EPCO-39. MULTIOMIC AND CLINICAL ANALYSIS OF MULTIPLY RECURRENT MENINGIOMAS REVEALS RISK FACTORS, UNDERLYING BIOLOGY, AND INSIGHTS INTO EVOLUTION

Abstract Although meningiomas, the most common primary brain tumor, are often effectively treated with surgery and radiation, an important subset of meningiomas behave aggressively and are characterized by treatment resistance and multiple recurrences. Prior work has yet to specifically study multiply recurrent meningiomas (MRMs), including whether they are molecularly distinct from non-recurrent meningiomas (NRMs) at initial diagnosis and whether the molecular features of MRMs evolve with subsequent recurrences. The objective of this study was to identify clinical and molecular features associated with MRMs and determine if longitudinal molecular changes occur in paired MRM samples. In this dual institution study, clinical parameters were collected for 1,186 meningioma patients. After propensity score matching, 31 MRMs were matched to 84 NRMs. Molecular sequencing including whole exome sequencing (n=44), EPIC bead chip methylation array (n=43), and RNA-sequencing (n=66) were performed. On multivariable binomial logistic regression, MRMs were significantly associated with male sex (P=0.012), subtotal resection (P=0.001), higher number of meningiomas on presentation (P=0.017), and histopathological sheeting (P=0.002). Multiomic analysis of primary meningiomas revealed MRMs exhibit greater global copy number alternations (CNA) (P=0.0113) and increased DNA methylation (P=0.0161). Integrated methylation profiling and RNA-sequencing identified candidate driver genes of MRMs. Among these genes, we demonstrate that knockdown of EDNRB, a locus with higher promoter methylation and decreased gene expression in MRMs, leads to increased meningioma cell proliferation, suggesting a tumor suppressor function. CNAs, subclonal evolution, and methylation profiles of MRMs did not significantly change from primary tumor to recurrence, even after radiation treatment, suggesting MRMs are molecularly aggressive from initial diagnosis. Overall, we identify several novel clinical and molecular risk factors associated with MRMs. MRMs harbor unique molecular features on presentation, which do not appear to change during evolution and after treatments, which has implications for development of biomarkers and therapeutic agents for these aggressive tumors.