Browse by author
Lookup NU author(s): Dr Ed Schwalbe, Dr Daniel Williamson, Dr Janet Lindsey, Dr Rebecca Hill, 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).
© 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.
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
URL: https://doi.org/10.1007/s00401-019-02020-0
DOI: 10.1007/s00401-019-02020-0
Altmetrics provided by Altmetric
