PATH-50. Genomic profiling of 1,104 consecutive, prospective meningiomas defines the population prevalence of molecular alterations and elucidates potential biomarkers of treatment response

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 research cohorts, and the population prevalence of meningioma genomic alterations is incompletely understood. Here we define DNA mutations and copy number alterations (CNAs) across a consecutive cohort of 1,104 meningiomas that were prospectively analyzed using the next-generation UCSF500 DNA sequencing assay from 2019 to 2025. Median patient age was 60 years (range 2-91) and 64.1% were female. Meningiomas were CNS WHO grade 1 (56.6%), 2 (35.4%), or 3 (8.0%). Loss of chromosomes 22q (63.2%), 1p (40.3%), and 14q (22.0%) were the most common CNAs. CNA burden was associated with higher WHO grade (p<2.2e-16). The most common somatic mutations were in NF2 (53.6%) and TRAF7 (16.3%), which were mutually exclusive in all but 2 meningiomas. AKT1 or KLF4 were co-mutated in 58.9% of TRAF7-mutant meningiomas. CDKN2A/B homozygous deletions and TERT promoter mutations were identified in 3.1% and 3.6%, respectively. 25.2% of meningiomas had no detected CNAs, 13.2% lacked somatic mutations, and 2.6% had no mutations or CNAs. Correlation analyses revealed novel co-mutated genes like BCORL1 and SPEN (co-mutated in 0.5%), and co-occurrent CNAs like loss of 12p and 17p (1.5%). Median tumor mutation burden (TMB) was 3.4/megabase. Mutations in ARID1A (p=6.9e-05), ARID2 (p=0.028), CDKN2A/B (p=0.017), KMT2D (p=0.011), SMARCB1 (p=0.0061), TERT (p=0.00057), TET2 (p=0.019), and TP53 (p=0.0033) were associated with elevated TMB, an emerging predictor of meningioma response to immune checkpoint inhibition. At least one gene associated with elevated TMB was mutated in 13.8% of meningiomas in the absence of mismatch repair deficiency, which was identified in only 1.0%. In conclusion, prospective next generation DNA sequencing of consecutive meningiomas defines the population prevalence of molecular alterations and elucidates potential biomarkers of treatment response.