Molecular landscape and clinical correlates of olfactory groove meningiomas: a multi-institutional study

Abstract

Objective: The aim of this study was to investigate the relationship between the clinical and radiological characteristics of olfactory groove meningiomas (OGMs) and their molecular profiles.

Methods: The authors performed targeted next-generation and whole-genome sequencing in 123 OGM samples collected from 4 international institutions, focusing on known meningioma-driver genes. They compared the molecular data with the clinical and radiographic features of the tumors. Patient and tumor data, including age, sex, radiological features, and overall survival, were retrospectively collected and analyzed.

Results: The study cohort comprised 90 females (73%) and 33 males (27%), with a median age at diagnosis of 57 years (range 25-87 years). The majority of tumors (88.6%, n = 109) were classified as WHO grade I meningioma. Known driver mutations were found in 86.2% of patients (n = 106), with the most common mutations found in the SMOL412F/W535L and AKT1E17K genes, each present in 36 cases (29.3%), followed by mutations in PIK3CA/PIK3R1 (19 cases, 15.4%; 14 PIK3CA and 5 PIK3R1), TRAF7 alone (7 cases, 5.7%), POLR2AQ403K (4 cases, 3.3%), and TRAF7/KLF4K409Q (3 cases, 2.4%), while 17 patients (13.8%) did not harbor known meningioma driver mutations (wildtype group). Within molecular subgroups, patients with AKT1 mutations were the youngest (median age 51 years, range 30-87 years) and patients with TRAF7-only mutations were the oldest (median 66 years, range 28-76 years). The median tumor volume at diagnosis was 18.04 cm3. SMO-mutant tumors were significantly larger (median volume 19.5 cm3) than both AKT1-mutant (median 7.5 cm3, p = 0.021) and TRAF7/KLF4-mutant (median 4.9 cm3, p = 0.002) tumors. Tumor-associated hyperostosis of the sphenoid planum was common (58.5%), led by PIK3CA/PIK3R1, SMO, and wildtype groups (73.7%, 72.2%, and 70.6%, respectively), compared with a notably lower rate in AKT1-mutant tumors (25%) (p < 0.001). Tumor invasion of the ethmoid sinuses occurred most frequently in the TRAF7-only mutant OGMs (42.9%), followed by PIK3CA/PIK3R1-mutant (31.6%) and wildtype (23.5%) OGMs. The mean progression-free survival (PFS) was 144.4 months (95% CI 123.8-165 months). Patients with SMO-mutant OGMs exhibited a significantly shorter mean PFS of 92.0 months (95% CI 70.1-113.9 months) compared with 158.2 months (95% CI 134.9-181.5 months) for SMO-wildtype OGMs (p = 0.004), identifying a tumor type that might benefit from adjuvant treatment after resection.

Conclusions: This study revealed that 70% of OGMs harbor SMO, AKT1, and PIK3CA mutations, influencing tumor behavior, symptoms, and outcomes, supporting molecular profiling for personalized treatment in OGM management.

Keywords: AKT1; KLF4; PIK3CA; POLR2A; SMO; TRAF7; molecular; olfactory groove meningioma; oncology; tumor.

FIG. 1.

Oncoprint illustrating the mutational landscape of OGMs. Each column represents an individual tumor, and key genes commonly altered in meningiomas are shown in the upper rows. The most frequently mutated genes in this cohort include AKT1, SMO, PIK3CA, TRAF7, and KLF4. Mutually exclusive mutation patterns are observed among several driver genes, supporting the existence of distinct molecular subgroups within OGMs. The Oncoprint highlights the predominance of NF2-wildtype (WT) tumors and the enrichment of AKT1 and SMO mutations. Tumor characteristics, such as location and histological subtype, are shown in the lower rows. Figure is available in color online only.

FIG. 2.

Left: Sagittal gadolinium-enhanced T1-weighted MR image obtained in a representative case of a small AKT1-mutant meningothelial WHO grade I OGM, without infiltration of the ethmoid sinus and with a sphenoid planum hyperostosis. Right: Sagittal gadolinium-enhanced T1-weighted MR image obtained in a representative case of a large SMO-mutant meningothelial WHO grade I OGM, with infiltration of the ethmoid sinus and hyperostosis of the sphenoid planum.

FIG. 3.

Coronal (left) and sagittal (right) CT scans obtained in an OGM patient with a PIK3CA mutation and hyperostosis of the sphenoid planum.

FIG. 4.

Kaplan-Meier estimates of PFS in WHO grade I OGMs based on molecular subgroups. Left: Comparison of PFS between SMO-mutant OGMs (red) and SMO-wildtype OGMs (blue). SMO-mutant OGMs demonstrate a significantly higher recurrence rate (p = 0.004), highlighting the prognostic impact of SMO mutations. Right: Kaplan-Meier curves illustrating PFS across different molecular subgroups, including AKT1-mutant (orange), SMO-mutant (red), PIK3CA-mutant (green), wildtype (blue), and other mutations (black). There is a significant difference in PFS among the groups (p = 0.020), with SMO-mutant OGMs showing the highest recurrence risk. Figure is available in color online only.