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Science 339 (6123): 1077-1080

Copyright © 2013 by the American Association for the Advancement of Science

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

Victoria E. Clark,1 E. Zeynep Erson-Omay,1 Akdes Serin,1 Jun Yin,2 Justin Cotney,2 Koray Özduman,3 Timuçin Avsar,4 Jie Li,5 Phillip B. Murray,1 Octavian Henegariu,1 Saliha Yilmaz,1 Jennifer Moliterno Günel,6 Geneive Carrión-Grant,1 Baran Yilmaz,7 Conor Grady,1 Bahattin Tanrikulu,7 Mehmet Bakircioglu,1 Hande Kaymakçalan,8 Ahmet Okay Caglayan,1 Leman Sencar,1 Emre Ceyhun,1 A. Fatih Atik,7 Yasar Bayri,7 Hanwen Bai,1 Luis E. Kolb,1 Ryan M. Hebert,1 S. Bulent Omay,1 Ketu Mishra-Gorur,1 Murim Choi,2 John D. Overton,9 Eric C. Holland,10 Shrikant Mane,2,9 Matthew W. State,11 Kaya Bilgüvar,1 Joachim M. Baehring,12 Philip H. Gutin,6 Joseph M. Piepmeier,13 Alexander Vortmeyer,5 Cameron W. Brennan,14 M. Necmettin Pamir,3 Türker Kiliç,15 Richard P. Lifton,2,16 James P. Noonan,2,17 Katsuhito Yasuno,1 Murat Günel1,18,*

Abstract: 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 AKT1E17K, 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.

1 Departments of Neurosurgery and Genetics, Yale Program in Brain Tumor Research, Yale School of Medicine, New Haven, CT 06510, USA.
2 Department of Genetics, Yale School of Medicine, New Haven, CT 06510, USA.
3 Department of Neurosurgery, Acibadem University School of Medicine, Istanbul 34848, Turkey.
4 Dr. Orhan Öcalgiray Molecular Biology-Biotechnology and Genetics Research Center, Istanbul Technical University, Maslak 34469, Istanbul, Turkey.
5 Department of Pathology, Yale School of Medicine, New Haven, CT 06510, USA.
6 Department of Neurosurgery and Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
7 Department of Neurosurgery, Marmara University School of Medicine, Istanbul 34854, Turkey.
8 Department of Genetics and Bioinformatics, Bahcesehir University, Istanbul 34353, Turkey.
9 Center for Genome Analysis, Yale School of Medicine, West Haven, CT 06516, USA.
10 Departments of Cancer Biology and Genetics, Neurosurgery, Neurology, and Surgery, Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
11 Departments of Genetics and Psychiatry, Yale Program on Neurogenetics and Child Study Center, Yale School of Medicine, New Haven, CT 06510, USA.
12 Departments of Neurology, Neurosurgery, and Internal Medicine, Yale Program in Brain Tumor Research and Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT 06510, USA.
13 Department of Neurosurgery, Yale Program in Brain Tumor Research and Yale Brain Tumor Center, Yale School of Medicine, New Haven, CT 06510, USA.
14 Department of Neurosurgery and Brain Tumor Center, Human Oncology and Pathogenesis Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
15 Department of Neurosurgery, Bahcesehir University School of Medicine, Istanbul 34349 Turkey.
16 Department of Internal Medicine, Howard Hughes Medical Institute, Yale School of Medicine, New Haven, CT 06510, USA.
17 Kavli Institute for Neuroscience, Yale School of Medicine, New Haven, CT 06520, USA.
18 Yale Program on Neurogenetics, Yale School of Medicine, New Haven, CT 06510, USA.

* To whom correspondence should be addressed. E-mail: murat.gunel{at}yale.edu


THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology.
J. D. Patel, L. Krilov, S. Adams, C. Aghajanian, E. Basch, M. S. Brose, W. L. Carroll, M. de Lima, M. R. Gilbert, M. G. Kris, et al. (2014)
J. Clin. Oncol. 32, 129-160
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The immune cell infiltrate populating meningiomas is composed of mature, antigen-experienced T and B cells.
L. Fang, D. E. Lowther, M. L. Meizlish, R. C. E. Anderson, J. N. Bruce, L. Devine, A. J. Huttner, S. H. Kleinstein, J.-Y. Lee, J. N. H. Stern, et al. (2013)
Neuro Oncology 15, 1479-1490
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