Wenya Linda Bi 1 , 2 , 3 , Noah F. Greenwald 1 , 2 , 3 , Malak Abedalthagafi 4 , 5 , 6 , Jeremiah Wala 2 , 3 , Will J. Gibson 2 , 3 , Pankaj K. Agarwalla 2 , 7 , Peleg Horowitz 8 , Steven E. Schumacher 2 , 3 , Ekaterina Esaulova 9 , 10 , Yu Mei 1 , Aaron Chevalier 3 , Matthew A. Ducar 11 , Aaron R. Thorner 11 , Paul van Hummelen 11 , Anat O. Stemmer-Rachamimov 12 , Maksym Artyomov 9 , Ossama Al-Mefty 1 , Gavin P. Dunn 9 , 13 , 14 , Sandro Santagata , 4 , Ian F. Dunn , 1 , Rameen Beroukhim , 2 , 3 , 15
26 April 2017
High-grade meningiomas frequently recur and are associated with high rates of morbidity and mortality. To determine the factors that promote the development and evolution of these tumors, we analyzed the genomes of 134 high-grade meningiomas and compared this information with data from 595 previously published meningiomas. High-grade meningiomas had a higher mutation burden than low-grade meningiomas but did not harbor any significantly mutated genes aside from NF2. High-grade meningiomas also possessed significantly elevated rates of chromosomal gains and losses, especially among tumors with monosomy 22. Meningiomas previously treated with adjuvant radiation had significantly more copy number alterations than radiation-induced or radiation-naïve meningiomas. Across serial recurrences, genomic disruption preceded the emergence of nearly all mutations, remained largely uniform across time, and when present in low-grade meningiomas correlated with subsequent progression to a higher grade. In contrast to the largely stable copy number alterations, mutations were strikingly heterogeneous across tumor recurrences, likely due to extensive geographic heterogeneity in the primary tumor. While high-grade meningiomas harbored significantly fewer overtly targetable alterations than low-grade meningiomas, they contained numerous mutations that are predicted to be neoantigens, suggesting that immunologic targeting may be of therapeutic value.
Meningiomas, which arise from the tissue surrounding the brain and spinal cord, are the most common primary brain tumor in adults. The majority of these are slow-growing and amenable to surgical resection, if treatment is indicated. However, a subset of aggressive meningiomas are considered high-grade, producing significantly worse mortality. In a first study of its kind, Drs. Wenya Linda Bi, Ian Dunn, Sandro Santagata, Rameen Beroukhim, and colleagues at Harvard Medical School sequenced the genomes of 134 high-grade meningiomas and compared their makeup with lower-grade meningiomas. They found that aggressive tumors were more likely to harbor mutations in the NF2 gene and exhibit widespread genomic disruption. They also harbored an elevated rate of predicted immunogenic mutations, with implications for the use of immuno-modulatory therapies.