Abstract

Anaplastic Astrocytoma (AA) is a diffusely infiltrating, malignant, primary brain tumour (typically classified as a Grade III glioma), which can occur de novo or progress from grade II astrocytomas. Despite numerous studies on the mutational landscape of astrocytomas, our understanding of the molecular mechanisms involved in the formation and progression of these tumours is far from complete. Here, we use whole genome sequencing to investigate eight anaplastic AA tumours samples, which exhibited both Grade II and Grade III pathology. In this study, we focused on the mutational and structural variant landscape of the Grade III component. Our analysis revealed widespread heterogeneity in the location, size and number of structural variants in Grade III AA tumours. Of the samples analysed, two showed a whole-genome doubling event and we further observed massive, clustered genomic rearrangements in another two samples, indicative of chromothripsis. We hypothesised that drastic, large-scale changes to cellular karyotype could result in selective vulnerabilities in AA. Studies in yeast have shown that increased transcription and translation resulting from hyperploidy increases accumulation of misfolded proteins and dependence on the proteasomal machinery. We find that treatment of hyperploid grade IV astrocytoma cell-lines with proteasome inhibitors resulted in increased cytotoxicity (as measured by LDH activity) compared to near-euploid astrocytoma cells. This suggests the potential for hyperploidy to be used as a selective or correlative biomarker for proteasome inhibition therapy in anaplastic astrocytoma.