Genomic Analysis of Non-Neurofibromatosis Type 2 Meningiomas (2013)

Meningiomas are the most common type of primary intracranial neoplasm, and they arise from arachnoid cap cells.1 The overwhelming majority of meningiomas are benign, World Health Organization (WHO) grade I lesions, while approximately 10% of meningiomas are atypical or malignant (WHO grades II and III respectively).2 It is well known that patients with Neurofibromatosis type 2 (NF2) commonly develop meningiomas and harbor a defect in the tumor suppressor gene Merlin (Neurofibromin 2), which codes for a membrane cytoskeleton protein.3 However, approximately 40% to 60% of sporadic meningiomas also have loss of this well-described tumor suppressor gene. The remaining genetic landscape of non-irradiated, non-NF2 meningiomas remains obscure. Recent research published in the March edition of Science from Gunel et al at Yale, has made great progress in comprehensively characterizing the genomics of multiple types meningiomas and the molecular mechanisms of their tumorgenesis.4 The researchers began by performing genotyping and exome sequencing of 50 non-irradiated grade I (n = 39) and grade II (n = 11) meningiomas along with matched normal DNA. They identified 10 genes within this banked tumor sample that met the criterion of having significantly more somatic mutations than expected by chance other than the putative NF2 gene mutation. From this analysis, they selected the top 5 genes, TRAF7, KLF4, AKT1, and SMO for targeted resequencing along with a chromosome 22 copy-number analysis in 250 unradiated meningiomas (204 grade I and 46 high grade meningiomas). In their combined analysis of all 300 meningiomas, they identified coding mutations in one of the fives genes and/or demonstrated chromosome 22 loss in 237 (79%) of all the tumor samples. The most common finding in the tumor set was NF2 mutations, which were present in 108 (36%) of the samples. TRAF7 mutations, which were always exclusive of the NF2 mutations, were observed in 72 (24%) of the meningiomas. Genetic aberrations were common in the transcription factor KLF4 (n = 31, 10%) that produced a K409Q mutation, which almost always co-occurred with TRAF7 mutations. The well-studied neoplasia-related mutation AKT1Ei7K, was identified in 38 meningiomas. Interestingly, the AKT1Ei7K co-occurred with TRAF7 mutations in 25 of the 38 tumors (66%), but was exclusive of the KLF4 and NF2 mutations, except for a single case. Finally, SMO mutations (L412F and W535L), were identified in 11 (3.7%) tumors. Eight of these 11 mutations were mutually exclusive of mutations from the other four genes. Subsequently, an analysis of chromosomal instability was performed which demonstrated chromosome 22 loss in 149 (50%) tumors and correlated strongly with the presence of NF2 mutations as well as higher tumor grade. In addition, the investigators correlated mutation type with anatomical distribution and histological subtype. Tumors with NF2 mutations or chromosome 22 loss showed a predilection for the cerebral convexities. Additionally, this tumor subtype accounted for virtually all posterior cerebral, cerebellar, or spinal meningiomas (Figure). Their analysis of skull base meningiomas was divided into medial and laterally based tumors. Meningiomas with the SMO L412F , mutation (n = 5) all localized to the medial anterior skull base. Interestingly, L412F may play a role in Hedgehog signaling pathways, which is essential for directing proper lateral cellular migration in embryogenesis. Finally, the mutational profiles of meningiomas which carried both TRAF7 and KLF4 mutations correlated with higher histologic grade. In conclusion, the researchers provide invaluable new information about the molecular characteristics of meningioma tumorgenesis. Their analysis of meningiomas suggests that we may be able to predict tumor behavior based on the location and genetic profile of these lesions. Furthermore, this research suggests that targeted therapeutics based on genetic profiling of meningiomas may one day be possible for the treatment of this common tumor.Figure: Along the skull base, NF2/chr22loss meningiomas originate from the lateral and posterior regions, whereas the vast majority of anterior and medial meningiomas are non-NF2 mutant (light blue). SMO meningiomas were found to preferentially distributed along the medial anterior skull base (light green). From 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):1077-1080. Reprinted with permission from AAAS.