Mutations in GNA11 in uveal melanoma.
Mutations in GNA11 in uveal melanoma.
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DOI：
10.1056/nejmoa1000584
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发表时间：
2010-12-02
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影响因子：
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通讯作者：
Bastian BC
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作者：
Van Raamsdonk CD;Griewank KG;Crosby MB;Garrido MC;Vemula S;Wiesner T;Obenauf AC;Wackernagel W;Green G;Bouvier N;Sozen MM;Baimukanova G;Roy R;Heguy A;Dolgalev I;Khanin R;Busam K;Speicher MR;O'Brien J;Bastian BC
葡萄膜黑色素瘤是最常见的眼内癌。对于转移性疾病没有有效的治疗方法。编码异源三聚体G蛋白α亚基的基因GNAQ突变在40%的葡萄膜黑色素瘤中被发现。我们对713例不同类型黑色素细胞肿瘤（葡萄膜黑色素瘤186例，蓝痣139例，其他痣106例，其他黑色素瘤282例）的GNAQ外显子5和GNAQ的一个旁系GNA11进行了测序。我们对其中453个样本的GNAQ和GNA11的外显子4进行了测序，并对97个葡萄膜黑色素瘤和45个蓝痣的GNAQ和GNA11的所有编码外显子进行了测序。我们发现GNA11和GNAQ的外显子5（影响Q209）和外显子4（影响R183）的体细胞突变呈互斥模式。影响GNA11 Q209的突变存在于7%的蓝痣、32%的原发性葡萄膜黑色素瘤和57%的葡萄膜黑色素瘤转移中。相比之下，我们在55%的蓝痣、45%的葡萄膜黑色素瘤和22%的葡萄膜黑色素瘤转移中观察到GNAQ的Q209突变。与Q209突变相比，GNAQ或GNA11中影响R183的突变不那么普遍（2%的蓝痣和6%的葡萄膜黑色素瘤）。在小鼠模型中，GNA11突变诱导肿瘤自发转移，并激活有丝分裂原激活的蛋白激酶途径。在我们分析的葡萄膜黑色素瘤中，83%有GNAQ或GNA11的体细胞突变。涉及这两个基因的通路的组成性激活似乎是葡萄膜黑色素瘤发展的主要因素。（由美国国立卫生研究院和其他机构资助。）
Uveal melanoma is the most common intraocular cancer. There are no effective therapies for metastatic disease. Mutations in GNAQ, the gene encoding an alpha subunit of heterotrimeric G proteins, are found in 40% of uveal melanomas. We sequenced exon 5 of GNAQ and GNA11, a paralogue of GNAQ, in 713 melanocytic neoplasms of different types (186 uveal melanomas, 139 blue nevi, 106 other nevi, and 282 other melanomas). We sequenced exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue nevi. We found somatic mutations in exon 5 (affecting Q209) and in exon 4 (affecting R183) in both GNA11 and GNAQ, in a mutually exclusive pattern. Mutations affecting Q209 in GNA11 were present in 7% of blue nevi, 32% of primary uveal melanomas, and 57% of uveal melanoma metastases. In contrast, we observed Q209 mutations in GNAQ in 55% of blue nevi, 45% of uveal melanomas, and 22% of uveal melanoma metastases. Mutations affecting R183 in either GNAQ or GNA11 were less prevalent (2% of blue nevi and 6% of uveal melanomas) than the Q209 mutations. Mutations in GNA11 induced spontaneously metastasizing tumors in a mouse model and activated the mitogen-activated protein kinase pathway. Of the uveal melanomas we analyzed, 83% had somatic mutations in GNAQ or GNA11. Constitutive activation of the pathway involving these two genes appears to be a major contributor to the development of uveal melanoma. (Funded by the National Institutes of Health and others.)