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

被引:656
作者
Clark, Victoria E. [1 ,2 ]
Erson-Omay, E. Zeynep [1 ,2 ]
Serin, Akdes [1 ,2 ]
Yin, Jun [2 ]
Cotney, Justin [2 ]
Oezduman, Koray [3 ]
Avsar, Timuin [4 ]
Li, Jie [5 ]
Murray, Phillip B. [1 ,2 ]
Henegariu, Octavian [1 ,2 ]
Yilmaz, Saliha [1 ,2 ]
Guenel, Jennifer Moliterno [6 ,7 ]
Carrion-Grant, Geneive [1 ,2 ]
Yilmaz, Baran [8 ]
Grady, Conor [1 ,2 ]
Tanrikulu, Bahattin [1 ,8 ]
Bakircioglu, Mehmet [2 ]
Kaymakcalan, Hande [9 ,10 ]
Caglayan, Ahmet Okay [2 ]
Sencar, Leman [2 ]
Ceyhun, Emre [2 ]
Atik, A. Fatih [8 ]
Bayri, Yasar [8 ]
Bai, Hanwen
Kolb, Luis E.
Hebert, Ryan M.
Omay, S. Bulent [1 ]
Mishra-Gorur, Ketu [1 ]
Choi, Murim [2 ]
Overton, John D. [11 ]
Holland, Eric C. [12 ,13 ,14 ]
Mane, Shrikant [2 ,11 ]
State, Matthew W. [15 ,16 ,17 ]
Bilguevar, Kaya [1 ,2 ]
Baehring, Joachim M. [18 ]
Gutin, Philip H. [7 ]
Piepmeier, Joseph M. [19 ]
Vortmeyer, Alexander [5 ]
Brennan, Cameron W. [20 ,21 ]
Pamir, M. Necmettin
Kilic, Tuerker [22 ]
Lifton, Richard P. [2 ,23 ]
Noonan, James P. [2 ,24 ]
Yasuno, Katsuhito [1 ,2 ]
Guenel, Murat [1 ,2 ,25 ]
机构
[1] Yale Univ, Sch Med, Dept Neurosurg, Yale Program Brain Tumor Res, New Haven, CT 06510 USA
[2] Yale Univ, Sch Med, Dept Genet, New Haven, CT 06510 USA
[3] Acibadem Univ, Dept Neurosurg, Sch Med, TR-34848 Istanbul, Turkey
[4] Istanbul Tech Univ, Dr Orhan Ocalgiray Mol Biology Biotechnol & Genet, TR-34469 Istanbul, Turkey
[5] Yale Univ, Sch Med, Dept Pathol, New Haven, CT 06510 USA
[6] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA
[7] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, New York, NY 10065 USA
[8] Marmara Univ, Dept Neurosurg, Sch Med, TR-34854 Istanbul, Turkey
[9] Bahcesehir Univ, Dept Genet & Bioinformat, TR-34353 Istanbul, Turkey
[10] Yale Univ, Ctr Genome Anal, Sch Med, West Haven, CT 06516 USA
[11] Yale Univ, Ctr Genome Anal, Sch Med, West Haven, CT 06516 USA
[12] Mem Sloan Kettering Canc Ctr, Dept Canc Biol & Genet, Brain Tumor Ctr, New York, NY 10065 USA
[13] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA
[14] Mem Sloan Kettering Canc Ctr, Dept Neurol & Surg, New York, NY 10065 USA
[15] Yale Univ, Sch Med, Dept Genet, Yale Program Neurogenet, New Haven, CT 06510 USA
[16] Yale Univ, Sch Med, Dept Psychiat, Yale Program Neurogenet, New Haven, CT 06510 USA
[17] Yale Univ, Sch Med, Ctr Child Study, New Haven, CT 06510 USA
[18] Yale Univ, Sch Med, Dept Internal Med, New Haven, CT 06510 USA
[19] Yale Univ, Sch Med, Dept Neurosurg, Yale Program Brain Tumor Res, New Haven, CT 06510 USA
[20] Mem Sloan Kettering Canc Ctr, Dept Neurosurg, New York, NY 10065 USA
[21] Mem Sloan Kettering Canc Ctr, Brain Tumor Ctr, Human Oncol & Pathogenesis Program, New York, NY 10065 USA
[22] Bahcesehir Univ, Dept Neurosurg, TR-34349 Istanbul, Turkey
[23] Yale Univ, Sch Med, Howard Hughes Med Inst, Dept Internal Med, New Haven, CT 06510 USA
[24] Yale Univ, Sch Med, Kavli Inst Neurosci, New Haven, CT 06520 USA
[25] Yale Univ, Sch Med, Yale Program Neurogenet, New Haven, CT 06510 USA
关键词
D O I
10.1126/science.1233009
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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 similar to 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.
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收藏
页码:1077 / 1080
页数:4
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