MEDB-71. Molecular characterisation of group 4 medulloblastoma improves risk-stratification and its biological understanding

Jack Goddard, Jemma Castle, Emily Southworth, Anya Fletcher, Stephen Crosier, Idoia Martin-Guerrero, Miguel Garcia-Ariza, Aurora Navajas, Julien Masliah-Planchon, Franck Bourdeaut, Christelle Dufour, Tobias Goschizk, Torsten Pietsch, Stacey Richardson, Rebecca M Hill, Daniel Williamson, Simon Bailey, Edward C Schwalbe, Steven C Clifford, Debbie Hicks

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Abstract

Group 4 (MBGrp4) accounts for ~40% of medulloblastoma and the majority of non-WNT/non-SHH cases, yet its underpinning biology is poorly understood, and survival outcomes are not sufficiently explained by established clinico-pathological risk factors. We investigated the clinical and molecular correlates of MBGrp4, including second-generation methylation non-WNT/non-SHH subtypes (I-VIII) and whole chromosome aberration (WCA) subtypes (defined by chromosome 7 gain, 8 loss, and 11 loss; WCA-favourable risk [WCA-FR] ≥2 features, WCA-high risk [WCA-HR] ≤1 feature). A clinically-annotated MBGrp4 discovery cohort (n=378) was assembled from UK CCLG institutions, collaborating centres and SIOP-UKCCSG-PNET3/HIT-SIOP-PNET4 clinical trials. Contemporary molecular profiling integrating methylation/WCA subtypes and next-generation sequencing was performed. Survival modelling was carried out with patients >3 years old who received craniospinal irradiation (n=336). Association analysis confirmed relationships between methylation and WCA subtypes. Subtypes VI and VII were enriched for WCA-FR (p<0.0001) and aneuploidy, whereas subtype VIII was defined solely by i17q (p<0.0001). Whilst we observed an overall low mutational burden, WCA-HR harboured recurrent mutations in genes involved in chromatin remodelling (p=0.007). No gene-specific events were associated with disease risk, however integration of both methylation subtype and WCA groups enabled improved risk-stratification survival models that outperformed current schemes. The optimal MBGrp4-specific model stratified patients into: favourable-risk (local disease, subtype VII or subtype VI with WCA-FR; 39/194 [20%], 97% 5-year PFS), very-high-risk (metastatic disease with WCA-HR; 71/194 [37%], 50% 5-year PFS) and high-risk (remaining patients; 84/194 [43%], 67% 5-year PFS). Findings were validated in independent cohorts. Comprehensive clinico-molecular assessment of MBGrp4 provides important understanding of its clinical and biological heterogeneity. Our novel MBGrp4 stratification scheme removes standard risk disease and identifies a favourable risk group (20% of MBGrp4) with potential for therapy de-escalation. Current therapeutic strategies are insufficient for the very-high risk group (encompassing 37% of MBGrp4), for whom novel therapies are urgently required.
Original languageEnglish
Pages (from-to)i123-i123
Number of pages1
JournalNeuro-Oncology
Volume24
Issue numberSupplement_1
Early online date3 Jun 2022
DOIs
Publication statusPublished - Jun 2022
Event20th International Symposium on Pediatric Neuro-Oncology - Congress Center, Hamburg, Germany
Duration: 12 Jun 202215 Jun 2022
https://www.ispno2022.de/

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