2088 Background: Atypical meningioma (AM) is a WHO grade II neoplasm arising from meningeal arachnoid cap cells and is distinguished from WHO grade I meningiomas by parenchymal invasion and rapid proliferation. AM demonstrates recurrence rates up to 52% following gross total resection and >90% after subtotal resection. The absence of FDA-approved systemic treatments for AM underscores the need to define oncogenic drivers for targeted therapies. This study leverages the American Association for Cancer Research (AACR) Project Genomics Evidence Neoplasia Information Exchange (GENIE) database to characterize the genomic landscape of AM and identify key genetic drivers for therapeutic targets. Methods: The AACR GENIE database was accessed from cBioPortal (v18.0-public) on December 12, 2025 to identify all AM patient samples. Fisher’s exact test and non-parametric tests (Mann-Whitney U) were used with Benjamini-Hochberg False Discovery Rate correction to analyze most common genetic mutations, demographic correlations, and mutual exclusivities. Unknown values were excluded from analysis. Results: The cohort identified 402 AM samples from 394 patients. The cohort was slightly female-predominant (52.8%) and largely adult (94.0%). Most patients were White (47.2%), followed by Asian (7.4%) and Black (3.6%). Most samples (n=307, 76.4%) were primary tumors and 48 (11.9%) were metastatic. NF2 was the most prevalent mutation (n=228; 56.7%), followed by TERT promoter mutations (n=52; 12.9%). Chromatin-modifying genes, including KMT2D (n=24; 6.0%), KMT2A (n=19; 4.7%), and KMT2C (n=16; 4.0%), were frequently altered. Additional recurrent mutations were observed in SPTA1 (n=21; 5.2%), MT-ND5 (n=20; 5.0%), FAT1 (n=20; 5.0%), PRKDC (n=18; 4.5%). Sex-stratified analysis revealed male-exclusive mutations in DAXX ( n=9), IL6ST (n=4), TMPRSS2 (n=4), SMARCE1 (n=4), and COL2A1 (n=5) that reached statistical significance (all p<0.05). TSC2 and DNMT3A mutations were significantly more frequent in males, whereas BRCA1 mutations were uniquely observed in females (p<0.05). NF2 mutations were enriched in Asian patients (p<0.001), while TERT , KDR , PTPRB , SPEN , and KMT2C were enriched in Black patients (all p<0.05). NF2 and TERT demonstrated significant mutual exclusivity (p<0.05). Co-occurrence was observed between ROS1 / ATM and KMT2D / TSC2 (p<0.05). Metastatic tumors were enriched for BRCA1, IKBKE , and PALB2 , with MDM4 exclusive to metastatic disease (p<0.001). Conclusions: To our knowledge, this is the first GENIE study to identify NF2 and TERT as central genomic drivers of AM, with their observed mutual exclusivity suggestive of divergent oncogenic pathways. Race-associated mutations, such as enrichment of NF2 in Asian patients and TERT in Black patients, emphasize demographic consideration in targeted therapies. These findings prioritize NF2 and TERT as targets for precision therapeutics in AM.
Chudziak et al. (Wed,) studied this question.