Mutations in GNA11 in Uveal Melanoma

By C. V. Raamsdonk, K. Griewank, M. B. Crosby, M. Garrido, Swapna S. Vemula, T. Wiesner, A. Obenauf, W. Wackernagel, G. Green, N. Bouvier and 10 more. New England Journal of Medicine, 2010

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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.)

Subfields: Genetics, Molecular Biology, Ophthalmology

View Paper: https://www.semanticscholar.org/paper/539b40f93fd6899bbb062db6e3100458a71efaaa

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Citations in the corpus

• Integrative Analysis Identifies Four Molecular and Clinical Subsets in Uveal Melanoma. (2018, result): “and Clinical Subsets in Uveal Melanoma A. Gordon Robertson,1,35 Juliann Shih,2,3,35 Christina Yau,4,35 Ewan A. Gibb,1 Junna Oba,5 Karen L. Mungall,1 Julian M. Hess,2 Vladislav Uzunangelov,6 Vonn Walter,7,8 Ludmila Danilova,9 Tara M. Lichtenberg,10 Melanie Kucherlapati,11,12 Patrick K. Kimes,7 Ming T”
• Hippo Pathway in Organ Size Control, Tissue Homeostasis, and Cancer. (2015, neutral): “GNAQ- or GNA11- (encoding Gaq or Ga11, respectively) activating mutations have been identified in 80% of uveal melanomas and function as driver mutations (Van Raamsdonk et al., 2009; Van Raamsdonk et al., 2010).”
• Regulation of the Hippo-YAP pathway by G-protein coupled receptor signaling (2012, background): “For instance, activating mutations of Gq and G11 are frequently associated with uveal melanoma, the most common tumor in the eye (Van Raamsdonk et al., 2010).”
• The Hippo pathway: regulators and regulations. (2013, background): “Activating mutations of Ga are also present in different types of cancers: Gaq/11-activating mutations have been identified in >80% of uveal melanomas (Van Raamsdonk et al. 2009, 2010); Gai2a and Gas mutations have been identified in ovarian and endocrine tumors (Lania et al. 2001).”