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Molecular and Prognostic Heterogeneity within MYC and MYCN Amplified Medulloblastomas

Lookup NU author(s): Dr Janet Lindsey, Dr Rebecca Hill, Dr Ed Schwalbe, Dr Christopher Howell, Dr Reza Rafiee, Dr Stephen Crosier, Amanda Smith, Dr Sarra Ryan, Dr Daniel Williamson, Professor Simon Bailey, Professor Steven Clifford

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This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License (CC BY-NC 4.0).


Abstract

MYC and MYCN are the most commonly amplified oncogenes in medulloblastoma; their association with poor prognosis in previous 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 very poor EFS regardless of additional risk factors. TP53 mutation was a frequent feature of MYCNSHH (12/23), usually in conjunction with loss of Chromosome 17p and GLI2 amplification, and conferred a quicker time to progression within MYCNSHH (p=0.05). The majority (20/30) of sub-grouped MYC-amplified tumours were MYCGroup3; LCA pathology was the poorest prognostic factor in this group. MYCGroup4 tumours were rare (5/30), had fewer (<50%) amplified tumour cells and a significantly 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.


Publication metadata

Author(s): Lindsey JC, Hill RM, Schwalbe EC, Shrimpton ER, Howell CI, Rafiee G, Crosier S, Smith A, Ryan SL, Williamson D, Bailey S, Clifford SC

Publication type: Conference Proceedings (inc. Abstract)

Publication status: Published

Conference Name: International Symposium on Paediatric Neuro-Oncology (ISPNO)

Year of Conference: 2016

Pages: iii99

Print publication date: 30/05/2016

Acceptance date: 28/03/2016

ISSN: 1522-8517

Publisher: Oxford University Press

URL: http://dx.doi.org/10.1093/neuonc/now076.12

DOI: 10.1093/neuonc/now076.12

Series Title: Neuro-Oncology


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