Multiomic and clinical analysis of multiply recurrent meningiomas reveals risk factors, underlying biology, and insights into evolution

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. In this dual institution study, we identify clinical, genetic, and epigenetic predictors of multiply recurrent meningiomas (MRMs) and also evaluate the evolution of these meningiomas in matched samples. 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 that MRMs exhibit greater global copy number alternations (CNA) (p=0.0113) and increased DNA methylation (p=0.0236). Integrated methylation profiling and RNA-sequencing identified candidate driver genes of MRMs. Among these genes, we demonstrated in meningioma cells that knockdown of EDNRB, a locus with greater promoter methylation and decreased gene expression in MRMs, leads to increased meningioma cell proliferation. CNA, subclonal evolution, and methylation profiles of MRMs did not significantly change from primary tumor to recurrences, even after radiation treatment, suggesting MRMs are molecularly aggressive from initial diagnosis. This first clinical and multiomic investigation of MRMs harbors implications for the future development of biomarkers and therapeutic agents for these challenging tumors. We samples 43 total tumors from institution A (n=15) which were EPIC Bead Chip Version 1 and Institution B (n=28) which were EPIC Beach Chip Version 2. 31 were primary tumors, 10 were recurrence 1 and 2 were recurrence 2. Of the 31 primary tumors, 13 were multiply recurrence and 18 were non-recurrent.