Longitudinal molecular trajectories of diffuse glioma in adults.

The evolutionary processes that drive universal therapeutic resistance in adult patients with diffuse glioma remain unclear1,2. Here we analysed temporally separated DNA-sequencing data and matched clinical annotation from 222 adult patients with glioma. By analysing mutations and copy numbers across the three major subtypes of diffuse glioma, we found that driver genes detected at the initial stage of disease were retained at recurrence, whereas there was little evidence of recurrence-specific gene alterations. Treatment with alkylating agents resulted in a hypermutator phenotype at different rates across the glioma subtypes, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent gliomas and was characterized by IDH mutation but without co-deletion of chromosome arms 1p/19q, and further converged with acquired alterations in the cell cycle and poor outcomes. The clonal architecture of each tumour remained similar over time, but the presence of subclonal selection was associated with decreased survival. Finally, there were no differences in the levels of immunoediting between initial and recurrent gliomas. Collectively, our results suggest that the strongest selective pressures occur during early glioma development and that current therapies shape this evolution in a largely stochastic manner

Supplementary Appendix from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

List of collaborator authors</p

Glioma progression is shaped by genetic evolution and microenvironment interactions

© 2022 Elsevier Inc.The factors driving therapy resistance in diffuse glioma remain poorly understood. To identify treatment-associated cellular and genetic changes, we analyzed RNA and/or DNA sequencing data from the temporally separated tumor pairs of 304 adult patients with isocitrate dehydrogenase (IDH)-wild-type and IDH-mutant glioma. Tumors recurred in distinct manners that were dependent on IDH mutation status and attributable to changes in histological feature composition, somatic alterations, and microenvironment interactions. Hypermutation and acquired CDKN2A deletions were associated with an increase in proliferating neoplastic cells at recurrence in both glioma subtypes, reflecting active tumor growth. IDH-wild-type tumors were more invasive at recurrence, and their neoplastic cells exhibited increased expression of neuronal signaling programs that reflected a possible role for neuronal interactions in promoting glioma progression. Mesenchymal transition was associated with the presence of a myeloid cell state defined by specific ligand-receptor interactions with neoplastic cells. Collectively, these recurrence-associated phenotypes represent potential targets to alter disease progression.N

Table S2 from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

Table S2: List of 132 pairs (ID of Initial and Recurrent samples)</p

Table S5 from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

Table S5: Treatment-related probes and samples (Related to Figure 3) S5A: List of 69 IDHmut pairs with treatment information (ID of Initial and Recurrent samples and group assignment) S5B: List of differentially methylated probes associated with treatment in IDHmut gliomas S5C: List of differentially methylated probes associated with treatment in IDHmut astrocytomas S5D: List of CpG-gene pairs (epigenetic regulation associated with treatment)</p

Table S1 from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

Table S1: GLASS surgery-level clinical and molecular characteristics (N=354)</p

Supp Figures from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

Supp Figures</p

Table S4 from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

Table S4: Master regulators - list of samples and features (Related to Figure 2) S4A: List of sample profiled for ChIP-seq S4B: Results of H3K4me3 differential analysis S4C: Results of H3K27Ac differential analysis S4D: Results of gene expression differential analysis S4E: List of IDHmut non-codels samples profiled for both gene expression and DNA methylation S4F: List of hypomethylated probes between IDHmut non-codel initial and first recurrent pairs S4G: List of anticorrelated genes S4H: List of HOXD13 predicted targets</p

Table S3 from The Epigenetic Evolution of Glioma Is Determined by the <i>IDH1</i> Mutation Status and Treatment Regimen

Table S3A/B/C/D: Clinical summary of GLASS epigenomic samples S3A: Clinical summary of IDHmut patients who switched from GCIMP-high to GCIMP-low S3B: Clinical summary of IDHmut and IDHwt patients with known hypermutator status S3C: Clinical summary of IDHmut and IDHwt patients with known treatment information S3D: Clinical summary of IDHmut patients with known treatment information</p