Genetic characterization and mutational profiling of foramen magnum meningiomas: a multi-institutional study

Lingyang Hua Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China;

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Majd Alkhatib Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;

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Shingo Fujio Department of Neurosurgery, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan;

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Boshr Alhasan Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;

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Sylvia Herold Department of Pathology, Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany;

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Silke Zeugner Department of Pathology, Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT/UCC), Dresden, Germany;

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Amir Zolal Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;

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Mido M. Hijazi Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;

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Victoria E. Clark Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

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Hiroaki Wakimoto Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

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Ganesh M. Shankar Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

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Priscilla K. Brastianos Department of Medicine, Massachusetts General Hospital Cancer Center, Harvard Medical School, Boston, Massachusetts; and

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Frederick G. Barker II Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

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Daniel P. Cahill Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;

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Leihao Ren Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China;

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Ilker Y Eyüpoglu Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;

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Ye Gong Department of Neurosurgery, Huashan Hospital, Shanghai Medical College, Fudan University, Shanghai, China;

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Gabriele Schackert Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;

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Tareq A. Juratli Department of Neurosurgery, Division of Neuro-Oncology, Faculty of Medicine and Carl Gustav Carus University Hospital, Technische Universität Dresden, Germany;
Department of Neurosurgery, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts;
National Center for Tumor Diseases (NCT), Dresden, Germany

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Open access

OBJECTIVE

Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles.

METHODS

The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated.

RESULTS

The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del ), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K ). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047).

CONCLUSIONS

These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

ABBREVIATIONS

FFPE = formalin-fixed paraffin-embedded; FM = foramen magnum; NF2 = neurofibromatosis type 2; NGS = next-generation sequencing.

OBJECTIVE

Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles.

METHODS

The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated.

RESULTS

The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del ), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K ). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047).

CONCLUSIONS

These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.

In Brief

The authors investigated clinically actionable mutations in foramen magnum (FM) meningiomas. Of 62 cases, 93.5% had driver mutations, with TRAF7 (41.9%) and AKT1 (30.6%) being the most common. Other common mutations included NF2 (17.7%), POLR2A (12.9%), KLF4 (11.3%), and PIK3CA (6.5%). These mutations were linked to specific tumor locations and histology. This study sheds light on the molecular genetics and clinicopathological characteristics of FM meningiomas, potentially guiding personalized treatments in the future.

Foramen magnum (FM) meningiomas are rare tumors that present formidable surgical challenges and carry the risk of postoperative complications because of their proximity to critical neurovascular structures.1,2 Consequently, FM meningiomas are associated with a higher incidence of morbidity and mortality compared with meningiomas occurring in other locations.2,3 Given these factors, it is crucial to delve deeper into the molecular characteristics of FM meningiomas to advance our understanding of their pathogenesis and guide the development of effective therapeutic strategies.

Recent advancements in genetic analysis have enabled the identification of specific driver mutations, shedding light on the molecular mechanisms underlying meningiomas.49 Particularly noteworthy is the discovery of clinically actionable mutations, including AKT1, SMO, and PIK3CA, which have provided valuable insights into the molecular landscape of these tumors.46,1012 These mutations exhibit distinct anatomical distributions and associations with various clinical characteristics, such as histology, WHO grade, tumor location, sex predominance, and age at diagnosis.1316 Unraveling the mutational profile of meningiomas holds great promise for tailoring personalized treatment approaches and facilitating prognostic assessments.17

Considering the limited knowledge regarding the genetic alterations and clinical implications specific to FM meningiomas, the objective of this study was to investigate the anatomical distribution of clinically actionable mutations within these tumors. Additionally, we aimed to explore potential associations between specific mutational profiles and relevant clinical characteristics, including sex predominance, age, and radiographic and histological features at diagnosis.

Methods

Sample and Data Acquisition

Sixty-two patients diagnosed with an FM meningioma who underwent resection were included in this study. The patients were from three independent neurosurgical centers: Huashan Hospital (n = 44), Dresden University Hospital (n = 13), and Graduate School of Medical and Dental Sciences, Kagoshima University Hospital (n = 5). Ethics approval for the study was obtained from the institutional review boards of Huashan Hospital, Fudan University, and University Hospital Dresden. All patients provided informed consent.

To ensure accurate inclusion of FM meningiomas, the exact topography on MRI and radiological features were carefully reviewed. FM meningiomas were defined as tumors arising anteriorly from the inferior one-third of the clivus to the superior edge of the C2 body, laterally from the jugular tubercle to the C2 laminae, and posteriorly from the anterior border of the occipital squama to the spinal process of C2. Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study.

Histological features, including subtypes and WHO grades, were independently reviewed by one member in each of the Departments of Pathology at Huashan Hospital, Dresden University Hospital, and Kagoshima University Hospital. This review was conducted to validate the histological characteristics of the meningiomas according to the 2016 WHO classification of tumors of the CNS.

Radiological Data Acquisition

Axial and sagittal T1-weighted postcontrast gadolinium-enhanced MR images, as well as CT scans, were collected for all cases. The presence of tumor calcification was evaluated using preoperative CT scans. Tumor axial location was classified as anterior, lateral, or posterior. A lesion was considered posterior if its base was located behind the dentate ligament, lateral if its base was between the midline and the dentate ligament, and anterior if its base extended on both sides of the anterior midline. To ensure accuracy and consistency, the preoperative CT scans and MR images were independently reviewed by three experienced neurosurgeons (L.H. at Huashan Hospital, T.A.J. at University Hospital Dresden, and S.F. at Kagoshima University Hospital).

For the cases from Huashan Hospital, tumor volumes were computed by manually segmenting the tumors on contrast-enhanced T1-weighted MR images using the OSIRIX software, using other sequences (nonenhanced T1-weighted, FLAIR, and T2-weighted sequences) for further reference. The volume measurement function of the software was then used to record the tumor volume.18 For the cases from University Hospital Dresden and Kagoshima University Hospital, tumor volumes were computed by manually segmenting the tumors on contrast-enhanced T1-weighted MR images using the ITK-SNAP software, using other sequences (nonenhanced T1-weighted, FLAIR, and T2-weighted sequences) for further reference. The volume measurement function of the software was then used to record the tumor volume.19

Tumor Sequencing

Because of the multi-institutional nature of this study, samples underwent targeted sequencing using two different next-generation sequencing (NGS) protocols, as previously described.16,20

NGS Protocol at Huashan Neurosurgical Center (n = 44)

The tumor DNA was extracted from 10 slides of 15-μm scrolls taken from archived formalin-fixed paraffin-embedded (FFPE) blocks using the GeneRead DNA FFPE kit (QIAGEN), following a standard technique. The extracted DNA was then profiled using a self-designed targeted panel sequencing consisting of 184 genes known to be frequently mutated in CNS tumors, including the common pathological genes relevant to meningiomas, as previously described. These genes include NF2, TRAF7, KLF4, AKT1, SMO, PIK3CA, SMARCE1, BAP1, CDKN2A/B, TERT-P, ARID1A, SUFU, SMARCB1, POLR2A, DMD, and PBRM1. Sequencing was performed using a custom hybrid capture approach (Agilent Technologies) on a Miniseq instrument (Illumina), with a mean coverage of more than 500-fold. Internal NGS controls were performed to ensure accurate sample assignment.

NGS Protocol at University Hospital Dresden (n = 18)

The FFPE sample from Kagoshima University Hospital (n = 5), along with the 13 fresh-frozen tumor tissues from University Hospital Dresden (n = 13), underwent sequencing using the NGS protocol at University Hospital Dresden. The tumor DNA was purified using the AllPrep DNA Universal Kit for fresh-frozen tissue (QIAGEN), following the manufacturer’s instructions. The regions of interest were amplified using a custom-designed amplicon panel, according to the "QIAseq Targeted DNA V3 Panel, May 2017" protocol (QIAGEN), which was custom-designed and manufactured by our group.20 The panel covered mutation hotspots or whole genes where loss of function is a known mechanism of action. The included meningioma-relevant genes were AKT1, CDKN2A, KLF4, NF1, NF2, PIK3CA, PIK3R1, POLR2A, PTEN, SMARCB1, SMO, STAG2, SUFU, TP53, TRAF7, and TERT promotor. During library preparation, unique molecular barcodes and sample-specific indices were incorporated following the protocol. The indexed libraries were then quantified using a Qubit dsDNA HS Assay Kit (Thermo Fisher Scientific) and sequenced in paired-end mode (2 × 150 bp) on the Illumina NextSeq platform. HG19 was used as the reference genome for bioinformatic analyses.

For all 64 samples, further bioinformatics analysis was performed using the Biomedical Workbench from CLC (version 21.0.3, QIAGEN) with a customized analysis algorithm. The analysis included filters such as coverage ≥ 100 and allele frequency ≥ 5%.

Statistical Analysis

Statistical analysis was performed using R software (version 3.4.1, R Foundation for Statistical Computing). R packages including ggplot2, Hmisc, reshape2, and tidyverse were used in our study. Categorical variables were compared with the chi-square test and Fisher exact test. Correlations between clinical variables (age, sex, tumor location, and calcification) and tumor mutational status (NF2, POLR2A, PIK3CA, KLF4, SMO, TRAF7, and AKT1) were analyzed with the Mann-Whitney U-test and Fisher exact test. Clinical information continuous variables were compared with the Student t-test. A p value < 0.05 was considered statistically significant.

Results

Clinical and Tumor Characteristics

Our study included 62 patients with FM meningiomas from three neurosurgical centers, all of whom had available molecular data. We identified 46 female and 16 male patients, resulting in a sex ratio of 2.9:1. The median age at diagnosis was 60 years (range 28–87 years).

To determine tumor locations, we used the Bruneau and George classification.2 Within our cohort, all meningiomas were situated at the FM, with the majority of tumors occupying the lateral location (32, 51.6%). The anterior location accounted for the second highest number of tumors (24, 38.7%), while only 6 cases (9.7%) originated in the posterior location. Among the 32 meningiomas in the lateral location, 14 (43.8%) were found below the vertebral artery, 10 (31.3%) were located above the vertebral artery, and the remaining 8 tumors (25%) were observed on both sides. Preoperative MRI revealed encasement of the vertebral artery in 7 cases (11.3%). In 13 cases (21.0%), subpial infiltration of the tumor to the brainstem was observed on both preoperative MRI and intraoperative examination. The median tumor volume measured 5.8 cm3 (range 0.5 cm3–27.7 cm3). Intratumoral calcification was observed in 10 patients (16.1%) based on preoperative MR images or CT scans.

The overwhelming majority of meningiomas were classified as WHO grade 1 (59, 95.2%), with the meningothelial subtype being by far the most common (54, 87.1%). This was followed by the transitional (2, 3.2%, including one WHO grade 2), atypical (2, 3.2%, WHO grade 2), fibrous (1, 1.6%), psammomatous (1, 1.6%), secretory (1, 1.6%), and angiomatous (1, 1.6%) subtypes. There was no case with WHO grade 3 meningioma.

The Molecular Profile of FM Meningiomas

The findings from our NGS analysis revealed distinct patterns of gene mutations in FM meningiomas. Clinically significant driver mutations were detected in 58 patients (93.5%). TRAF7 (26, 41.9%) emerged as the most frequently mutated gene, followed by AKT1E17K (19, 30.6%), NF2 (11, 17.7%), POLR2A (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q (7, 11.3%), and PIK3CA (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). Notably, 4 patients (6.5%; 1 female, 3 males) did not exhibit any known driver mutations.

Within our cohort, meningiomas with a TRAF7 mutation (n = 26) often exhibited additional mutations in AKT1 (n = 7), KLF4 (n = 7), and PIK3CA (n = 2), while 10 meningiomas harbored a TRAF7 mutation only. Co-occurring mutations in NF2-mutant meningiomas included SMARCB1 (n = 1) and TP53 (n = 1) mutations. Importantly, KLF4 mutations were consistently observed alongside TRAF7 mutations. Moreover, a mutually exclusive relationship was observed between TRAF7 and NF2 mutations (p < 0.001). Among the AKT1 mutations, 7 (36.8%) occurred simultaneously with TRAF7 mutations but were mutually exclusive with KLF4, POLR2A, NF2, and PIK3CA mutations (Fig. 1).

FIG. 1.
FIG. 1.

Summary of clinical features and molecular alterations of 62 FM meningiomas. Figure is available in color online only.

Corrections Between Genetic Findings and Clinical Characteristics

Distinct patterns of genetic mutations were observed in meningiomas based on their locations. TRAF7 and AKT1 mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). In contrast, NF2 mutations were significantly more common in posteriorly located tumors compared with AKT1 mutations (p = 0.012) or TRAF7 mutations (p = 0.0045) (Fig. 2).

FIG. 2.
FIG. 2.

Anatomical distribution of meningiomas along the FM and in relation to the brainstem. Figure is available in color online only.

Within our cohort, we identified 46 female patients, indicating a notable female predominance. Among these female patients, 20 had TRAF7 mutations, 12 had AKT1 mutations, 9 had POLR2A mutations, 8 had NF2 mutations, 7 had KLF4 mutations, and 3 had PIK3CA mutations. Interestingly, all patients with POLR2A and KLF4 mutations were female. The median age at the initial diagnosis was 60 years for the entire cohort, 51 years for POLR2A-mutant meningioma patients, 66 years for NF2-mutant meningioma patients, and 60 years for TRAF7-mutant meningioma patients. Patients with POLR2A mutations tended to be younger at the time of the first diagnosis, although the difference was not statistically significant compared with patients with NF2 (p = 0.096) or TRAF7 (p = 0.12) mutations.

In terms of tumor volume, POLR2A-mutant tumors exhibited the largest size, measuring a median of 9.2 cm3 (Fig. 3). They were followed by AKT1-alone mutant tumors (6.5 cm3), NF2-mutant tumors (6.0 cm3), TRAF7-alone mutant tumors (5.7 cm3), and PIK3CA-mutant FM meningiomas (5.4 cm3). On the other hand, TRAF7/KLF4-mutant and TRAF7/AKT1-mutant tumors showed the smallest tumor volumes, measuring 2.1 cm3 and 2.4 cm3, respectively. Regarding subpial infiltration of the tumor into the brainstem, no significant differences were observed between the molecular groups. Approximately half of the NF2-mutant meningiomas (5/11, 45.5%) exhibited subpial infiltration of the brainstem surface, followed by AKT1-mutant (5/19, 26.3%) and POLR2A-mutant (2/8, 25%) meningiomas. In addition, encasement of the vertebral artery was observed in 3 cases with TRAF7 mutations, 2 cases with POLR2A mutations, and 1 case each with NF2 and AKT1 mutations (Fig. 3).

FIG. 3.
FIG. 3.

Upper row: Axial, coronal, and sagittal gadolinium-enhanced T1-weighted MR images (left to right) obtained from a representative case of a large POLR2A-mutant FM meningioma (20.5 cm3) with encasement of the left vertebral artery (red arrow) and subpial infiltration of the brainstem surface (yellow arrow). Lower row: Axial, coronal, and sagittal gadolinium-enhanced T1-weighted MR images (left to right) obtained from a representative case of a small TRAF7/KLF4-mutant FM meningioma (2.5 cm3) with no encasement of the vertebral arteries (red arrow) and no subpial infiltration of the brainstem surface. Figure is available in color online only.

Regarding a potential link between genetics and histology, all tumors harboring AKT1 (n = 19) and POLR2A (n = 8) mutations displayed meningothelial histology. Lastly, 10 meningiomas exhibited calcifications on preoperative MR images or CT scans, with 4 of these tumors harboring NF2 mutations. NF2-mutant meningiomas showed a significantly higher incidence of calcification compared with AKT1 mutants (p = 0.047) and other mutants. All the patient data analyzed in this work are presented in Supplementary Table 1.

Discussion

FM meningiomas account for 1% to 3% of all meningiomas and 7% of all posterior fossa meningiomas.2 The results of our study provide valuable insights into FM meningiomas, emphasizing several important findings. First, we have provided the first description of the mutational profile specific to FM meningiomas, including TRAF7, AKT1, NF2, POLR2A, and KLF4. Our study revealed a strikingly high prevalence of TRAF7 mutations, constituting about 42% of cases. This phenomenon has not been previously reported in the context of posterior fossa meningiomas (Supplementary Table 2).5,21 Furthermore, we have confirmed the recurrent presence of AKT1 mutations, accounting for 30% of cases, as previously elucidated.12 Additionally, our findings indicate that KLF4 mutations, typically associated with anterior skull base meningiomas, are unexpectedly prevalent in FM meningiomas (11% in the current study).14,21 More importantly, these mutations were found to be associated with patient demographics and specific tumor features, such as the location of the tumor anterior or posterior to the FM. Specifically, TRAF7 mutations were significantly more common in anteriorly located tumors compared with NF2 mutations. On the other hand, NF2 mutations were significantly more prevalent in posteriorly located tumors compared with AKT1 mutations. It is noteworthy that our study reveals an NF2 mutation rate of 17.7%, which closely aligns with the findings of a recent study on NF2 mutation rates in skull base meningiomas. In that study, NF2 mutations were detected in 11.5% of posterior fossa cases.22 We have previously reported on the frequency of AKT1 mutations in spinal meningiomas, predominantly located in the cervical spine ventrally or ventrolaterally to the spinal cord.16 This discovery, in conjunction with the high rate of AKT1 mutations in anteriorly and laterally located FM meningiomas may indicate a potential origin of these tumors in the spinal meninges or reflect their development at the embryonic transition zone between the neural crest–derived anterior skull base dura and the mesoderm-derived spinal meninges.12,16 Similar to NF2-mutant spinal meningiomas, NF2-mutant FM meningiomas showed a higher incidence of calcification compared with AKT1 mutants.16

Interestingly, we observed a significantly higher frequency of FM meningiomas in female patients, suggesting a sex predisposition for this particular tumor location. In this context, POLR2A and KLF4 mutations were exclusively detected in female patients, aligning with prior reports.6,14,23 Moreover, all patients with POLR2A mutations were significantly younger at the time of first diagnosis and exhibited larger tumor volume at diagnosis compared with patients with NF2 or TRAF7 mutations who were older and harbored smaller tumors. This suggests potential age-related differences in the development or progression of meningiomas associated with these specific mutations. The finding that tumors harboring dual mutations (TRAF7/KLF4 and TRAF7/AKT1) displayed the smallest tumor volumes is noteworthy and suggests a potential association between these specific genetic alterations and tumor size. In terms of histology, AKT1 and POLR2A mutants consistently showed an association with meningothelial histology, emphasizing the potential role of these mutations in specific tumor subtypes. From a surgical perspective, no significant differences were observed between the molecular groups in terms of two challenging tumor features: subpial infiltration of the brainstem surface and encasement of the vertebral artery.

From a molecular standpoint, the AKT1E17K mutation emerges as a prevalent oncogenic alteration, appearing in approximately 30% of our current cohort. This rate reveals a higher prevalence compared with other publications, in which only 8.5% to 19% of cases exhibited AKT1 mutations5,21 (Supplementary Table 2). This discrepancy may be attributed to the underrepresentation of FM meningiomas in those studies.21 It is important to mention that the rate of AKT1 mutations in posterior fossa meningiomas can vary significantly. This variation may be due to earlier studies that combined different meningiomas from various areas within the posterior fossa into a single group without specifying where they came from. This underscores the strength of our current study, in which we have specifically focused on FM meningiomas, allowing for a more precise assessment of the mutational landscape in this unique subset of posterior fossa tumors.

Importantly, AKT1 mutations also occur in a subset of other cancer types, including breast, ovarian, lung, prostate, and colorectal cancers.24 Encouragingly, ongoing research is actively exploring targeted inhibitors like capivasertib. In a multiarm phase 2 clinical trial (NCT02523014, Alliance A071401; clinicaltrials.gov) that includes patients with progressive meningioma, capivasertib has been incorporated as one of four genomics-guided treatments for individuals with AKT1-mutant meningiomas. Given the challenges associated with resection of FM meningiomas,2 the inclusion of eligible patients with incompletely resected tumors in this ongoing multicenter study could potentially transform the treatment paradigm by incorporating medical intervention as an adjuvant therapy.17 This approach requires molecular screening of FM meningiomas, especially considering that AKT1-alone mutant FM meningiomas constituted the molecular group with the second largest tumor sizes in our study, further complicating their complete resection compared with their counterparts harboring TRAF7/KLF4 mutations. In addition, it is worth noting that AKT1-mutant FM meningiomas predominantly originate in anterior locations, which adds to the challenge of achieving complete resection in these cases.

While our study offers valuable insights into the molecular characteristics of FM meningiomas, it is essential to recognize its limitations. We did not report patient outcomes, primarily because of the limited number of recurrences within the study’s follow-up period. Additionally, we acknowledge the use of two distinct NGS panels at separate institutions for sequencing the samples. However, it is worth noting that both panels encompassed the key driver genes associated with meningiomas, including TRAF7, NF2, AKT1, SMO, PIK3CA, PLOR2A, and KLF4. Furthermore, it is important to highlight that our study’s sample size, while comprehensive, may still be insufficient to establish significant correlations between certain tumor features and their mutational status. Finally, the sample size of nonmeningothelial cases was relatively limited, which may have affected our ability to identify statistically significant associations between mutations and specific histological subtypes. Taken together, our results underscore the heterogeneity of FM meningiomas in terms of genetic mutations, sex distribution, tumor location, age at diagnosis, and histological characteristics. These findings contribute to a deeper understanding of the molecular mechanisms underlying this tumor type and may have implications for personalized treatment strategies and prognostic assessments.

Conclusions

Genotyping of FM meningiomas may enable a better understanding of tumor features and guide their resection. Our findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future. A large subset of FM meningiomas harbor AKT1E17K mutations and are therefore potentially amenable to adjuvant targeted medical therapy in cases with tumor remnants. Further studies are needed to confirm these observations and to elucidate the underlying mechanisms of these genetic alterations in the development and progression of these tumors.

Acknowledgments

This work is supported by the Sibylle Assmus Foundation. Dr. Juratli received the Sibylle Assmus Foundation 2021 Neurooncology Award.

Disclosures

Dr. Shankar reported being a consultant for DePuy and Johnson & Johnson; and research support from NuVasive. Dr. Brastianos reported institutional grants to Massachusetts General Hospital from Merck, Mirati, Kinnate, Eli Lilly, and BMS; personal fees from CraniUS, Medscape, SK Life Sciences, ElevateBio, Voyager Therapeutics, Genentech, Advise Connect Inspire, InCephalo, MPM Capital Advisors, Sintetica, Axiom Healthcare Strategies, Kazia, Dantari, and Pfizer; grant support for clinical trial (including drug) from Genentech-Roche, Eli Lilly, Merck, AstraZeneca, Kazia, BMS, and Pfizer; grants from BCRF, NIH, Hellenic Women’s Club Demetra Fund, and AACR; and nonfinancial support (drug supply for research) from Verastem outside the submitted work. Dr. Cahill reported personal fees from GSK, Incephalo, Boston Pharmaceuticals, and Boston Scientific; and equity options from Pyramid Biosciences outside the submitted work. Dr. Juratli reported personal fees from CSL Behring outside the submitted work.

Author Contributions

Conception and design: Juratli, Hua, Zolal, Shankar, Eyüpoglu. Acquisition of data: Juratli, Hua, Alkhatib, Fujio, Alhasan, Herold, Zeugner, Schackert. Analysis and interpretation of data: Juratli, Alkhatib, Herold, Zolal, Shankar, Brastianos, Barker, Cahill. Drafting the article: Juratli, Hua, Shankar. Critically revising the article: Juratli, Fujio, Herold, Hijazi, Clark, Wakimoto, Shankar, Barker, Cahill, Eyüpoglu, Schackert. Reviewed submitted version of manuscript: Juratli, Hua, Alkhatib, Fujio, Alhasan, Zeugner, Hijazi, Clark, Wakimoto, Shankar, Brastianos, Barker, Cahill. Approved the final version of the manuscript on behalf of all authors: Juratli. Statistical analysis: Juratli, Ren. Administrative/technical/material support: Juratli, Fujio, Herold, Ren, Schackert. Study supervision: Juratli, Gong.

Supplemental Information

Online-Only Content

Supplemental material is available with the online version of the article.

References

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    Arnautović KI, Al-Mefty O, Husain M. Ventral foramen magnum meninigiomas. J Neurosurg. 2000;92(1 suppl):7180.

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    Bruneau M, George B. Foramen magnum meningiomas: detailed surgical approaches and technical aspects at Lariboisière Hospital and review of the literature. Neurosurg Rev. 2008;31(1):1933.

    • PubMed
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    George B, Lot G, Boissonnet H. Meningioma of the foramen magnum: a series of 40 cases. Surg Neurol. 1997;47(4):371379.

  • 4

    Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet. 2013;45(3):285289.

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    Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339(6123):10771080.

  • 6

    Clark VE, Harmancı AS, Bai H, et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48(10):12531259.

  • 7

    Williams EA, Santagata S, Wakimoto H, et al. Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic. Acta Neuropathol Commun. 2020;8(1):171.

    • PubMed
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  • 8

    Williams EA, Wakimoto H, Shankar GM, et al. Frequent inactivating mutations of the PBAF complex gene PBRM1 in meningioma with papillary features. Acta Neuropathol. 2020;140(1):8993.

    • PubMed
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    Sahm F, Schrimpf D, Stichel D, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 2017;18(5):682694.

    • PubMed
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    Abedalthagafi M, Bi WL, Aizer AA, et al. Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol. 2016;18(5):649655.

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    Strickland MR, Gill CM, Nayyar N, et al. Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas. J Neurosurg. 2017;127(2):438444.

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    Williams SR, Juratli TA, Castro BA, et al. Genomic analysis of posterior fossa meningioma demonstrates frequent AKT1 E17K mutations in foramen magnum meningiomas. J Neurol Surg B Skull Base. 2019;80(6):562567.

    • PubMed
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    • Export Citation
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    Youngblood MW, Clark V, Harmanci AS, et al. Clinical and molecular features of genomic subgroups in meningioma. J Neurosurg. 2017;126(4):A1424.

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    Youngblood MW, Duran D, Montejo JD, et al. Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas. J Neurosurg. 2019;133(5):13451354.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Jin L, Youngblood MW, Gupte TP, et al. Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas. J Neurooncol. 2021;154(2):237246.

  • 16

    Hua L, Alkhatib M, Podlesek D, et al. Two predominant molecular subtypes of spinal meningioma: thoracic NF2-mutant tumors strongly associated with female sex, and cervical AKT1-mutant tumors originating ventral to the spinal cord. Acta Neuropathol. 2022;144(5):10531055.

    • PubMed
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    Ijad N, Dahal A, Kim AE, Wakimoto H, Juratli TA, Brastianos PK. Novel systemic approaches for the management of meningiomas: immunotherapy and targeted therapies. Neurosurg Clin N Am. 2023;34(3):447454.

    • PubMed
    • Search Google Scholar
    • Export Citation
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    Rosset A, Spadola L, Ratib O. OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging. 2004;17(3):205216.

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    Yushkevich PA, Piven J, Hazlett HC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):11161128.

    • PubMed
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  • 20

    Juratli TA, Prilop I, Saalfeld FC, et al. Sporadic multiple meningiomas harbor distinct driver mutations. Acta Neuropathol Commun. 2021;9(1):8.

  • 21

    Yesilöz Ü, Kirches E, Hartmann C, et al. Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro Oncol. 2017;19(8):10881096.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Tabor JK, O’Brien J, Vasandani S, et al. Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas. J Neurosurg. 2023;139(6):16481656.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lee YS, Lee YS. Molecular characteristics of meningiomas. J Pathol Transl Med. 2020;54(1):4563.

  • 24

    Hyman DM, Smyth LM, Donoghue MTA, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):22512259.

  • Collapse
  • Expand
  • FIG. 1.

    Summary of clinical features and molecular alterations of 62 FM meningiomas. Figure is available in color online only.

  • FIG. 2.

    Anatomical distribution of meningiomas along the FM and in relation to the brainstem. Figure is available in color online only.

  • FIG. 3.

    Upper row: Axial, coronal, and sagittal gadolinium-enhanced T1-weighted MR images (left to right) obtained from a representative case of a large POLR2A-mutant FM meningioma (20.5 cm3) with encasement of the left vertebral artery (red arrow) and subpial infiltration of the brainstem surface (yellow arrow). Lower row: Axial, coronal, and sagittal gadolinium-enhanced T1-weighted MR images (left to right) obtained from a representative case of a small TRAF7/KLF4-mutant FM meningioma (2.5 cm3) with no encasement of the vertebral arteries (red arrow) and no subpial infiltration of the brainstem surface. Figure is available in color online only.

  • 1

    Arnautović KI, Al-Mefty O, Husain M. Ventral foramen magnum meninigiomas. J Neurosurg. 2000;92(1 suppl):7180.

  • 2

    Bruneau M, George B. Foramen magnum meningiomas: detailed surgical approaches and technical aspects at Lariboisière Hospital and review of the literature. Neurosurg Rev. 2008;31(1):1933.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 3

    George B, Lot G, Boissonnet H. Meningioma of the foramen magnum: a series of 40 cases. Surg Neurol. 1997;47(4):371379.

  • 4

    Brastianos PK, Horowitz PM, Santagata S, et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet. 2013;45(3):285289.

  • 5

    Clark VE, Erson-Omay EZ, Serin A, et al. Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science. 2013;339(6123):10771080.

  • 6

    Clark VE, Harmancı AS, Bai H, et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48(10):12531259.

  • 7

    Williams EA, Santagata S, Wakimoto H, et al. Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic. Acta Neuropathol Commun. 2020;8(1):171.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8

    Williams EA, Wakimoto H, Shankar GM, et al. Frequent inactivating mutations of the PBAF complex gene PBRM1 in meningioma with papillary features. Acta Neuropathol. 2020;140(1):8993.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9

    Sahm F, Schrimpf D, Stichel D, et al. DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol. 2017;18(5):682694.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10

    Abedalthagafi M, Bi WL, Aizer AA, et al. Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol. 2016;18(5):649655.

  • 11

    Strickland MR, Gill CM, Nayyar N, et al. Targeted sequencing of SMO and AKT1 in anterior skull base meningiomas. J Neurosurg. 2017;127(2):438444.

  • 12

    Williams SR, Juratli TA, Castro BA, et al. Genomic analysis of posterior fossa meningioma demonstrates frequent AKT1 E17K mutations in foramen magnum meningiomas. J Neurol Surg B Skull Base. 2019;80(6):562567.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 13

    Youngblood MW, Clark V, Harmanci AS, et al. Clinical and molecular features of genomic subgroups in meningioma. J Neurosurg. 2017;126(4):A1424.

  • 14

    Youngblood MW, Duran D, Montejo JD, et al. Correlations between genomic subgroup and clinical features in a cohort of more than 3000 meningiomas. J Neurosurg. 2019;133(5):13451354.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 15

    Jin L, Youngblood MW, Gupte TP, et al. Type of bony involvement predicts genomic subgroup in sphenoid wing meningiomas. J Neurooncol. 2021;154(2):237246.

  • 16

    Hua L, Alkhatib M, Podlesek D, et al. Two predominant molecular subtypes of spinal meningioma: thoracic NF2-mutant tumors strongly associated with female sex, and cervical AKT1-mutant tumors originating ventral to the spinal cord. Acta Neuropathol. 2022;144(5):10531055.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17

    Ijad N, Dahal A, Kim AE, Wakimoto H, Juratli TA, Brastianos PK. Novel systemic approaches for the management of meningiomas: immunotherapy and targeted therapies. Neurosurg Clin N Am. 2023;34(3):447454.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 18

    Rosset A, Spadola L, Ratib O. OsiriX: an open-source software for navigating in multidimensional DICOM images. J Digit Imaging. 2004;17(3):205216.

  • 19

    Yushkevich PA, Piven J, Hazlett HC, et al. User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability. Neuroimage. 2006;31(3):11161128.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20

    Juratli TA, Prilop I, Saalfeld FC, et al. Sporadic multiple meningiomas harbor distinct driver mutations. Acta Neuropathol Commun. 2021;9(1):8.

  • 21

    Yesilöz Ü, Kirches E, Hartmann C, et al. Frequent AKT1E17K mutations in skull base meningiomas are associated with mTOR and ERK1/2 activation and reduced time to tumor recurrence. Neuro Oncol. 2017;19(8):10881096.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22

    Tabor JK, O’Brien J, Vasandani S, et al. Clinical and genomic differences in supratentorial versus infratentorial NF2 mutant meningiomas. J Neurosurg. 2023;139(6):16481656.

    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23

    Lee YS, Lee YS. Molecular characteristics of meningiomas. J Pathol Transl Med. 2020;54(1):4563.

  • 24

    Hyman DM, Smyth LM, Donoghue MTA, et al. AKT inhibition in solid tumors with AKT1 mutations. J Clin Oncol. 2017;35(20):22512259.

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