Genomic Landscape of High-grade Meningiomas

Objective: High-grade meningiomas present a therapeutic challenge, given their propensity to recur even with surgery and adjuvant radiation. Relatively little is known about the genomic landscape of these tumors or their evolution over time. We characterized a large cohort of high-grade meningiomas using next-generation sequencing to better understand the relationship between clinical pathology and the underlying biology of these tumors.

Methods: Whole-genome or whole-exome sequencing was performed on 60 grade II and III meningiomas to identify somatic copy-number alterations, mutations, insertions and deletions, and rearrangements. Targeted capture sequencing was performed on additional 60 grade II and III tumors.

Results: High-grade meningiomas harbor an elevated rate of mutations, indels, and copy number alterations compared with grade I meningiomas. Alterations affecting NF2, such as inactivating mutations, focal deletions, and broad losses of chromosome 22, occurred significantly more frequently in high-grade than low-grade meningiomas. Other recurrently mutated genes that have been observed in low-grade meningiomas, such as TRAF7, AKT1, SMO, KLF4, and PIK3CA were not significantly altered in high-grade tumors. However, alternative mutations were observed in several targetable signaling pathways. Analysis of multiple recurrences from high-grade meningiomas revealed significant temporal and spatial heterogeneity, with few shared events between samples from the same patient.

Conclusion: Genomic characterization of sporadic high-grade meningiomas reveals a distinct landscape from low-grade meningiomas, with increased genomic disruption, a preponderance of NF2 alterations, scarcity of other previously identified non-NF2 driver mutations, and substantial intra- and inter-tumor heterogeneity.

No conflict of interest has been declared by the author(s).