Distinct genomic subclasses of high-grade/progressive meningiomas: NF2-associated, NF2-exclusive, and NF2-agnostic

Abstract

Background Genomic studies of high-grade/progressive meningiomas have reported a heterogeneous mutation spectrum, identifying few recurrently mutated genes. Most studies have been underpowered to detect genomic subclasses of aggressive meningiomas due to relatively small number of available samples. Here, we present a genomic survey of one of the largest multi-institutional cohorts of high-grade/progressive meningiomas to date. Methods 850 high-grade/progressive meningiomas, including 441 WHO grade 2 and 176 WHO grade 3 meningiomas and 220 progressive WHO grade 1 meningiomas, were tested as part of a clinical testing program by hybridization capture of 406 cancer-related genes to detect base substitutions, indels, amplifications, deletions, and rearrangements. Information from pathology reports, histopathology review, and patient clinical data was assessed. Results Genomic analyses converged to identify at least three distinct patterns of biologically-aggressive meningiomas. The first and most common contained NF2-mutant tumors (n = 426, 50%), was associated with male sex (64.4% %, p = 0.0001) and often harbored additional mutations in CDKN2A/B (24%), and the chromatin regulators ARID1A (9%), and KDM6A (6%). A second group (NF2-agnostic) featured TERT promoter (TERTp; n = 56) or TP53 mutations (n = 25) and were either NF2-mutant or wild-type, and displayed no association with either sex (p = 0.39). The remaining group generally lacked NF2 mutations, and accounted for 40% of the cases—with three subgroups. One consistent primarily of grade 3 lesions harboring alterations in chromatin regulators BAP1 (n = 22) or PBRM1 (n = 16). A second subgroup contained AKT1 (n = 26), PIK3CA (n = 14) and SMO (n = 7) mutant skull-based meningiomas, and a third mixed subgroup included 237 meningiomas with a heterogeneous spectrum of low frequency and non-recurrent alterations. Conclusions Our findings indicate that the patterns of genomic alterations in high-grade/progressive meningiomas commonly group into three different categories. The most common NF2-associated canonical group frequently harbored CDKN2A/B alterations, which is potentially amenable to targeted therapies. An NF2-agnostic group harbored frequent TERTp and TP53 mutations. The final subclass, distinct from the canonical NF2 mutant associated pathway, was partly characterized by BAP1/PBRM1 alterations (rhabdoid/papillary histology) or skull-base disease. Overall, these data increase our understanding of the pathobiology of high-grade/progressive meningiomas and can guide the design of clinical trials. IRB approval status Reviewed and approved by Western IRB; Protocol No. 20152817.

Molecular Profiling of 22 Primary Atypical Meningiomas Shows the Prognostic Significance of 18q Heterozygous Loss and CDKN2A/B Homozygous Deletion on Recurrence-Free Survival

“…Among the NF2- mutated meningiomas, two cases, resected from male patients and located at the convexity, showed 1p and/or 22q deletion, and ARID1A or FBXW7 mutation. These cases could follow the canonical NF2 -mutant pattern of progressive meningioma recently described by Williams et al [ 9 ]. This, indeed, is characterized by mutations of several genes including ARID1A and FBXW7, by 1p and/or 22q deletion, and by the association with male sex and localization at the convexity, in addition to NF2 mutation [ 9 ].…”

“…The most frequent cytogenetic alteration in meningiomas is the loss of chromosome 22q [ 8 , 9 ]. This latter harbors the NF2 gene, which is inactivated by copy number variations and/or point mutations in around 60% of cases [ 9 , 10 , 11 , 12 , 13 ]. Tumors with intact NF2 have mutations in other genes, including AKT1 , SMO , TRAF7 , and KLF4 [ 14 , 15 ].…”

“…A recent study showed that grade II meningiomas are molecularly heterogeneous and, based on the mutational status of NF2 , TERT promoter, TP53 , BAP1 , PRBM1 , AKT1 , SMO and PIK3CA, they can be subgrouped into three different categories, each characterized by peculiar clinical-pathological features [ 9 ]. Other studies demonstrated that the integration of the histopathological diagnosis with the methylation profile, karyotype, or mutational status of the TERT promoter could allow for a better prognostic stratification of meningiomas [ 18 , 19 , 20 , 21 , 22 ].…”

Sporadic multiple meningiomas harbor distinct driver mutations

“…Familial syndromes that are commonly associated with MM are neurofibromatosis type 2 (NF2) and familial meningiomatosis in patients with germline NF2 and SMARCB1 mutations, respectively [ 2 , 15 ]. While the mutational landscape of single meningiomas has been extensively studied [ 3 – 5 , 10 , 20 ], understanding of the molecular pathogenesis of sporadic MM remains incomplete. Older studies and case reports have reported molecular testing in patients with sporadic MM that have principally been focused on tumors with NF2 mutations [ 8 , 16 – 18 ].…”

Meningioma epigenetic grouping reveals biologic drivers and therapeutic vulnerabilities

“…Druggable somatic short variants in meningiomas are rare and are not associated with adverse outcomes 10,[14][15][16][17][18][19][44][45][46][47][48][49] , with rare exceptions [50][51][52][53] . Differential expression of enhancers and super-enhancers within the consensus meningioma peakset revealed the enhancer landscape of Hypermitotic meningiomas was dominated by epigenetic mechanisms and transcription factors, such as FOXM1, that are impractical pharmacologic targets (Extended Data Fig.…”