MEDB-36. Clinical and molecular heterogeneity withinMYC andMYCN amplified medulloblastoma

MYC and MYCN are the most commonly amplified oncogenes in medulloblastoma. Their overall association with a poor prognosis has supported their adoption as high-risk disease biomarkers in trials. However, emerging evidence suggests that certain patients with MYN/MYCN focally-amplified tumours can achieve long-term survival and therefore may suffer unnecessary late-effects associated with intensified therapies. To investigate this heterogeneity, we characterised the molecular and clinico-pathological features of curated cohorts of MYC (n=64) and MYCN (n=95) amplified tumours, drawn from >1000 diagnostic cases, and assessed their associations with disease outcome. Within the MYCN-amplified cohort, survival was related to molecular group; patients with MYCNGrp3 or MYCNGrp4 tumours with no other clinico-pathological risk factors (subtotal resection (STR), metastatic disease, LCA pathology) were intermediate-risk (n=25;70% 5-year PFS). In contrast, a very-high-risk group was defined by positivity for MYCNSHH, STR and/or LCA (n=64;32% 5-year PFS). 22/35 assessable MYCNSHH harboured TP53 mutations; 9/12 with data were germline. MYCGrp3 represented the majority (46/58; 79%) of molecularly-grouped MYC-amplified tumours. Importantly, while radiotherapy receipt conferred a modest survival advantage, for MYC-amplified tumours with additional clinico-molecular risk factors (LCA, metastasis, STR, Grp3), survival was dismal, irrespective of radiotherapy receipt. A very-high-risk group of MYC-amplified tumours was identified (n=51;10% 5-year PFS), defined by positivity for ≥1 additional risk factors (STR, LCA and/or metastasis). Alternatively, membership of subgroups II/V defined a smaller, very-high-risk patient group (n=28;7% 5-year PFS). Long-term survival was seen in the majority of remaining MYC-amplified tumours negative for these specified features (61% 5-year PFS; high-risk). MYC and MYCN-amplified medulloblastomas are biologically heterogeneous with diverse clinical outcomes. Molecular subgroup assignment and established clinical features are critical for their improved stratification. Patient subgroups identified may be eligible for therapy de-escalation; in contrast, the very-high-risk patient groups are incurable using current therapies and urgently require novel experimental treatment strategies upfront.