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Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

Abstract

Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of all meningiomas1, but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas had simple genomes, with fewer mutations, rearrangements and copy-number alterations than reported in other tumors in adults. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements, including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers in an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (p.Glu17Lys) and SMO (p.Trp535Leu) and exhibited immunohistochemical evidence of activation of these pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.

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Figure 1: Landscape of somatic alterations in the grade I meningioma genome.
Figure 2: Somatic rearrangements disrupt tumor suppressors in several meningiomas.
Figure 3: Significant and selected cancer-related somatic mutations, indels and translocations in meningiomas.
Figure 4: Associations between mutations in Hedgehog and AKT-mTOR pathways and histological findings.

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Acknowledgements

The authors would like to thank M. Lawrence, N. Stransky, M. Imielinski, K. Cibulskis, S. Carter, C. Stewart, C.-Z. Zhang, Y. Drier, S. Schumacher and B. Tabak for their assistance with genomic analyses; P. Wen, O. Al-Mefty, T. Batchelor, B. Reisler, M. Johnson, W. Richards and J. Kim for their assistance with tissue acquisition; and A. Pisarek-Horowitz, S.A. Horowitz, G. Bergthold and C.H. Brastianos for critical review of the manuscript. This work was supported by the Brain Science Foundation (I.F.D., P.K.B., R.B. and S.S.), the Pediatric Low-Grade Astrocytoma Foundation (R.B. and W.C.H.), the American Brain Tumor Association (P.K.B.), a Conquer Cancer Foundation Young Investigator Award (P.K.B.), US National Institutes of Health (NIH) grants K08 CA122833 (R.B.), K08 NS064168 (S.S.) and K12 CA090354-11 (P.K.B.), and US Department of Defense grant W81XWH-12-1-0136 (P.M.H.).

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Authors

Contributions

P.K.B., P.M.H., I.F.D., R.B. and W.C.H. conceived the study, designed the experiments, analyzed the data and wrote the manuscript. P.M.H. performed the bioinformatics analyses, and A.M., G.G., R.B. and M.D.D. provided analytical advice. S.S., A.O.S.-R. and D.N.L. reviewed the histopathology, and S.S. performed the immunohistochemistry. K.L.L. managed the tissue repository. R.T.J., E.P., P.V.H., A.R., A.S. and L.E.M. provided technical support and performed sequencing. W.C.H., I.F.D. and R.B. supervised the study. All authors discussed the results and implications and commented on the manuscript.

Corresponding authors

Correspondence to William C Hahn, Ian F Dunn or Rameen Beroukhim.

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Competing interests

W.C.H. is a consultant for Blueprint Medicines and Thermo Fisher. R.B. is a shareholder for AstraZeneca. W.C.H. and R.B. are consultants for and receive research support from Novartis.

Supplementary information

Supplementary Text and Figures

Supplementary Note, Supplementary Tables 1 and 6 and Supplementary Figures 1–5 (PDF 6192 kb)

Supplementary Table 2

Genes sequenced in the Validation set (separate excel file) (XLSX 31 kb)

Supplementary Table 3

Rearrangements in WGS samples (separate excel file) (XLSX 25 kb)

Supplementary Table 4

All mutated genes and significance (separate excel file) (XLSX 29 kb)

Supplementary Table 5

Samples and their individual mutations (separate excel file) (XLSX 16 kb)

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Brastianos, P., Horowitz, P., Santagata, S. et al. Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45, 285–289 (2013). https://doi.org/10.1038/ng.2526

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