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Lookup NU author(s): Dr Ed Schwalbe, Dr Janet Lindsey, Dr Marina Danilenko, Dr Rebecca Hill, Dr Stephen Crosier, Sarra Ryan, Dr Daniel WilliamsonORCiD, Jemma CastleORCiD, Dr Debbie Hicks, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.Background.MYC/MYCN are the most frequent oncogene amplifications in medulloblastoma (MB) and its primary biomarkers of high-risk (HR) disease. However, while many patients’ MYC(N)-amplified tumors are treatment-refractory, some achieve long-term survival. We therefore investigated clinicobiological heterogeneity within MYC(N)-amplified MB and determined its relevance for improved disease management. Methods. We characterized the clinical and molecular correlates of MYC- (MYC-MB; n = 64) and MYCN-amplified MBs (MYCN-MB; n = 95), drawn from >1600 diagnostic cases. Results. Most MYC-MBs were molecular group 3 (46/58; 79% assessable) and aged ≥3 years at diagnosis (44/64 [69%]). We identified a “canonical” very high-risk (VHR) MYC-amplified group (n = 51/62; 82%) with dismal survival irrespective of treatment (11% 5-year progression-free survival [PFS]), defined by co-occurrence with ≥1 additional established risk factor(s) (subtotal surgical-resection [STR], metastatic disease, LCA pathology), and commonly group 3/4 subgroup 2 with a high proportion of amplified cells. The majority of remaining noncanonical MYC-MBs survived (i.e. non-group 3/group 3 without other risk features; 11/62 (18%); 61% 5-year PFS).MYCN survival was primarily related to molecular group; MYCN-amplified SHH MB, and group 3/4 MB with additional risk factors, respectively defined VHR and HR groups (VHR, 39% [35/89]; 20% 5-year PFS/HR, 33% [29/89]; 46% 5-year PFS). Twenty-two out of 35 assessable MYCN-amplified SHH tumors harbored TP53 mutations; 9/12 (75%) with data were germline.MYCN-amplified group 3/4 MB with no other risk factors (28%; 25/89) had 70% 5-year PFS. Conclusions.MYC(N)-amplified MB displays significant clinicobiological heterogeneity. Diagnostics incorporating molecular groups, subgroups, and clinical factors enable their risk assessment. VHR “canonical” MYC tumors are essentially incurable and SHH-MYCN-amplified MBs fare extremely poorly (20% survival at 5 years); both require urgent development of alternative treatment strategies. Conventional risk-adapted therapies are appropriate for more responsive groups, such as noncanonical MYC and non-SHH-MYCN MB.
Author(s): Schwalbe EC, Lindsey JC, Danilenko M, Hill RM, Crosier S, Ryan SL, Williamson D, Castle J, Hicks D, Kool M, Milde T, Korshunov A, Pfister SM, Bailey S, Clifford SC
Publication type: Article
Publication status: Published
Journal: Neuro-Oncology
Year: 2025
Volume: 27
Issue: 1
Pages: 222-236
Print publication date: 01/01/2025
Online publication date: 08/10/2024
Acceptance date: 02/04/2018
Date deposited: 19/02/2025
ISSN (print): 1522-8517
ISSN (electronic): 1523-5866
Publisher: Oxford University Press
URL: https://doi.org/10.1093/neuonc/noae178
DOI: 10.1093/neuonc/noae178
Data Access Statement: Data is available from the authors on reasonable request
PubMed id: 39377358
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