Patient demographics
We identified 850 biologically-aggressive meningiomas (defined further below) with available molecular data that were profiled in the comprehensive genomic profiling (CGP) program at Foundation Medicine between 2013 and 2019. These tumors were resected from different patients; 466 females and 384 males (ratio 1.2:1). The median patient age was 57 years (range 0–89 + years). While the cohort included meningiomas of all WHO grades (1, 2 and 3), it predominantly consisted of high-grade meningiomas (441 WHO grade 2 and 176 WHO grade 3), in addition to 220 “progressive” WHO grade 1 meningioma defined as relapsed or “under-treatment” progressive tumors. Tumor locations included the skull base (n = 243), supratentorial area (non-skull base, n = 430), non-CNS sites including the skin of the head and distant metastases (n = 32), and spine (n = 30; three of these spine meningiomas were clinically considered as likely drop metastases). The data about tumor location was not available for 114 cases. (Additional file 1: Table S1).
Genomic alterations
Loss of chromosome 22q (84.1% of eligible cases) and loss of chromosome 1p (68.8%) were the most common copy number alterations in our cohort (Additional file 2: Figure S1). NF2 mutations represented the most frequent gene mutations (n = 474/850, 55.7%). While NF2 mutations and 22q loss events were correlated, there were several cases with 22q loss without detectable NF2 mutation, raising the possibility of cryptic NF2 inactivation. The frequency of NF2 mutations increased significantly with the WHO grade: 81/220 of grade 1 (36.8%), 265/441 of grade 2 (60.1%, p = 0.0001) and 122/176 of grade 3 (69.3%, p = 0.0001) meningiomas harbored NF2 mutations. Moreover, male patients (n = 245/384, 64%) were significantly more affected by NF2-mutant meningiomas than female patients (n = 227/466, 48.7%, p = 0.0001). We detected frequent genomic alterations of genes encoding regulators of the cyclin-dependent kinase inhibitor pathway, including CDKN2A/B deletions (n = 123/850, 14.4%), CDKN2C mutations (n = 16/850, 1.9%), and CDK4 amplifications (17/850 cases with high level amplifications ≥ 4 gene copies, 2%). Additional frequently altered genes included: TERT (7.1%, 56 promoter hotspot mutations of 789 sequenced cases), ARID1A (5.4%, 46 cases, including one gene structural translocation), PTEN (4.3%, 27 mutations, 10 focal gene deletions and one PTEN_TMEM38A_rearrangement), KDM6A (3.5%; 30 cases, including focal exon deletions), SUFU (2.7%, 17 mutations, 5 focal exon deletions and one gene rearrangement), TP53 (2.9%, 23 mutations, 1 focal deletion and 1 gene translocation), BAP1 (2.7%, 18 mutations and 5 exon deletions) and PBRM1 (1.8%, 10 mutations and 5 focal exon deletions). This comprehensive genomic characterization suggested that high-grade/progressive meningiomas could be separate into largely distinct classes; for further analysis, we divided the tumors into three overall subclasses (Figs. 1, 2). All genomic data are shown in Additional file 1: Table S1.
The NF2-associated pathway of meningiomas (the canonical pathway)
This group included 426 meningiomas (50.1%), and represented the largest group of tumors. The NF2 alterations involved 393 NF2 missense mutations (93%), 21 two copy deletions (4.5%) and 12 NF2 structural rearrangements (2.5%). The vast majority of tumors (99.7%) showed synchronous chromosome 22q LOH and 76.9% showed a 1p chromosome loss. The median age of patients was 59 years (range 0–89 + years). We also observed an enrichment in alterations in CDKN2A/B, KDM6A, ARID1A, PTEN, FBXW7, and SUFU in comparison with NF2-wt meningiomas (Additional file 3: Figure S2).
Bi-allelic CDKN2A/B deletions occurred in 93/472 of all NF2-mutant (19.7%) versus 30/377 in NF2-wt meningiomas (8.0%) (p = 0.0001). In the canonical NF2-mutant group, 17.1% (n = 72/426) harbored a CDKN2A/B deletion (Fig. 2). Interestingly, meningiomas harboring CDKN2A/B alterations were significantly more common in males (n = 77/123, 62.6%) than in females (p = 0.0001). CDKN2A/B alterations were significantly enriched in WHO grade 3 meningiomas (n = 75/176, 42.6%) in comparison to WHO grade 2 (n = 47/441, 10.6%, p = 0.0001). Only one WHO grade 1 meningioma had a CDKN2A/B alteration (n = 1/220, 0.4%, p = 0.0001).
Furthermore, were observed a significant association of alterations in the chromatin regulator ARID1A in NF2-mutant meningiomas (n = 34/472, 7%) versus NF2-wt meningiomas (n = 12/377, 3.2%, p = 0.0138). ARID1A alterations were significantly more common in WHO grade 3 meningiomas (n = 26/176, 14.8%) than in WHO grade 2 (n = 18/441, 4.1%, p = 0.0001) and WHO grade 1 meningiomas (n = 1/220, 0.4%, p = 0.0001). ARID1A alterations were significantly more frequently seen in male patients (29/46, 63%, p = 0.0146). Moreover, a mutual co-occurrence of ARID1A mutations was detected in a subset of meningiomas that harbored aberrations of CDKN2A/B (n = 18), KDM6A (n = 16), PTEN (n = 13), FBXW7 (n = 3) and SUFU (n = 7), as shown in Fig. 3.
PTEN mutations were identified in 28/472 of all NF2-mutant (5.9%) and in 10/376 of NF2-wt meningiomas (2.6%) (p = 0.0287). Additionally, PTEN mutations were found to be more frequently associated with a WHO grade 3 (n = 15/176, 8.5%) than grade 2 (n = 17/441, 3.8%, p = 0.025) or grade 1 (5/220, 2.3%, p = 0.0094) meningioma in our cohort. Notably, PTEN mutations occurred mutually concurrent with CDKN2A/B (n = 13), KDM6A (n = 5) and SUFU aberrations (n = 2), as shown in Fig. 3.
Importantly, we detected KDM6A alterations in 23/472 of all NF2-mutant (4.9%) versus 7/377 in NF2-wt meningiomas (1.9%) (p = 0.0234). Similarly, KDM6A alterations occurred significantly more often in WHO grade 3 meningiomas (n = 15/176, 9%) versus 13/441 (2.9%, p = 0.0046) and 2/220 (0.9%, p = 0.0001) in WHO grade 2 and 1 meningiomas, respectively.
In addition, the meningiomas of 23 patients showed SUFU mutations, 18 in NF2-mutant (3.7%) and 5 in NF2-wt meningiomas (1.3%, p = 0.033). SUFU mutations were found more frequently in WHO grade 3 (n = 11/176, 6.3%) than grade 2 (n = 11/441, 2.5%, p = 0.030) or grade 1 meningiomas (2/220, 0.9%, p = 0.0036) in our cohort.
FBXW7 mutations were present in 23/472 of all NF2-mutant (4.9%) and in 3/377 of NF2-wt meningiomas (0.8%) (p = 0.0004). No significant difference was identified between grades. Interestingly, we observed that FBXW7 mutations were mutually exclusive to PTEN or KDM6A mutations (Fig. 3).
Finally, in contrast to NF2, CDKN2A/B, and ARID1A alterations, male sex was not significantly associated with gene alterations in KDM6A, PTEN, FBXW7 or SUFU.
The NF2-agnostic group of meningiomas
This group (n = 79, 9.3%) was characterized by TERTp and TP53 mutations. The median age of patients was 60.1 years (range 31–86 years). TERTp mutations occurred in 35/441 (8.1%) of NF2-mutant meningiomas and in 21/348 of NF2-wt patients (5.7%, p = 0.21). WHO grade 3 meningiomas harbored the highest percentage of TERTp mutations (23/159, 14.5%), followed by WHO grade 2 (n = 28/421, 6.7%, p = 0.0048) and WHO grade 1 meningiomas (n = 5/199, 2.5%, p = 0.0001, Additional file 3: Figure S2).
Likewise, TP53 hotspot mutations were detected in 9/472 NF2-mutant meningiomas (1.9%), compared with 16/373 NF2-wt meningiomas (4.2%, p = 0.063). TP53 mutations occurred mainly in WHO grade 3 meningiomas (n = 12/176, 6.8%) followed by WHO grade 2 (n = 10/441, 2.2%, p = 0.0135) and a significantly lower percentage in grade 1 (n = 2/220, 0.9%, p = 0.0018) meningiomas. Notably, two meningiomas harbored simultaneous TERTp and TP53 mutations (Fig. 4). Neither TERTp (25 females, 31 males) nor TP53 (13 females, 12 males) mutations were significantly associated with patient sex. Further frequent genomic alterations in this group were CDKN2A/B deletions (n = 29/79, 36.7%), chromosome 22q loss (91.2%) and chromosome 1p loss (82.5%), Fig. 2).
The NF2 exclusive group of meningiomas contains three subclasses
There were several mutations identified in this third group of high-grade/progressive meningiomas which we further split into three largely distinct subclasses. In one of these subclasses, we found frequent BAP1 (n = 22) and PBRM1 (n = 16) alterations—including 5 cases with BAP1 and PBRM1 aberrations in the same tumor (total n = 33 tumors, Fig. 4). In addition, 81% of BAP1 and 87.5% PBRM1 mutant meningiomas were classified as WHO grades 2 and 3 meningiomas. Simultaneous NF2 mutations were very infrequently detected (n = 4/33 cases) in this subgroup. Likewise, only 45% and 40% of the meningiomas in this group harbored chromosome 22q and 1p loss, respectively. The median age of patients was 52 years (range 25–76 years). The hallmark of this subgroup is the substantial enrichment for rhabdoid and papillary histology and the not infrequent co-occurrence of these histologic features in the same tumor resection. As previously reported, 11 of 16 PBRM1 mutations (68.7%) occurred in meningioma with papillary histologic features [41].
A second subclass within this group contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 6) mutant meningiomas (total n = 46, Additional file 2: Figure S1). We observed a marked predominance of female patients in this subgroup (37 females vs. 9 males). In addition, the majority of these NF2-wt tumors were classified as WHO grade 1 meningioma (n = 31, 70.4%) and were located almost exclusively in the skull base (Fig. 2). Notwithstanding, this subclass also contained 14 WHO grade 2 meningiomas (8 AKT1, 5 PIK3CA, and 1 SMO case), and a subset of these higher grade cases harbored additional genomic alterations such as TERTp mutation (one AKT1-mutant meningioma), TP53 mutation (one PIK3CA-mutant case), PTEN alterations (2 meningiomas with an AKT1 mutation), and CDKN2A 2 copy loss (1 AKT1 case; 1 PIK3CA case). This finding suggests, due to anatomic location, a more biological aggressive course can occur during progression in these meningiomas that are largely regarded as “benign” and that the presence of these mutations is not invariably indicative of a WHO grade 1 designation.
The last subclass in this group contained a mix of 237 meningiomas with a heterogeneous spectrum of mutations outside of the genes mutated in other subclasses such as NF2, TERTp, TP53, BAP1, PBRM1, AKT1, SMO and PIK3CA. The majority of tumors in this subgroup occurred in women (n = 140, 59%). Chromosome 22q monosomy was detected in 112 cases (47.2%). The WHO grading was 88, 120 and 24 of grade 1, 2 and 3, respectively. This group will require further genomic characterization; some of the tumors in this class may ultimately be assigned to one of the other classes (for instance, 22q loss cases resolving to the NF2-associated canonical pathway above), whereas others may contain genomic or non-genomic drivers that are not yet associated with meningioma pathogenesis.
Disseminated meningiomas
Our cohort includes genomic data from 35 (4%) metastatic meningiomas (21 females and 14 males) with 3 occurring as metastases in the spine and 32 occurring outside of the CNS. Extracranial systemic metastases (e.g., in lung, kidney, liver) were reported in 17 cases (49%), whereas the remaining cases disseminated to skin and spine. The majority of disseminated meningiomas were WHO grade 2 (n = 16) and grade 3 (n = 11). Metastatic meningiomas were observed across all three molecular subclasses. Alterations in NF2 (n = 19, 54.3%), CDKN2A (n = 8, 22.9%), BAP1 (n = 4, 11.4%), ARID1A (n = 4, 11.4%), TERTp (n = 3, 9.4%), and TP53 (n = 2, 5.7%) were the most frequent relevant alterations detected in these cases. Interestingly, we did not observe significant association between any of these alterations with dissemination.
Finally, we did not detect recurrent clinically targetable gene rearrangements in our cohort (Additional file 1: Table S1).