MB-14MOLECULAR AND PROGNOSTIC HETEROGENEITY WITHINMYCANDMYCNAMPLIFIED MEDULLOBLASTOMAS

Abstract

MYC and MYCN are the most commonly amplified oncogenes in medulloblastoma; their association with poor prognosis in disease-wide studies has supported their adoption as high-risk disease biomarkers in current clinical trials. However, recent observations suggest some patients with MYC/MYCN amplified tumours achieve long term survival and may suffer unnecessary side effects associated with intensified therapies. To further understand this heterogeneity, we characterised the molecular, clinical and pathological features of focussed cohorts of MYC (n = 37) and MYCN (n = 57) amplified tumours (identified by FISH and/or copy number profiling), and assessed their associations with disease outcome. Within the MYCN cohort (24 MYCNSHH; 24 MYCNGroup4; 3 MYCNGroup3; 6 NA), patient survival was subgroup-dependent; patients with MYCNGroup4 and no other clinico-pathological risk factors (subtotal resection, metastatic disease or LCA pathology) had a favourable event free survival (EFS). In contrast, MYCNSHH was associated with LCA (MYCNSHH vs MYCNGroup4, p< 0.0001) and a dismal EFS regardless of additional risk factors. TP53 mutation was a frequent feature of MYCNSHH (12/23), usually in conjunction with Chromosome 17p loss and GLI2 amplification, and conferred a quicker time to progression within MYCNSHH (p = 0.05). LCA pathology was the poorest prognostic factor in MYC-amplified tumours. The majority (20/30) of sub-grouped MYC-amplified tumours were MYCGroup3. Rare MYCGroup4 tumours (5/30), had fewer (<50%) amplified tumour cells and a better EFS than MYCGroup3 (p = 0.04). These data highlight the importance of subgroup identification as a basis for refined stratification of medulloblastoma risk using MYC/MYCN amplification, and suggest that MYC/MYCNGroup4 as isolated risk-factors do not confer high-risk disease.