Genomic profiling of 1,104 consecutive, prospective meningiomas defines the population prevalence of molecular alterations and elucidates potential biomarkers of treatment response

Background: Molecular profiling of meningioma has revealed biologic drivers and therapeutic vulnerabilities that have refined risk stratification and guided clinical trials. Most molecular studies of meningioma are limited to retrospective cohorts, and the population prevalence of meningioma genomic alterations is incompletely understood. Methods: DNA mutations and copy number alterations (CNAs) were defined across a consecutive cohort of 1,104 meningiomas that were prospectively analyzed using the next-generation UCSF500 DNA sequencing assay at a single institution from 2019 to 2025. Results: Meningiomas were CNS WHO grade 1 (49.4%), grade 2 (30.9%), grade 3 (7.0%), or undefined (12.7%). Median patient age was 60 years (range 2-91) and 64.1% were female. Patient race included white (39.2%), Asian (10.4%), Black or African American (3.6%), Native American or Alaska Native (0.6%), Native Hawaiian (0.3%), other Pacific Islander (0.3%), other (9.5%), or unknown. Ethnicity was reported as Hispanic or Latino in 125 cases (11.3%). Loss of chromosomes 22q (64.1%), 1p (40.7%), and 14q (22.3%) were the most common CNAs. Multivariate regression identified male sex, increasing age, and Asian vs. white race as significant predictors of multiple CNAs that are associated with poor clinical outcomes, including co-occurrent 1p loss/1q gain (odds ratio [OR] for male sex: 2.79, p<0.001; increasing age OR 1.02, p=0.028; Asian vs. white race OR 2.77, p=0.001). CNA burden was enriched in high grade meningiomas (p<0.001), and male sex (OR 10.1, p<0.001), increasing age (OR 1.04, p=0.026), and Asian vs. white race (OR 4.31, p=0.047) were significant predictors of higher CNA burden. The most common short somatic variants (SSVs) were in NF2 (53.6%) and TRAF7 (16.3%), which were mutually exclusive in all but 2 meningiomas. CDKN2A/B homozygous deletions and TERT promoter mutations were identified in 3.1% and 3.6% of meningiomas, respectively. Increasing age was a significant predictor of NF2 (OR 1.02, p<0.001) and TERT promoter mutation (OR 1.06, p=0.001), and Asian vs. white race was a significant predictor of CDKN2A/B mutation (OR 4.26, p=0.003). Median tumor mutation burden (TMB) was 3.4/megabase. Mutations in ARID1A (p<0.001), ARID2 (p=0.028), CDKN2A/B (p=0.017), KMT2D (p=0.011), SMARCB1 (p=0.0061), TERT (p<0.001), TET2 (p=0.019), and TP53 (p=0.0033) were associated with elevated TMB. Increasing age (OR 1.01, p=0.02) and Asian (OR 5.02, p<0.001) and Black (OR 2.54, p=0.004) vs. white race were significant predictors of higher TMB. Conclusion: Prospective next-generation DNA sequencing of consecutive meningiomas defines the population prevalence of molecular alterations. These data fill a critical gap in the understanding of biological drivers of meningioma behavior and therapeutic response across demographic groups.