EMBR-25. Genome-wide genetic and epigenetic assessment of group 4 Medulloblastoma for improved, biomarker driven, prognostication and risk-stratification

Jack Goddard, Jemma Castle, Emily Southworth, Stephen Crosier, Idoia Martin-Guerrero, Miguel Garcia-Ariza, Aurora Navajas, Franck Bourdeaut, Christelle Dufour, Tobias Goschzik, Torsten Pietsch, Dan Williamson, Simon Bailey, Ed Schwalbe, Steven Clifford, Debbie Hicks

Research output: Contribution to journalConference articlepeer-review

Abstract

Introduction:                                                                               Medulloblastoma (MB) is the most common malignant brain tumour in children. The most frequent molecular subgroup, Group 4 (MBGrp4) accounts for ~35/40% of cases, however it has the least understood underlying biology. Clinical outcomes are heterogeneous in MBGrp4 and are not accounted for by established clinico-pathological risk factors. There is now a requirement for a comprehensive study of MBGrp4, considering established clinico-pathological features and novel molecular biomarkers to enhance risk-stratification and identify novel therapeutic targets. 
                                                                                                              Methods:                                                                                                             A clinically-annotated, retrospective MBGrp4 discovery cohort (n = 420) was generated from UK CCLG institutions, collaborating European centres and SIOP-UKCCSG-PNET3 and HIT-SIOP-PNET4 clinical trials. Contemporary, multi-omics profiling was performed. Focal and arm level copy number aberrations (CNAs) were determined from molecular inversion probe (MIP) or DNA methylation array which additionally provided next generation non-WNT/non-SHH (Grp3/Grp4) subtype classifications. Targeted next-generation DNA sequencing was performed to overlay the mutational landscape. Survival modelling was carried out with patients >3 years old who received craniospinal irradiation. 
                                                                                                                Results:                                                                                                     MBGrp4 subtypes were assigned to 88% of tumours with available data. Subtype VIII was strongly associated with i17q (p<0.0001). The favourable-risk cytogenetic signature (2 or 3 of; chromosome 7 gain, chromosome 8 loss and/or chromosome 11 loss) associated with both subtypes VI and VII (p<0.0001). MYCN amplifications were strongly associated with subtype V (p<0.0001) in addition to 16q loss (p<0.0001). The high-risk CNA group was enriched for mutations in genes involved in chromatin remodelling (p<0.0001). Risk factors were identified from multivariate survival modelling. Subtype and CNA groups contributed to improved risk-stratification models that outperformed current clinical schemes. 
                                                                                                          Conclusion:                                                                                    Comprehensive genetic and epigenetic profiling in this large retrospective cohort has improved our understanding of the molecular and clinical heterogeneity within MBGrp4. Incorporation of molecular biomarkers improved risk-stratification for MBGrp4.
Original languageEnglish
Pages (from-to)i11-i11
Number of pages1
JournalNeuro-Oncology
Volume23
Issue numberSupplement_1
Early online date1 Jun 2021
DOIs
Publication statusPublished - 1 Jun 2021
Event2021 SNO Pediatric Conference: 6th Biennial Pediatric Neuro-Oncology Research Conference - Virtual
Duration: 10 Jun 202112 Jun 2021
https://www.soc-neuro-onc.org/WEB/Events/2021_Pediatric/WEB/Event_Content/2021_Pediatric.aspx

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