Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>Meningiomas are the most common primary intracranial tumors, and treatments for meningiomas are limited to surgery and radiotherapy. Clinically tractable biomarkers for meningiomas are under development, and multiple retrospective studies have reported genetic, epigenetic, or gene expression grouping schemes shedding light on meningioma biology, outcomes, or druggable dependencies. Here we report biologically distinct subgroups within the Hypermitotic meningioma DNA methylation group, validating an architecture that unifies contrasting theories of meningioma biology. To do so, we re-analyzed meningioma DNA methylation profiles from a discovery cohort (n=200) and an independent, consecutive validation cohort (n=365). Median follow-up was 5.6 years for 388/142/35 WHO grade 1/2/3 meningiomas. Copy number variants (CNVs) were calculated for all meningiomas, and RNA sequencing was performed on the discovery cohort. Unsupervised hierarchical clustering of β methylation values was performed on the discovery cohort, controlling for artifacts and inaccurate β methylation values due to the presence of CNVs. As previously reported, meningioma clustering was validated with the validation cohort and revealed 3 DNA methylation groups (Merlin-intact, Immune-enriched, or Hypermitotic) that were associated with distinct biological drivers, clinical outcomes, and therapeutic vulnerabilities. Further analysis using RNA sequencing revealed differential enrichment of FOXM1 target genes across 2 subgroups of Hypermitotic meningiomas. Gene expression programs in these subgroups were concordant with Proliferative or Hypermetabolic meningiomas reported by other investigators. Analysis of meningiomas by DNA methylation subgroup conserved biological features distinguishing DNA methylation groups, including CNVs deleting NF2, immune cell enrichment, or lymphatic gene expression. Analysis of clinical outcomes suggested subgroups may refine prediction of postoperative 5-year local freedom from recurrence (54.1% for Hypermetabolic vs 5.9% for Proliferative) or overall survival (82.2% for Hypermetabolic vs 21.8% for Proliferative) within DNA methylation groups. In summary, meningioma DNA methylation groups and the subgroups they harbor provide a framework unifying contrasting theories of meningioma biology.</jats:p>