Identification of Novel Therapeutic Targets Through Genomic Analysis of Meningiomas
Komotar, Ricardo J.; Starke, Robert M.; Connolly, E. Sander
Meningiomas are the most common primary extraaxial brain tumors.1 Although the majority of meningiomas are benign it is difficult to discern atypical or anaplastic meningiomas without pathological diagnosis. As these tumors are often in proximity to key neural and vascular structures, complete surgical resection is often associated with significant morbidity and mortality. Stereotactic radiosurgery is a commonly employed adjuvant or primary therapy, but can also lead to genetic mutations and additional primary tumors.2 Medical therapy is limited in the treatment of meningiomas in part due to our incomplete understanding of DNA alterations in meningiomas. A number of genetic alterations have been identified in meningiomas including loss of Neurofibromin 2 (NF2, marlin) in 40%-60% of sporadic meningiomas, but further genetic pathways remain incompletely defined.3-5 A greater evaluation of the genetic alterations in meningiomas could also help predict those that are more likely to be or transform into anaplastic lesions.
Recently, publications in Science6 and Nature Genetics7 reported key mutations in a number of genes in meningiomas. Studies found that meningiomas had a small number of somatic genetic events as compared to other tumor types, but was more likely in high grade meningiomas. Clark et al performed a genome-wide genotyping analysis of 50 meningiomas along with matched normal DNA.6 A number of mutations were found that occurred more likely than would be found by chance, for example NF2, TNF receptor-associated factor 7 (TRAF7), Krupple-like factor 4 (KLF4), v-akt murine thymoma viral oncogene homolog 1 (AKT1), and Smoothened, frizzled family receptor (SMO) (source). Additionally, NF2 occurred independently of those in TRAF7, KLF4, AKT1, and SMO. Targeted resequencing of these genes along with another cohort of 250 meningiomas reveled mutations in 1 of these genes and/or loss of chromosome 22 in 79% of samples.
TRAF7 mutations occurred in approximately 25% of samples.6 This has important functional implications as TRAF7 plays a role in many pathways proapoptotic mechanisms. KLF4 has been recently found to be a key pluropotency factor that can help transform differentiated somatic cells into pluripotent stem cells8 and was found in approximately 10% of meningiomas samples.6 AKT1 can induce PI3K/mTOR signaling pathways, is a known recurrent mutation in tumorgenesis, and occurred in approximately 13% of samples.6 Mutations in SMO which has been shown to active that Hedgehog signaling pathway in other tumors were found in approximately 4% of meningiomas.6 Similarly, Brastianos et al used genome analysis of a set of meningiomas and focused sequence analysis in a validation set to identify a number of mutations including NF2, SMO, and AKT1.7 The authors also found significant gains on chromosomes 5 and 20 and losses on 1p, 7p, 14p, and 19 which have been previously noted in the literature.9 Additionally, recurrent losses were found on 10q and 14q which found been previously found in anaplastic meningiomas.10
Both studies carried out additional studies to further assess pathway activation in meningiomas samples. GAB1 immunoreactivity has been used in medullobstomas to assess Hedgehog pathway activation.11 Brastianos et al found strong immunoreactivity for 7 tumors along including 3 meningiomas with SMO mutations.7 Similarly, STMN1 has been used to characterize PI3K-AKT induction.12 The authors also found that all meningiomas with AKT1 and MTOR mutations had strong immunoreactivity for STMN1.7 Additionally, 3 meningiomas with SMO mutations had STMN1 immunostaining. This supports prior studies that have indicated interactions between the PI3K-AKT-mTOR pathways.13
Mutations were further assessed to determine if they were associated with specific clinical and histological subtypes. Chromosome 22 loss, occurring 50% of samples was significantly associated with NF2 mutations, higher grade meningiomas, male gender, and cerebral hemisphere location.6 The majority of non-NF2 meningiomas were located medially and more likely to occur along with skull base.6 Those with TRAF7 and KLF4 were also associated with a histological secretory component (source).6 Brastianos et al also found that meningiomas with SMO and AKT1 mutations may be more likely to be located in therapeutically challenging locations such as the skull base.7 Additionally, they found that tumors with SMO and AKT1 mutations were more likely to have meningothelial histology and grade 1, NF2 mutated tumors were more likely to be of the transitional or fibroblastic subtype.7
These studies provide further evidence of the growing differentiation of specific tumors into genetic subtypes rather than just histological variants. Further studies may confirm that a number of these mutations are mutually exclusive, provide a significant risk of aggressive malignancy, are associated with specific anatomical locations, and demonstrate a specific histological diagnosis. Additionally, there are currently a number of medications that are either FDA-approved or in clinical trails that inhibit MTOR, AKT1, and SMO and may be particularly beneficial for specific meningiomas.
Figure. Fluid attenu...Image Tools
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