A four-hit mechanism is sufficient for meningioma development

J Neurooncol. 2024 Nov 25. doi: 10.1007/s11060-024-04877-y. Online ahead of print.

Abstract

Purpose: Meningiomas are central nervous system tumors whose incidence increases with age. Benign meningioma pathogenesis involves germline or somatic mutation of target genes, such as NF2, leading to clonal expansion. We used an established cancer epidemiology model to investigate the number of rate-limiting steps sufficient for benign meningioma development.

Methods: Incidence data was obtained from the Surveillance, Epidemiology and End Results Program (SEER) for nonmalignant meningioma from 2004 to 2020. Age-adjusted incidence rates per 100,000 person-years were divided into 5-year bands. This was repeated for vestibular schwannomas as a negative control. The Armitage-Doll methodology was applied. Mathematical solutions correcting for volatile tumor microenvironments were applied to fit higher-order models using polynomial regression when appropriate. A 75:25 training:test split was utilized for validation.

Results: 222,509 cases of benign meningiomas were identified. We noted strong linear relationships between log-transformed incidence and age across the cohort and multiple subpopulations: male, white, black, Hispanic, Asian/Pacific Islander, and American Indian subpopulations all demonstrated R2 = 0.99. Slopes were between 3.1 and 3.4, suggesting a four-step process for benign meningioma development. Female patients exhibited nonlinear deviations, but the corrected model demonstrated R2 = 0.99 with a four-hit pathway. This model performed robustly on test data with R2 = 0.99. Vestibular schwannomas demonstrated a slope of 2.1 with R2 = 0.99, suggesting a separate three-step process.

Conclusion: Four mutations are uniquely required for the development of benign meningiomas. Correcting for volatile tumor microenvironments reliably accounted for nonlinear deviations in behavior. Further studies are warranted to elucidate genomic findings suggestive of key mutations in this pathway.

Keywords: Genetic models; Incidence; Meningioma; Theoretical model; Tumor microenvironment.