LONGITUDINAL MOLECULAR TRAJECTORIES OF DIFFUSE GLIOMA IN ADULTS

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear(1,2). Here, we analyzed temporally separated DNA sequencing data and matched clinical annotation from 222 patients with glioma. Through mutational and copy number analyses across the three major subtypes of diffuse glioma, we observed that driver genes detected at initial disease were retained at recurrence, while there was little evidence of recurrence-specific gene alterations. Treatment with alkylating-agents resulted in a hypermutator phenotype at different rates across glioma subtypes, and hypermutation was not associated with differences in survival. Acquired aneuploidy was frequently detected in recurrent gliomas characterized by presence of an IDH mutation but without 1p/19q codeletion and further converged with acquired cell cycle alterations and poor outcomes. We show that the clonal architecture of each tumor remains similar over time and that absence of clonal selection was associated with increased survival. Finally, we did not observe differences in immunoediting levels between initial and recurrent glioma. Our results collectively argue that the strongest selective pressures occur early during glioma development and that current therapies shape this evolution in a largely stochastic manner.