47. Molecular heterogeneity in glioblastoma multiforme influences variant clonality and neoantigen prediction accuracy

      Glioblastoma multiforme (GBM) is an aggressive astrocytoma that accounts for approximately half of all glioma cases. Due to its location and diffuse morphology, GBM has only a 30% two-year survival rate and additional treatment strategies are needed. Clinical trials for GBM personalized neoantigen vaccines have reported neoantigen-specific T cell responses, but treatment efficacy remains low. This may be due to GBM's high molecular heterogeneity, which could complicate the identification of clonal neoantigens for vaccine design. To address this topic, we performed whole-exome sequencing (WES) and RNA-seq to compare 30 multi-sampled GBM and brain metastases. Mutation and neoantigen burden varied widely between the two tumor types. The range of variant counts for GBM samples is 7-169 (median 81), while the brain metastases have a range of 158-1317 (median 274.5). In addition, the former's class I and II neoantigen counts range from 1-312 (median 14), while the latter's range from 3-1159 (median 23.5). Overall, GBM patients had a lower proportion of clonal variants and neoantigens than brain metastases. In addition, the proportion of variants and neoantigens missed by single sector sequencing was significantly higher in GBM. Immune cell infiltration was assessed using transcriptome data, and many tumors demonstrated cellular heterogeneity in CD8+ and CD4+ T cell subsets. We are performing TCR sequencing to further investigate TCR clonality diversity. This analysis demonstrates that GBM contains cellular and molecular heterogeneity, which can complicate clonal neoantigen selection. Multi-sample sequencing as a standard for GBM genomic analysis could improve neoantigen vaccine design and increase treatment efficacy.
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