Molecular characterisation of Group 4 medulloblastoma to develop novel and risk-adapted therapies

Abstract

Group 4 (MBGrp4) accounts for 40% of medulloblastoma cases. Its biology is complex, and clinical course is poorly predicted by current risk-factors. MBGrp4 molecular substructure has been identified (i.e. second-generation methylation subgroups (1-8) and whole chromosome aberration (WCA) groups; WCA-favourable-risk (WCA-FR) and WCA-high-risk (WCA-HR)). However, their inter-relationships and potential to improve clinical sub-classification/riskstratification remain undefined. This project aimed to characterise the molecular landscape of MBGrp4 and determined its utility to improve clinical management. A clinically-annotated discovery cohort (n=362 MBGrp4) was assembled from UK-CCLG institutions and SIOP-UKCCSG-PNET3, HIT-SIOP-PNET4 and PNET HR+5 clinical trials. Molecular profiling was undertaken, integrating focal/arm-level/WCAs, driver mutations, second-generation methylation subgroups and RNA-sequencing. Survival models were derived for non-infants who received contemporary multi-modal therapies (n=323). WCA-risk groups were re-derived, confirming WCA-FR to be characterised by ≥2 from chromosome 7 gain, 8 loss, and 11 loss. Its favourable prognosis was maintained in this riskindependent cohort. Subgroups 6 and 7 were enriched for WCA-FR (p<0.0001) and aneuploidy. Subgroup 8 was defined by predominantly balanced genomes with isolated isochromosome 17q (p<0.0001). While no mutations were associated with outcome and overall mutational burden was low, WCA-HR harboured recurrent chromatin remodelling mutations (p=0.007). Integration of methylation and WCA groups improved risk-stratification models and outperformed established schemes. The MBGrp4 risk-stratification scheme defined: favourable-risk (non-metastatic disease and (i) subgroup 7 or (ii) WCA-FR (21% of patients, 5-year PFS 97%)), very-high-risk (metastatic disease with WCA-HR (36%, 5-year PFS 49%)) and high-risk (remaining patients; 43%, 5-year PFS 67%). Findings were validated in an independent MBGrp4 cohort (n=668). Finally, RNA-sequencing of WCA groups identified candidate genes/pathways that potentially inform the processes behind their differential response to therapies. This study advances our understanding of the biology and clinical behaviour of MBGrp4 and its findings require urgent assessment in prospective clinical trials, for improved and personalised therapies.