Novel Molecular Subgroups Improve Clinical Classification and Outcome Prediction for Childhood Medulloblastoma

Ed Schwalbe, Janet Lindsey, Sirintra Nakjang, Stephen Crosier, Amanda Smith, Debbie Hicks, Gholamreza Rafiee, Rebecca Hill, Alice Iliasova, Thomas Stone, Barry Pizer, Anthony Michalski, Abhijit Joshi, Keith Robson, Stephen Wharton, Thomas Jacques, Simon Bailey, Daniel Williamson, Steven Clifford

Research output: Contribution to conferencePaper

Abstract

Background - International consensus recognises four medulloblastoma molecular subgroups - WNT (MBWNT), SHH (MBSHH), Group 3 (MBGrp3) and Group 4 (MBGrp4) - each defined by their characteristic genome-wide transcriptomic and DNA methylomic profiles. Subgroups harbor distinct clinico-pathological and molecular features, underpin current disease sub-classification and initial subgroup-directed therapies are underway in clinical trials (i.e. reduced risk-adapted treatments for favorable-risk MBWNT patients; SMO inhibitors for MBSHH patients). However, significant biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. Methods - We undertook comprehensive molecular profiling and unsupervised class discovery (non-negative matrix factorization, t-SNE) of test and validation cohorts (n=704 in total), to identify consensus primary molecular subgroups within childhood medulloblastoma (3.0 years). Findings - Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified, characterized by distinct biological/clinical features. For instance, MBSHH comprised two age-dependent subgroups, while MBGrp3 and MBGrp4 each split into two subgroups with significantly different survival rates. Survival analysis identified secondary features predictive of outcome. Cross-validated subgroup-dependent models incorporating these novel subgroups along with secondary features and established disease risk-factors, outperformed current disease risk-stratification schemes. These schema stratified patients into four clinical risk-groups - favorable-risk (91% 5-year survival, 25% of patients), standard-risk (81%, 23%), high-risk (42%, 38%) and very high-risk (28%, 13%) - to be considered for treatment reduction, intensification or novel therapies respectively. Interpretation - The discovery of seven novel, clinically-significant, subgroups significantly improves disease risk-stratification and provides a new foundation for future research and clinical investigations.
Original languageEnglish
Pagesiv38
DOIs
Publication statusPublished - Jun 2017
Event4th Biennial Conference on Pediatric Neuro-Oncology Basic and Translational Research - New York
Duration: 1 Jun 2017 → …

Conference

Conference4th Biennial Conference on Pediatric Neuro-Oncology Basic and Translational Research
Period1/06/17 → …

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