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The molecular landscape and associated clinical experience in infant medulloblastoma: prognostic significance of second-generation subtypes

Lookup NU author(s): Dr Debbie Hicks, Dr Reza Rafiee, Dr Ed Schwalbe, Dr Christopher Howell, Dr Janet Lindsey, Dr Rebecca Hill, Amanda Smith, Peter Adidharma, Charlotte Steel, Dr Stacey Richardson, Dr Louise Pease, Dr Marina Danilenko, Dr Stephen Crosier, Dr Daniel Williamson, Professor Simon BaileyORCiD, Professor Steven CliffordORCiD



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


© 2020 The Authors. Neuropathology and Applied Neurobiology published by John Wiley & Sons Ltd on behalf of British Neuropathological Society. Aims: Biomarker-driven therapies have not been developed for infant medulloblastoma (iMB). We sought to robustly sub-classify iMB, and proffer strategies for personalized, risk-adapted therapies. Methods: We characterized the iMB molecular landscape, including second-generation subtyping, and the associated retrospective clinical experience, using large independent discovery/validation cohorts (n = 387). Results: iMBGrp3 (42%) and iMBSHH (40%) subgroups predominated. iMBGrp3 harboured second-generation subtypes II/III/IV. Subtype II strongly associated with large-cell/anaplastic pathology (LCA; 23%) and MYC amplification (19%), defining a very-high-risk group (0% 10yr overall survival (OS)), which progressed rapidly on all therapies; novel approaches are urgently required. Subtype VII (predominant within iMBGrp4) and subtype IV tumours were standard risk (80% OS) using upfront CSI-based therapies; randomized-controlled trials of upfront radiation-sparing and/or second-line radiotherapy should be considered. Seventy-five per cent of iMBSHH showed DN/MBEN histopathology in discovery and validation cohorts (P < 0.0001); central pathology review determined diagnosis of histological variants to WHO standards. In multivariable models, non-DN/MBEN pathology was associated significantly with worse outcomes within iMBSHH. iMBSHH harboured two distinct subtypes (iMBSHH-I/II). Within the discriminated favourable-risk iMBSHH DN/MBEN patient group, iMBSHH-II had significantly better progression-free survival than iMBSHH-I, offering opportunities for risk-adapted stratification of upfront therapies. Both iMBSHH-I and iMBSHH-II showed notable rescue rates (56% combined post-relapse survival), further supporting delay of irradiation. Survival models and risk factors described were reproducible in independent cohorts, strongly supporting their further investigation and development. Conclusions: Investigations of large, retrospective cohorts have enabled the comprehensive and robust characterization of molecular heterogeneity within iMB. Novel subtypes are clinically significant and subgroup-dependent survival models highlight opportunities for biomarker-directed therapies.

Publication metadata

Author(s): Hicks D, Rafiee G, Schwalbe EC, Howell CI, Lindsey JC, Hill RM, Smith AJ, Adidharma P, Steel C, Richardson S, Pease L, Danilenko M, Crosier S, Joshi A, Wharton SB, Jacques TS, Pizer B, Michalski A, Williamson D, Bailey S, Clifford SC

Publication type: Article

Publication status: Published

Journal: Neuropathology and Applied Neurobiology

Year: 2021

Volume: 47

Issue: 2

Pages: 236-250

Print publication date: 01/02/2021

Online publication date: 11/08/2020

Acceptance date: 29/07/2020

Date deposited: 03/12/2020

ISSN (print): 0305-1846

ISSN (electronic): 1365-2990

Publisher: Wiley-Blackwell Publishing Ltd


DOI: 10.1111/nan.12656

PubMed id: 32779246


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Funder referenceFunder name
Action Medical Research
Cancer Research UK. Grant Numbers: C8464/A13457, C8464/A23391
JGW Patterson Foundation
Tom Grahame Trust
The Brain Tumour Charity, Children With Cancer UK and Great Ormond Street Hospital Children's Charity (INSTINCT Network)