Mutations in GNA11 in uveal melanoma Journal Article
| Authors: | Van Raamsdonk, C. D.; Griewank, K. G.; Crosby, M. B.; Garrido, M. C.; Vemula, S.; Wiesner, T.; Obenauf, A. C.; Wackernagel, W.; Green, G.; Bouvier, N.; Sozen, M. M.; Baimukanova, G.; Roy, R.; Heguy, A.; Dolgalev, I.; Khanin, R.; Busam, K.; Speicher, M. R.; O'Brien, J.; Bastian, B. C. |
| Article Title: | Mutations in GNA11 in uveal melanoma |
| 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.) N Engl J Med 2010;363:2191-9. |
| Keywords: | melanocytes; skin; tumors; braf; human cancer; activation; frequency; exposure; somatic mutations; alpha-subunit |
| Journal Title: | New England Journal of Medicine |
| Volume: | 363 |
| Issue: | 23 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2010-12-02 |
| Start Page: | 2191 |
| End Page: | 2199 |
| Language: | English |
| ACCESSION: | ISI:000284832900006 |
| DOI: | 10.1056/NEJMoa1000584 |
| PROVIDER: | wos |
| PMCID: | PMC3107972 |
| PUBMED: | 21083380 |
| Notes: | --- - Article - "Source: Wos" |
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