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Genomic Analysis of Non- NF2 Meningiomas Reveals Mutations in TRAF7 , KLF4 , AKT1 , and SMO

2013; American Association for the Advancement of Science; Volume: 339; Issue: 6123 Linguagem: Inglês

10.1126/science.1233009

1095-9203

Victoria Clark, E. Zeynep Erson‐Omay, Akdes Serin, Jun Yin, Justin Cotney, Koray Özduman, Timuçin Avşar, Jie Li, Phillip B. Murray, Octavian Henegariu, Saliha Yılmaz, Jennifer Moliterno Günel, Geneive Carrión-Grant, Baran Yılmaz, Conor Grady, Bahattin Tanrıkulu, Mehmet Bakırcıoğlu, Hande Kaymakçalan, Ahmet Okay Çağlayan, Leman Sencar, Emre Ceyhun, Ahmet Atik, Yaşar Bayri, Hanwen Bai, Luis Kolb, Ryan Hebert, Sacit Bulent Omay, Ketu Mishra-Gorur, Murim Choi, John D. Overton, Eric C. Holland, Shrikant Mane, Matthew W. State, Kaya Bilgüvar, Joachim M. Baehring, Philip H. Gutin, Joseph M. Piepmeier, Alexander O. Vortmeyer, Cameron Brennan, M. Necmettin Pamir, Türker Kılıç, Richard P. Lifton, James P. Noonan, Katsuhito Yasuno, Murat Günel,

Neurofibromatosis and Schwannoma Cases

We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.