TY - JOUR
T1 - MEDB-71. Molecular characterisation of group 4 medulloblastoma improves risk-stratification and its biological understanding
AU - Goddard, Jack
AU - Castle, Jemma
AU - Southworth, Emily
AU - Fletcher, Anya
AU - Crosier, Stephen
AU - Martin-Guerrero, Idoia
AU - Garcia-Ariza, Miguel
AU - Navajas, Aurora
AU - Masliah-Planchon, Julien
AU - Bourdeaut, Franck
AU - Dufour, Christelle
AU - Goschizk, Tobias
AU - Pietsch, Torsten
AU - Richardson, Stacey
AU - Hill, Rebecca M
AU - Williamson, Daniel
AU - Bailey, Simon
AU - Schwalbe, Edward C
AU - Clifford, Steven C
AU - Hicks, Debbie
PY - 2022/6
Y1 - 2022/6
N2 - 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.
AB - 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.
U2 - 10.1093/neuonc/noac079.445
DO - 10.1093/neuonc/noac079.445
M3 - Meeting Abstract
SN - 1522-8517
VL - 24
SP - i123-i123
JO - Neuro-Oncology
JF - Neuro-Oncology
IS - Supplement_1
T2 - 20th International Symposium on Pediatric Neuro-Oncology
Y2 - 12 June 2022 through 15 June 2022
ER -