Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.
Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.
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DOI：
10.1126/science.1233009
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发表时间：
2013-03-01
期刊：
影响因子：
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通讯作者：
Günel M
中科院分区：
文献类型：
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作者：
Clark VE;Erson-Omay EZ;Serin A;Yin J;Cotney J;Ozduman K;Avşar T;Li J;Murray PB;Henegariu O;Yilmaz S;Günel JM;Carrión-Grant G;Yilmaz B;Grady C;Tanrikulu B;Bakircioğlu M;Kaymakçalan H;Caglayan AO;Sencar L;Ceyhun E;Atik AF;Bayri Y;Bai H;Kolb LE;Hebert RM;Omay SB;Mishra-Gorur K;Choi M;Overton JD;Holland EC;Mane S;State MW;Bilgüvar K;Baehring JM;Gutin PH;Piepmeier JM;Vortmeyer A;Brennan CW;Pamir MN;Kiliç T;Lifton RP;Noonan JP;Yasuno K;Günel M
我们报告了300例脑膜瘤（最常见的原发性脑肿瘤）的基因组分析，发现TRAF 7（一种促凋亡的E3泛素连接酶）在近四分之一的脑膜瘤中存在突变。TRAF 7的突变通常发生在KLF 4的复发突变（K409 Q）中，KLF 4是一种已知在诱导多能性中发挥作用的转录因子，或AKT 1 E17 K，一种已知激活PI 3 K通路的突变。在~5%的非NF 2突变脑膜瘤中发现了激活Hedgehog信号的SMO突变。这些非NF 2脑膜瘤在临床上是独特的，几乎总是良性的，染色体稳定，起源于内侧颅底。相反，NF 2突变和/或22号染色体缺失的脑膜瘤更可能是非典型的，表现出基因组不稳定性，并局限于大脑和小脑半球。总的来说，这些发现确定了不同的脑膜瘤亚型，提示了靶向治疗的途径。
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 TRAF7commonly 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.