Genomic characterization of meningiomas.

Abstract

2020 Background: Understanding the genetic alterations in cancer has lead to groundbreaking discoveries in targeted therapies. Meningiomas are among the most common primary brain tumors, with approximately 18,000 new cases diagnosed annually. Though certain genes have been associated with the development of meningiomas, most notably the tumor suppressor gene neurofibromatosis 2 (NF2), the genetic changes that drive meningiomas remain poorly understood. Our objective was to comprehensively characterize the somatic genetic alterations of meningiomas to gain insight into the molecular pathways that drive this disease. Methods: Fresh frozen specimens and paired blood were collected from 16 consented patients. DNA was extracted from regions of high tumor purity determined by evaluation of H&E slides. Whole-genome sequencing from 10 tumor-normal pairs and whole-exome sequencing from 6 tumor-normal pairs was carried out. We performed an unbiased screen for point mutations, insertions-deletions, rearrangements and copy-number changes across the exomes and genomes. Recurrent (potential driver) events were then analyzed with additional algorithms for statistical significance. Results: Alterations in the NF2 gene were present in 9 of 16 patients. Multiple novel rearrangements and recurrent non-NF2 mutations were also identified in the cohort. Massive genomic rearrangement termed chromothripsis was observed in chromosome 1 in one sample, which has never previously been described in meningiomas, and represents a potentially new mechanism of malignant transformation in this tumor type. Conclusions: While NF2 mutations appear to drive a majority of these tumors, our analysis has uncovered additional potential driver genes in meningiomas, particularly in those tumors negative for NF2 alterations. To our knowledge, this is the first study to comprehensively characterize the totality of somatic genetic alterations in meningiomas, and brings us closer to the development of new therapeutic targets for this disease.