Novel Oncogenic SMO and AKT1 Mutations in Meningiomas

Introduction: Meningiomas are the most common primary nervous system tumor. Although many of these are benign in histology and location, resection of skull base meningiomas can be associated with higher morbidity, and recurrence rates are not insignificant. Higher grade meningiomas recur with greater frequency and affect long-term survival as well. The tumor suppressor NF2 is disrupted in approximately half of meningiomas, but the complete spectrum of genetic changes remains undefined.

Methods: To identify novel genetic alterations that might contribute to meningioma genesis and present opportunities for new chemotherapeutic interventions, we undertook genetic sequencing of a cohort of 65 meningiomas. We performed whole-genome sequencing on 11 tumor-normal pairs, whole-exome sequencing on 6, and focused sequencing on an additional 48 tumors, to comprehensively identify and validate somatic genetic alterations.

Results: Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than other published adult malignancies. However, several meningiomas harbored more complex patterns of copy-number changes (hyperdiploid) and multiple DNA translocations, including one tumor with chromothripsis, a simultaneous catastrophic rearrangement of one chromosome. We confirmed focal NF2 inactivation in 43% of tumors and found novel perturbations in the histone-demethylase KDM5C. Isolated mutations in other histone- and DNA-modifying genes, including SMARCB1 (implicated in schwannomatosis), were also observed. Meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in two oncogenes, AKT1 (E17K) and SMO (W535L), and exhibited immunohistochemical evidence of activation of their pathways. Additional genotyping experiments uncovered a grade III meningioma with AKT1 (E17K) mutation as well.

Conclusions: These results begin to define the spectrum of genetic alterations in meningiomas and identify potential novel therapeutic targets. The finding of mutations in two oncogenes with existing targeted therapeutics, SMO and AKT1, translates directly into opportunities for clinical trials for patients with meningiomas.