Sequential omics analysis reveals molecular signatures of malignant transformation in recurrent meningiomas.

Meningiomas are the most common primary brain tumors in adults and have the potential for recurrence. Although most recurrent meningiomas retain their initial World Health Organization grade, a subset undergoes malignant transformation (MT). The molecular mechanisms underlying this transformation remain poorly understood. We aimed to characterize distinct recurrence subtypes-MT and grade 1-retained recurrence (GR)-using sequential multi-omic analyses. In this study, we reviewed meningioma patients with paired histological evaluations. Among these, 10 patients experienced MT and 25 showed GR. Patients with MT exhibited significantly higher Ki-67 proliferation indices and shorter overall survival. Comprehensive molecular profiling, including matched sequential recurrences, was performed on samples from six patients each with MT and GR meningiomas. Compared to GR tumors, MT tumors demonstrated a marked increase in tumor mutation burden and copy number alterations, with deletion of cyclin-dependent kinase inhibitor 2A emerging as a key acquired event. MT cases also showed selective upregulation of cell cycle-related genes, including Forkhead box M1, a feature absent in GR tumors. Notably, even prior to recurrence, MT tumors displayed distinct global DNA methylation patterns, particularly in regions targeted by the polycomb repressive complex 2 and H3K27me3 marks. Our findings suggest that molecular signatures evolve during MT and that certain intermediate aggressive meningiomas may progress toward malignancy. This study underscores the importance of DNA methylation and transcriptomic profiling in understanding tumor progression and recurrence. While molecular profiling holds promise for prognostication, further research is needed to identify key drivers of MT and clarify their roles in meningioma pathogenesis.