Benign Meningiomas Develop Through a Four-Hit Mechanism

Introduction: Meningiomas are central nervous system tumors whose incidence increases with age. Benign meningioma pathogenesis commonly involves the mutation of one or more target genes, such as NF2, which leads to clonal expansion.

Objective: We used an established cancer epidemiology model to investigate the number of rate-limiting steps required for benign meningioma development in American patients and high-risk subpopulations.

Method: Incidence data were 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 from 20 to 80 years of age. The Armitage-Doll methodology was applied. This methodology was applied as well to vestibular schwannomas for comparison with another tumor type affected by NF2. We corrected for volatile tumor microenvironment as described by Webster 2019 to fit higher-order models using polynomial regression when linear models were not appropriate.

Results: A total of 222,509 cases of benign meningiomas were identified. We noted a linear relationship between log incidence and log age across multiple subpopulations and the overall cohort: all patients r(2) = 0.99, male r(2) = 0.99, white r(2) = 0.99, black r(2) = 0.99, and Hispanic r(2) = 0.99. Subpopulations demonstrated slopes between 3.1 and 3.4 with overlap of confidence intervals. The overall cohort demonstrated a slope of 3.2 (3.1, 3.3), suggesting a four-step process for the development of benign meningiomas. Female patients exhibited a nonlinear relationship, but after correction demonstrated a r(2) = 0.99 when the number of steps m equaled 4. Patients with vestibular schwannoma demonstrated a slope of 2.1 with r(2) = 0.99, suggesting a three-step process for the parallel yet distinct tumorigenesis.

Conclusion: The slope of the linear relationship suggests that 4 mutations are uniquely required for the development of benign meningiomas. Incidence in female patients was reliably predicted after correcting for volatile tumor microenvironment, suggesting a role of the microenvironment in affecting the number of mutations. Further studies are warranted to investigate the effect of driver mutations and identify the steps.

Die Autoren geben an, dass kein Interessenkonflikt besteht.

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Artikel online veröffentlicht:
05. Februar 2024