Author(s): Van Raamsdonk CD, Griewank KG, Crosby MB, Garrido MC, Vemula S,
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Abstract BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.).
This article was published in N Engl J Med
and referenced in Advances in Molecular Diagnostics