1237 The Mutational Landscape of Molecularly Defined Oligodendrogliomas

Abstract

INTRODUCTION: Oligodendrogliomas are molecularly defined by IDH1/2 mutation and codeletion of chromosome arms 1p/19q. Prior studies identified capicua transcriptional repressor (CIC), far upstream binding protein (FUBP1), and the promoter region of telomerase reverse transcriptase (TERTp) as commonly mutated in oligodendrogliomas. However, prognostically relevant molecular signatures have yet to be identified. METHODS: A retrospective single-center study evaluated adults with pathologically confirmed IDH-mutant and 1p/19q co-deleted oligodendrogliomas that underwent surgery between 2005 and 2021. Genetic data from formalin-fixed, paraffin-embedded specimens were analyzed with the NGS Solid Tumor Panel at the Johns Hopkins Medical Laboratories, which tested over 400 genes. Kaplan-Meier curves and log-rank tests were used to compare progression-free survival (PFS) and overall survival (OS). Chi-squared tests compared clinical characteristics between mutation status in the ten most frequently mutated genes. RESULTS: From 277 patients with IDH-mutated, 1p/19q co-deleted oligodendrogliomas, 95 patients with NGS were included. Ten genes had 9 or more patients with a mutation, with CIC and FUBP1 being the most frequently mutated genes (n = 60 and n = 23, respectively). Kaplan-Meier curves showed that most genes were not associated with differences in PFS or OS. CIC conferred a reduction in PFS in patients with a PFS <100 months (p = 0.038), though this significance was lost when including all PFS durations (p = 0.52). While no biomarkers had sufficient statistical power, our analysis showed trends in shortened survival in patients with TP53 (p = 0.01) and PIK3CA (p = 0.03) mutations. CONCLUSIONS: Oligodendrogliomas harbor frequent mutations in CIC, FUBP1, and TERTp, but most patients typically have minimal additional alterations. As NGS becomes routine, understanding these mutations may inform therapeutic and prognostic recommendations or the development of novel targeted therapies. Additional molecular assays beyond mutation analysis with NGS may reveal prognostically relevant biologic subgroups of oligodendrogliomas.