Multiplatform molecular analysis of vestibular schwannoma reveals two robust subgroups with distinct microenvironment

Abstract BTFC travel award recipient Vestibular schwannoma (VS) is the most common tumour of the cerebellopontine angle and poses a significant morbidity for patients. While many exhibit benign behaviour, others have a more aggressive nature and pattern of growth. Predicting who will fall into which category consistently remains uncertain. There is a need for a better understanding of the molecular landscape, and important subgroups therein, of this disease. METHODS: We select all vestibular schwannomas from our tumour bank with both methylation and RNA profiling available. Unsupervised clustering methods were used to define two distinct molecular subgroups of VS which were explored using computational techniques including bulk deconvolution analysis, gene pathway enrichment analysis, and drug repurposing analysis. Methylation data from two other cohorts were used to validate our findings, given a paucity of external samples with available multi-omic data. RESULTS: A total of 75 tumours were analyzed. Consensus clustering and similarity network fusion defined two subgroups ("immunogenic" and "proliferative”) with significant differences in immune, stroma, and tumour cell abundance (p<0.05). Gene network analysis and computational drug repurposing found critical differences in targets of immune checkpoint inhibition PD-1 and CTLA-4, the MEK pathway, and the epithelial to mesenchymal transition program, suggesting a need for subgroup-specific targeted treatment/trial design in the future. CONCLUSIONS: We leverage computational tools with multi-omic molecular data to define two robust subgroups of vestibular schwannoma with differences in microenvironment and therapeutic vulnerabilities.