Determining the Underlying Mechanisms of Glioma Progression and Recurrence

INTRODUCTION: Gliomas are the most common malignant brain tumour. Despite standard-of-care therapy, these tumours inevitably recur. Recurrent tumours are often treatment-resistant and associated with a poor prognosis, and there is an urgent need for novel treatments. METHODS: The epigenome-wide methylome, transcriptome, and proteome was analyzed in a total of 271 samples from 176 patients with gliomas, including 166 primary (pre-treatment) and 105 recurrent (post-treatment) tumours. Included is a unique cohort of 81 patients with paired tumour samples collected at both pre- and post- treatment. RESULTS: Epigenomics accounted for the majority of observed variance between samples and was driven by IDH status. Paired analyses identified epigenetic stability in IDH wildtype tumours at recurrence, compared to a loss of methylation at recurrence in IDH mutant tumours. Loss of methylation in IDH mutant gliomas at recurrence was driven by astrocytomas undergoing malignant transformation. Integrated, multi-platform analyses of paired samples undergoing malignant transformation identified novel genetic markers and pathways of transformation. Finally, a novel subgroup of IDH wildtype GBM with improved survival and a distinct proteomics signature was discovered. Multi-platform analyses characterized this novel subgroup as exhibiting hypermethylation, increased DNA mismatch repair and cell cycle regulation, and an altered tumour microenvironment. CONCLUSIONS: In conclusion, this study identifies targetable molecular factors that promote malignant transformation in IDH mutant gliomas and classifies a novel subgroup of IDH wildtype GBM with improved prognosis.