Gene-28. Longitudinal Molecular Trajectories of Diffuse Glioma in Adults

Abstract

Treatment options for adult patients with glioma has remained largely unchanged over the past three decades. Targeted inhibitors and immunotherapies have improved outcomes for many cancer types but their relevance in glioma is unclear. The inevitability of glioma disease recurrence demands an understanding of mechanisms driving therapy resistance. The Glioma Longitudinal Analysis (GLASS) Consortium was initiated to establish a definitive portrait of the recurrence process and to discover vulnerabilities that render the tumor sensitive to therapeutic intervention. GLASS is a community-driven effort that seeks to overcome the logistical challenges in constructing adequately powered longitudinal genomic glioma datasets by pooling data from patients treated at institutions worldwide. Currently, the GLASS Data Resource comprises DNA sequencing data (exome and/or whole-genome) from 288 patients of whom high-quality data in at least two time points are present from 222 patients (n = 134 IDHwt, n = 63 IDHmutant-noncodel, n = 25 IDHmutant-codel). We inferred longitudinal mutation, copy number, clonal frequency, and neoantigen profiles and demonstrated that driver genes found at initial disease persisted into recurrence. Treatment with alkylating-agents resulted in a hypermutator phenotype at different rates across glioma subtypes, most frequently among IDHmutant-noncodels, and hypermutation was not associated with differences in overall survival. Acquired aneuploidy was frequently detected in recurrent IDHmutant-noncodel gliomas and further converged with acquired cell cycle pathway alterations and poor outcomes. We showed that the clonal architecture of each tumor remains largely intact over time and that genetic drift was associated with increased survival. Finally, we found that neoantigens were exposed to stable selective pressures throughout a tumor’s progression. Our results collectively suggest that the strongest selective pressures occur early during glioma development and that current therapies shape this evolution in a largely stochastic manner. The GLASS Data Resource provides a genomic reference to study the patterns of glioma evolution.

Tumor mutational burden and purity adjustment before and after treatment with temozolomide in 27 paired samples of glioblastoma: a prospective study

“…This illustrates the complexity in obtaining paired samples in GBM patients. To address these challenges and increase availability of datasets from paired samples, the international GLASS consortium has been initiated with the aim of generating longitudinal genomic and molecular data in IDH-WT, IDH-mutant and 1p/19q co-deleted tumors [30,9]. Upfront, we had to exclude two samples from patients not having true progression and hence limited mutations in the samples.…”

“…A recent large-scale study of 288 glioma patients with paired samples included 134 IDH-wild-type (WT) tumors, thereby resembling our cohort. They identified a TMB of 2.85, using Mutect2 [9]. We analyzed our data using Mutect1 but for the matter of comparison, we pooled all mutations together per patient and found a combined median TMB/Mb of 0.96 (Mutect1) vs. 1.05 (Mutect2), (Supplementary Table ST1).…”

“…been shown that shared mutations represent the clones responsible for the positive selection driving tumorigenesis [9] thereby making identification of specific tumor mutations important instead of the total, unselected TMB. This contributes to the fact that results from relapse studies cannot be directly translated to newly diagnosed patients.…”

“…Mutations in melanoma and NSCLC are mainly caused by exogenous mutagenesis and have a TMB-average of 3-400/Megabase (Mb) (range to more than 1000) [7]. This is opposite of glioblastoma (GBM) [8] with TMB estimates of approximately 1-3/Mb (0-76) [8][9][10]7] and despite a huge unmet medical need, the clinical role of TMB in GBM has not been fully explored. GBM is incurable with a progression free survival (PFS) of 7-8 months and a median overall survival (OS) of 16-22 months depending on prognostic and predictive markers [11][12][13][14], including isocitrate dehydrogenase (IDH)-status, O 6 -methylguanine-DNA methyl-transferase (MGMT)-promotor methylation-status, performance status (PS), use of corticosteroids and extent of surgery.…”

“…Response to IT in GBM has been shown in case series based upon mutations in MMR genes [18][19][20] making TMB clinically interesting in GBM. Tumors with high TMB are more prevalent in TMZ-exposed high-grade gliomas with a prevalence of 3.5% to 17% and is more often seen in IDH-mutated samples [9,[21][22][23]17]. This clonal evolution during TMZ exposure may make the resistant tumor more susceptible to IT.…”