NOVEL MOLECULAR SUBGROUPS FOR CLINICAL CLASSIFICATION AND OUTCOME PREDICTION IN CHILDHOOD MEDULLOBLASTOMA: A COHORT STUDY

Edward C. Schwalbe, Janet C. Lindsey, Sirintra Nakjang, Stephen Crosier, Amanda J. Smith, Debbie Hicks, Gholamreza Rafiee, Rebecca M. Hill, Alice Iliasova, S. Bailey, Thomas Stone, Barry Pizer, Antony Michalski, Abhijit Joshi, Stephen B. Wharton, Thomas S Jacques, Simon Bailey, Daniel Williamson, Steven C. Clifford

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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. These subgroups have distinct clinicopathological and molecular features, and underpin current disease subclassification and initial subgroup-directed therapies that are underway in clinical trials. However, substantial biological heterogeneity and differences in survival are apparent within each subgroup, which remain to be resolved. We aimed to investigate whether additional molecular subgroups exist within childhood medulloblastoma and whether these could be used to improve disease subclassification and prognosis predictions. Methods In this retrospective cohort study, we assessed 428 primary medulloblastoma samples collected from UK Children's Cancer and Leukaemia Group (CCLG) treatment centres (UK), collaborating European institutions, and the UKCCSG-SIOP-PNET3 European clinical trial. An independent validation cohort (n=276) of archival tumour samples was also analysed. We analysed samples from patients with childhood medulloblastoma who were aged 0–16 years at diagnosis, and had central review of pathology and comprehensive clinical data. We did comprehensive molecular profiling, including DNA methylation microarray analysis, and did unsupervised class discovery of test and validation cohorts to identify consensus primary molecular subgroups and characterise their clinical and biological significance. We modelled survival of patients aged 3–16 years in patients (n=215) who had craniospinal irradiation and had been treated with a curative intent. Findings Seven robust and reproducible primary molecular subgroups of childhood medulloblastoma were identified. MBWNTremained unchanged and each remaining consensus subgroup was split in two. MBSHHwas split into age-dependent subgroups corresponding to infant (
Original languageEnglish
Pages (from-to)958-971
Number of pages14
JournalLancet Oncology
Volume18
Issue number7
Early online date22 May 2017
DOIs
Publication statusPublished - Jul 2017

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