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Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of Group 3 and Group 4 subtypes

Lookup NU author(s): Dr Ed Schwalbe, Dr Daniel Williamson, Dr Janet Lindsey, Dr Rebecca Hill, Dr Debbie Hicks, Professor Simon Bailey, Professor Steven Clifford



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


© 2019, The Author(s). In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, and Group 4), each associated with distinct genomic features and clinical behavior. Independently, multiple recent reports have defined further intra-subgroup heterogeneity in the form of biologically and clinically relevant subtypes. However, owing to differences in patient cohorts and analytical methods, estimates of subtype number and definition have been inconsistent, especially within Group 3 and Group 4. Herein, we aimed to reconcile the definition of Group 3/Group 4 MB subtypes through the analysis of a series of 1501 medulloblastomas with DNA-methylation profiling data, including 852 with matched transcriptome data. Using multiple complementary bioinformatic approaches, we compared the concordance of subtype calls between published cohorts and analytical methods, including assessments of class-definition confidence and reproducibility. While the lowest complexity solutions continued to support the original consensus subgroups of Group 3 and Group 4, our analysis most strongly supported a definition comprising eight robust Group 3/Group 4 subtypes (types I–VIII). Subtype II was consistently identified across all component studies, while all others were supported by multiple class-definition methods. Regardless of analytical technique, increasing cohort size did not further increase the number of identified Group 3/Group 4 subtypes. Summarizing the molecular and clinico-pathological features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events amongst subtypes, and identified highly disparate survival outcomes, further supporting their biological and clinical relevance. Collectively, this study provides continued support for consensus Groups 3 and 4 while enabling robust derivation of, and categorical accounting for, the extensive intertumoral heterogeneity within Groups 3 and 4, revealed by recent high-resolution subclassification approaches. Furthermore, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) which may additionally inform medulloblastoma subclassification. Outputs from this study will help shape definition of the next generation of medulloblastoma clinical protocols and facilitate the application of enhanced molecularly guided risk stratification to improve outcomes and quality of life for patients and their families.

Publication metadata

Author(s): Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M, Rutkowski S, Robinson GW, Gajjar A, Cavalli F, Ramaswamy V, Taylor MD, Lindsey JC, Hill RM, Jager N, Korshunov A, Hicks D, Bailey S, Kool M, Chavez L, Northcott PA, Pfister SM, Clifford SC

Publication type: Article

Publication status: Published

Journal: Acta Neuropathologica

Year: 2019

Volume: 138

Pages: 309-326

Print publication date: 01/08/2019

Online publication date: 10/05/2019

Acceptance date: 23/04/2019

Date deposited: 29/05/2019

ISSN (print): 0001-6322

ISSN (electronic): 1432-0533

Publisher: Springer Verlag


DOI: 10.1007/s00401-019-02020-0


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Funder referenceFunder name
C8464/A13457Cancer Research UK CRUK (open competition)
C8464/A23391Cancer Research UK CRUK (open competition)
Children with Cancer UK
Great Ormond Street Hospital Children's Charity
The Brain Tumour Charity