Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
N Engl J Med. 2010 Dec 2;363(23):2191-9. doi: 10.1056/NEJMoa1000584. Epub 2010 Nov 17.
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.).
葡萄膜黑素瘤是最常见的眼内癌。对于转移性疾病尚无有效的治疗方法。在 40%的葡萄膜黑素瘤中发现了 GNAQ 基因（编码异源三聚体 G 蛋白的α亚基）的突变。
我们对不同类型的 713 种黑素细胞肿瘤（186 例葡萄膜黑素瘤、139 例蓝色痣、106 例其他痣和 282 例其他黑素瘤）进行了 GNAQ 和 GNAQ 旁系同源物 GNA11 的外显子 5 测序。我们对其中 453 例样本进行了 GNAQ 和 GNA11 的外显子 4 测序，并对 97 例葡萄膜黑素瘤和 45 例蓝色痣进行了 GNAQ 和 GNA11 的所有编码外显子测序。
我们发现 GNA11 和 GNAQ 的外显子 5（影响 Q209）和外显子 4（影响 R183）均存在体细胞突变，且呈相互排斥的模式。GNA11 中影响 Q209 的突变存在于 7%的蓝色痣、32%的原发性葡萄膜黑素瘤和 57%的葡萄膜黑素瘤转移灶中。相比之下，我们在 55%的蓝色痣、45%的葡萄膜黑素瘤和 22%的葡萄膜黑素瘤转移灶中观察到 GNAQ 中的 Q209 突变。GNAQ 或 GNA11 中影响 R183 的突变比 Q209 突变更为罕见（蓝色痣 2%，葡萄膜黑素瘤 6%）。GNA11 中的突变在小鼠模型中诱导自发转移肿瘤，并激活丝裂原活化蛋白激酶途径。
我们分析的葡萄膜黑素瘤中有 83%存在 GNAQ 或 GNA11 的体细胞突变。涉及这两个基因的途径的组成性激活似乎是葡萄膜黑素瘤发生的主要原因。（由美国国立卫生研究院等资助）。
