled an international cohort of infants with non-WNT/non-SHH medulloblastoma identified from non-trial cohorts in nine countries. Inclusion criteria were age 0–5 years and a principal non-WNT/non-SHH medulloblastoma classification (group 3 [MBGroup3] or group 4 [MBGroup4]; confidence score >0·8) using DNA methylation array-based classification. Patient clinical and molecular data were collected from contributing institutions and centrally reviewed using standardised annotation protocols. A survival cohort was defined by the availability of complete progression-free and overall survival data, and grouped by whether principal upfront therapy included craniospinal irradiation or consisted of chemotherapy only. Chemotherapy was subclassified into high-dose, intraventricular methotrexate-based, and standard-dose regimens. We assessed the relationships between tumour molecular pathology, treatments received, and outcomes (progression-free and overall survival) using Kaplan–Meier plots, univariable log-rank tests, and Cox regression. Findings: The total collected cohort (n=375) comprised 262 males and 110 females (three patients had missing sex data), with a median age of 3·0 years (IQR 2·5–4·0). MBGroup3 tumours predominated (246 [66%] of 375 patients), among which molecular subgroups 4 (98 [40%]), 2 (75 [30%]), and 3 (46 [19%]) were most common. The remaining 129 (34%) of 375 patients had MBGroup4 tumours. 313 patients were included in the survival cohort. Upfront craniospinal irradiation was associated with significantly better 5-year progression-free survival (62% [95% CI 55–70]) than non-craniospinal irradiation approaches (including focal radiotherapy or chemotherapy-only strategies; 33% [23–44]; p<0·0001). When upfront chemotherapy-only approaches were used, high-dose chemotherapy produced better survival rates (5-year overall survival 60% [95% CI 42–87]) than standard-dose chemotherapy (27% [13–57]). Patients with MBGroup3 subgroup 4 represented a novel chemosensitive group, with 5-year progression-free survival of 64% (95% CI 44–95) when treated upfront with high-dose chemotherapy only (n=14). Patients with MBGroup3 subgroup 2 or 3 with MYC amplification (n=10) had 5-year progression-free and overall survival rates of 0% when treated with chemotherapy only. Patients with MBGroup3 subgroup 2 or 3 without MYC amplification who were treated upfront with chemotherapy only (n=10) had 5-year progression-free survival of 30% (12–77) and 5-year overall survival of 58% (34–100). Interpretation: Non-WNT/non-SHH infant medulloblastoma outcomes are associated with specific biomarkers and type of therapy received. This real-world experience identifies a favourable-risk group (MBGroup3 subgroup 4) with good prognosis and a very-high-risk group (MBGroup3 subgroup 2 or 3 with MYC amplification) with poor prognosis, providing a foundation for biomarker-driven MBGroup3 clinical trials. Funding: Cancer Research UK, Children with Cancer UK, Children's Cancer North, Star for Harris, JGW Patterson Foundation, Little Hero, and Blue Skye Thinking.
Author(s): Richardson S, Hicks D, Gough M, Butler ER, Thompson D, Castle J, Crosier S, Garcia-Ariza M, Martin-Guerrero I, Plasschaert S, Bourdeaut F, Dufour C, Masliah-Planchon J, Buttarelli FR, Biassoni V, Massimino M, Ichimura K, Kanemura Y, Ramaswamy V, Gajjar A, Mynarek M, Rutkowski S, Kool M, Pfister SM, Korshunov A, Schwalbe EC, Bailey S, Clifford SC
Publication type: Article
Publication status: Published
Journal: The Lancet Child and Adolescent Health
Year: 2026
Pages: Epub ahead of print
Online publication date: 18/05/2026
Acceptance date: 02/04/2018
Date deposited: 01/06/2026
ISSN (print): 2352-4642
ISSN (electronic): 2352-4650
Publisher: Elsevier Ltd
URL: https://doi.org/10.1016/S2352-4642(26)00067-2
DOI: 10.1016/S2352-4642(26)00067-2
Data Access Statement: Raw and processed DNA methylation microarray data and associated link-anonymised patient metadata have been deposited in the NCBI Gene Expression Omnibus (https://www.ncbi.nlm.nih.gov/geo/) with accession number GSE317378.
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