Abstract Introduction Medulloblastoma (MB) is the most common malignant paediatric brain tumour with standard-risk five-year survival approaching 75%12 . Multimodal therapy imposes substantial neurocognitive burden and diminished health-related quality of life in long-term survivors13. Identifying biological determinants of survivorship outcomes represents a priority for risk-stratified intervention345678910. Methods We undertook an integrated clinico-molecular analysis of patients from the SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Quality of survival was assessed in 218 patients using the Health Utilities Index (HUI3), Strength and Difficulties Questionnaire (SDQ), and Pediatric Quality of Life Inventory (PedsQL). Neuropsychometric assessment employed Wechsler Intelligence Scale (WISC IV) in 140 patients. Patients were classified into molecular groups (WNT, SHH, MBGrp3, MBGrp4)1112. In HIT-SIOP-PNET4 patients (n = 74), 39 single nucleotide polymorphisms with reported neurocognitive-modifying effects were genotyped by Agena MassARRAY. Results SIOP-UKCCSG-PNET3 patients receiving chemotherapy prior to craniospinal irradiation demonstrated significantly reduced health status (p = 0.019) and increased behavioural difficulties (p 0.001) compared to both conventional and hyperfractionated radiotherapy arms in HIT-SIOP-PNET4. SHH patients demonstrated superior quality of life relative to WNT and MBgrp4 (p 0.0191). Neuropsychometric performance showed no association with molecular group or clinico-demographic variables. However, 7 SNPs (rs1050450, rs11611788, rs1695, rs1801131, rs4708867, rs4880, and rs9476886) were significantly associated with WISC domains, with five showing associations across multiple cognitive domains. Conclusion This integrated analysis identifies distinct clinical and molecular determinants of survivorship outcomes. Germline genetic modifiers of neurocognitive function provide potential targets for risk stratification and targeted therapeutic development. These findings support integrating biological determinants, patient-reported outcomes, and direct neuropsychometric assessments into clinical trial design to inform risk-adapted therapeutic strategies and precision approaches to counselling, surveillance, intervention and rehabilitation. 1. S. Bailey, S. Jacobs, M. Kourti, M. Massimino, N. Andre, F. Doz, C. Dufour, S. Vennarini, L. Padovani, K. Aquilina, U. Thomale, A. Joshi, T. Pietsch, S. Avula, G. Morana, S. Rutkowski, B. Pizer, SC Clifford, Medulloblastoma therapy: Consensus treatment recommendations from SIOP-Europe and the European Reference Network, EJC Paediatric Oncology, Volume 5, 2025, 100205, ISSN 2772-610X, https://doi.org/10.1016/j.ejcped.2024.100205. 2. Mani S, Chatterjee A, Dasgupta A, Shirsat N, Epari S, Chinnaswamy G, Gupta T. WNT-pathway medulloblastoma: what constitutes low-risk and how low can one go? Oncotarget. 2023 Feb 7;14:105-110. doi: 10.18632/oncotarget.28360. PMID: 36749287; PMCID: PMC9904321. 3. Chevignard M, Câmara-Costa H, Doz F, Dellatolas G. Core deficits and quality of survival after childhood medulloblastoma: a review. Neurooncol Pract. 2017 Jun;4(2):82-97. doi: 10.1093/nop/npw013. Epub 2016 Aug 26. PMID: 31385962; PMCID: PMC6655396. 4. Frič, R., Due-Tønnessen, B.J., Lundar, T. et al. Long-term outcome of posterior fossa medulloblastoma in patients surviving more than 20 years following primary treatment in childhood. Sci Rep 10, 9371 (2020). https://doi.org/10.1038/s41598-020-66328-8 5. Aktekin, E.H., Kütük, M.Ö., Sangün, Ö. et al. Late effects of medulloblastoma treatment: multidisciplinary approach of survivors. Childs Nerv Syst 40, 417–425 (2024). https://doi.org/10.1007/s00381-023-06146-1 6. Hugo Câmara-Costa, Kim S Bull, Colin Kennedy, Andreas Wiener, Gabriele Calaminus, Anika Resch, Virginie Kieffer, Clémence Lalande, Geraldina Poggi, Katja von Hoff, Jacques Grill, François Doz, Stefan Rutkowski, Maura Massimino, Rolf-Dieter Kortmann, Birgitta Lannering, Georges Dellatolas, Mathilde Chevignard, on behalf of the Quality of Survival working group of the Brain Tumour Group of SIOP-Europe, Quality of survival and cognitive performance in children treated for medulloblastoma in the PNET 4 randomized controlled trial, Neuro-Oncology Practice, Volume 4, Issue 3, September 2017, Pages 161–170, https://doi.org/10.1093/nop/npw028 7. Bull, K.S., Kennedy, C.R., Bailey, S. et al. Improved health-related quality of life outcomes associated with SHH subgroup medulloblastoma in SIOP-UKCCSG PNET3 trial survivors. Acta Neuropathol 128, 151–153 (2014). https://doi.org/10.1007/s00401-014-1300-4 8. Kim S. Bull et al. Reduction of Health Status 7 Years After Addition of Chemotherapy to Craniospinal Irradiation for Medulloblastoma: A Follow-Up Study in PNET 3 Trial Survivors—on Behalf of the CCLG (formerly UKCCSG). JCO 25, 4239-4245(2007). DOI:10.1200/JCO.2006.08.7684 9. Colin Kennedy, Kim Bull, Mathilde Chevignard, David Culliford, Helmuth G. Dörr, François Doz, Rolf-Dieter Kortmann, Birgitta Lannering, Maura Massimino, Aurora Navajas Gutiérrez, Stefan Rutkowski, Helen A. Spoudeas, Gabriele Calaminus, Quality of Survival and Growth in Children and Young Adults in the PNET4 European Controlled Trial of Hyperfractionated Versus Conventional Radiation Therapy for Standard-Risk Medulloblastoma, International Journal of Radiation Oncology*Biology*Physics, Volume 88, Issue 2, 2014, Pages 292-300, ISSN 0360-3016, https://doi.org/10.1016/j.ijrobp.2013.09.046. 10. Hugo Câmara-Costa, Anika Resch, Virginie Kieffer, Clémence Lalande, Geraldina Poggi, Colin Kennedy, Kim Bull, Gabriele Calaminus, Jacques Grill, François Doz, Stefan Rutkowski, Maura Massimino, Rolf-Dieter Kortmann, Birgitta Lannering, Georges Dellatolas, Mathilde Chevignard, Neuropsychological Outcome of Children Treated for Standard Risk Medulloblastoma in the PNET4 European Randomized Controlled Trial of Hyperfractionated Versus Standard Radiation Therapy and Maintenance Chemotherapy, International Journal of Radiation Oncology*Biology*Physics, Volume 92, Issue 5, 2015, Pages 978-985, ISSN 0360-3016, https://doi.org/10.1016/j.ijrobp.2015.04.023. 11. Goschzik T, Schwalbe EC, Hicks D, Smith A, Zur Muehlen A, Figarella-Branger D, Doz F, Rutkowski S, Lannering B, Pietsch T, Clifford SC. Prognostic effect of whole chromosomal aberration signatures in standard-risk, non-WNT/non-SHH medulloblastoma: a retrospective, molecular analysis of the HIT-SIOP PNET 4 trial. Lancet Oncol. 2018 Dec;19(12):1602-1616. doi: 10.1016/S1470-2045(18)30532-1. Epub 2018 Nov 1. PMID: 30392813; PMCID: PMC6262170. 12. Schwalbe EC, Williamson D, Lindsey JC, Hamilton D, Ryan SL, Megahed H, Garami M, Hauser P, Dembowska-Baginska B, Perek D, Northcott PA, Taylor MD, Taylor RE, Ellison DW, Bailey S, Clifford SC. DNA methylation profiling of medulloblastoma allows robust subclassification and improved outcome prediction using formalin-fixed biopsies. Acta Neuropathol. 2013 Mar;125(3):359-71. doi: 10.1007/s00401-012-1077-2. Epub 2013 Jan 5. PMID: 23291781; PMCID: PMC4313078.
Butler et al. (Tue,) studied this question.