Abstract B73: Second-generation molecular subgrouping of medulloblastoma: An international meta-analysis of Group 3 and Group 4 subtypes
Authors: Sharma Tanvi , Schwalbe Edward C. , Williamson Daniel W. , Sill Martin , Hovestadt Volker , Mynarek Martin , Rutkowski Stefan , Robinson Giles W. , Gajjar Amar , Cavalli Florence , Ramaswamy Vijay , Taylor Michael D. , Lindsey Janet C. , Hill Rebecca M. , Jäger Natalie , Korshunov Andrey , Hicks Debbie , Bailey Simon , Kool Marcel , Chavez Lukas , Northcott Paul A. , Pfister Stefan M. , Clifford Steven C. 
Published: August 2020

Abstract
In 2012, an international consensus paper reported that medulloblastoma comprises four molecular subgroups (WNT, SHH, Group 3, 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 1,501 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 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 clinicopathologic features of these eight subtypes indicated enrichment of specific driver gene alterations and cytogenetic events among subtypes and identified highly disparate survival outcomes, further supporting their biologic 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. Further, these findings provide a basis for application of emerging methods (e.g., proteomics/single-cell approaches) that 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.
Citation Format: Tanvi Sharma, Edward C. Schwalbe, Daniel W. Williamson, Martin Sill, Volker Hovestadt, Martin Mynarek, Stefan Rutkowski, Giles W. Robinson, Amar Gajjar, Florence Cavalli, Vijay Ramaswamy, Michael D. Taylor, Janet C. Lindsey, Rebecca M. Hill, Natalie Jäger, Andrey Korshunov, Debbie Hicks, Simon Bailey, Marcel Kool, Lukas Chavez, Paul A. Northcott, Stefan M. Pfister, Steven C. Clifford. Second-generation molecular subgrouping of medulloblastoma: An international meta-analysis of Group 3 and Group 4 subtypes [abstract]. In: Proceedings of the AACR Special Conference on the Advances in Pediatric Cancer Research; 2019 Sep 17-20; Montreal, QC, Canada. Philadelphia (PA): AACR; Cancer Res 2020;80(14 Suppl):Abstract nr B73.