Associations of meningioma molecular subgroup and tumor recurrence

Abstract

Background: We and others have identified mutually exclusive molecular subgroups of meningiomas; however, the implications of this classification for clinical prognostication remain unclear. Integrated genomic and epigenomic analyses implicate unique oncogenic processes associated with each subgroup, suggesting the potential for divergent clinical courses. The aim of this study was to understand the associated clinical outcomes of each subgroup, as this could optimize treatment for patients.

Methods: We analyzed outcome data for 469 meningiomas of known molecular subgroup, including extent of resection, postoperative radiation, surveillance imaging, and time to recurrence, when applicable. Statistical relationships between outcome variables and subgroup were assessed. Features previously associated with recurrence were further investigated after stratification by subgroup. We used Kaplan-Meier analyses to compare progression-free survival, and identified factors significantly associated with recurrence using Cox proportional hazards modeling.

Results: Meningioma molecular subgroups exhibited divergent clinical courses at 2 years of follow-up, with several aggressive subgroups (NF2, PI3K, HH, tumor necrosis factor receptor-associated factor 7 [TRAF7]) recurring at an average rate of 22 times higher than others (KLF4, POLR2A, SMARCB1). PI3K-activated tumors recurred earlier than other subgroups but had intermediate long-term outcome. Among low-grade tumors, HH and TRAF7 meningiomas exhibited elevated recurrence compared with other subgroups. Recurrence of NF2 tumors was associated with male sex, high grade, and elevated Ki-67. Multivariate analysis identified molecular subgroup as an independent predictor of recurrence, along with grade and previous recurrence.

Conclusion: We describe distinct clinical outcomes and recurrence rates associated with meningioma molecular subgroups. Our findings emphasize the importance of genomic characterization to guide postoperative management decisions for meningiomas.

Keywords: meningioma genomics; molecular subgroups; precision medicine; tumor prognosis.

Fig. 1

Subgroup relationships with clinical and therapeutic variables. (A) The distribution of genomic subgroups in our cohort is similar to previous reports, but with enrichment of non-NF2 cases. SB1: SMARCB1, POL: POLR2A, HH: Hedgehog, TRAF: TRAF7. (B) Plots of expected vs observed percentages for gross total resection (left) and use of postoperative radiation (right). significance was assessed using sample counts (not percentages).

Fig. 2

Progression free survival by genomic subgroup. Recurrence rates of HH, NF2, TRAF7, and PI3K meningiomas were elevated relative to other subgroups. Survival curves show significant deviation of these subgroups from others (log-rank P-value = 8.7 × 10⁻⁴).

Fig. 3

Timing of meningioma recurrence. Shown is the time to recurrence (solid dots) or last recurrence-free scan (gray, decreased opacity) for each subgroup in months. The average time to recurrence of PI3K meningiomas was significantly less than other tumors (P = 7.5 × 10⁻³). Averages for each subgroup are shown in solid lines. Density plots of each subgroup’s recurrences are shown on the right, along with the mean (μ), standard deviation (σ), and number of recurrences (n).

Fig. 4

Effect of subgroup on recurrence rates stratified by covariates. (A) Samples classified as HH or TRAF7 were more likely to recur relative to other subgroups (adj. P = 0.01). (B) Among low-grade samples, subgroups exhibited distinct PFS curves, with KLF4 meningiomas exhibiting better prognosis than NF2 (log-rank P = 0.035), TRAF7 (log-rank P = 1.7 × 10⁻³) and HH (log-rank P = 0.016) meningiomas. Subgroups with > 10 samples available for analysis at 60 months are included. (C) Among NF2 mutant samples, recurrence was enriched among High-Grade, High Ki-67, and Male patients. Samples falling within each corner of the displayed cube are associated with the corresponding values for these features. Solid green circles indicate recurrences, while gray circles indicate samples that did not recur.

Fig. 5

Stratification of recurrence rate by subgroup and feature. Shown is a heatmap of recurrence rates stratified by subgroup and feature. Boxes that represent less than 4 samples are grayed out. LG: Low-Grade, HG: High-Grade, Mening: Meningothelial, Secr: Secretory, Fibr: Fibrous, Trans: Transitional, Atyp: Atypical, SB: Skull Base, NSB: Non-Skull Base, M: Midline, NM: Non-Midline, GTR: Gross Total Resection, STR: Sub-Total Resection, Fe: Female, Ma: Male.

Fig. 6

Proportional hazards modeling. (A) Univariate proportional hazards modeling identified low-grade , GTR, female sex, NM location, non-atypical histology, low Ki-67, and primary lesions as protective factors. Among subgroups, KLF4 meningiomas were positively associated with PFS, while NF2 lesions were negatively associated. The 95% confidence interval of the hazard ratio is labeled. Clinical features that were not significant are omitted. (B) Further analysis with Cox multivariate regression identified grade, previous recurrence, and Hedgehog subgroup as significant independent factors associated with recurrence.