Transcriptional and chromatin-accessibility heterogeneity in idh-mutant gliomas

Abstract Diffuse gliomas are a common type of adult brain tumour, comprising about 80% of adult malignant brain tumours, and are incurable. IDH-mutant gliomas, oligodendroglioma and astrocytoma, can be treated initially but eventually recur and are generally fatal. In this study, we profiled and analysed 23 frozen samples from primary and recurrent IDH-mutant glioma patients with single nucleus multiome sequencing (RNA- and ATAC-seq). In total we assayed around 70,000 malignant cells as well as 30,000 cells from the tumour microenvironment. Using a matrix factorisation approach, we characterised biological signals in the malignant cells from each sample, thereby identifying known and novel processes which vary within and recur across samples. Trajectory analysis was used to reconstruct the developmental hierarchy in IDH-mutant glioma and to investigate plasticity at different hierarchy levels, highlighting differences and similarities across patients and cancer types. Finally, master regulators, which drive malignant transcriptional programs were identified, using the complimentary and concurrent RNA and chromatin accessibility assays. This study provides a unique opportunity to investigate the transcriptomic and epigenetic heterogeneity present in gliomas, as well as the events leading to the development of more aggressive and treatment-resistant glioma tumours.