Abstract
Abstract BACKGROUND Malignant gliomas exhibit varied failure patterns upon recurrence; however, genomic backgrounds of these distinct phenotypes have not been evaluated. We aimed to explore the genomic traits associated with distinct failure patterns in malignant glioma patients. METHODS This study involved 272 malignant glioma patients. Failure pattern was defined for the spatial relationship between recurrent tumor and the original tumor as follows: local recurrence (LR), remote recurrence, leptomeningeal seeding (LMC), and combined failure pattern. Molecular characteristics underlying different failure patterns were investigated for the mutation profile, copy number variation (CNV), and transcriptomic signatures. RESULTS Local recurrence was the most prominent failure pattern (62.9%), followed by combined recurrence (22.8%). Multivariate Cox regression analysis confirmed failure pattern as one of the independent prognostic factors. Patients with combined failure patterns exhibited the worst prognoses, whereas patients with remote recurrence exhibited the most favorable outcomes (median overall survival = 11.4 and 25.2 months, respectively). In IDH1-wild type glioblastoma (GBM) patients, TERT and PIK3CA mutation were significantly associated with the development of combined failure pattern and leptomeningeal seeding, respectively (p-value=0.015 & p-value=0.004, respectively). Transcriptomic analysis exhibited that inter-neuronal synaptic transmission was enriched in GBMs with combined failure pattern and this finding was further validated in proteomic analysis; neuronal myelination and synaptic transmission-related pathways were upregulated in GBMs which exhibited combined failure pattern. CONCLUSIONS Collectively, we demonstrated that the inherent molecular characteristics of the tumors might contribute to the eventual relapse patterns; tracking their evolutionary pathways may unravel novel therapeutic vulnerabilities of these tumors.
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