BRAF and NRAS are common targets for somatic mutations in benign and malignant neoplasms that arise from melanocytes situated in epithelial structures, and lead to constitutive activation of the mitogen-activated protein (MAP) kinase pathway1,2. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which the equivalent oncogenic events are currently unknown3. Here we report frequent somatic mutations in the heterotrimeric G protein α-subunit, GNAQ, in blue naevi (83%) and ocular melanoma of the uvea (46%). The mutations occur exclusively in codon 209 in the Ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting oncogene. Our results demonstrate an alternative route to MAP kinase activation in melanocytic neoplasia, providing new opportunities for therapeutic intervention.
Subscribe to Journal
Get full journal access for 1 year
only $3.90 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)
Pollock, P. M. et al. High frequency of BRAF mutations in nevi. Nature Genet. 25, 25 (2002)
Saldanha, G. et al. High BRAF mutation frequency does not characterize all melanocytic tumor types. Int. J. Cancer 111, 705–710 (2004)
Horsman, D. E. & White, V. A. Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. Cancer 71, 811–819 (1993)
Singh, A. D., Bergman, L. & Seregard, S. Uveal melanoma: epidemiologic aspects. Ophthalmol. Clin. North Am. 18, 75–84 (2005)
Zembowicz, A. & Mihm, M. C. Dermal dendritic melanocytic proliferations: an update. Histopathology 45, 433–451 (2004)
Singh, A. D. et al. Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology 105, 195–198 (1998)
Van Raamsdonk, C. D., Fitch, K. R., Fuchs, H., de Angelis, M. H. & Barsh, G. S. Effects of G-protein mutations on skin color. Nature Genet. 36, 961–968 (2004)
Markby, D. W., Onrust, R. & Bourne, H. R. Separate GTP binding and GTPase activating domains of a G alpha subunit. Science 262, 1895–1901 (1993)
Landis, C. A. et al. GTPase inhibiting mutations activate the α chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 340, 692–696 (1989)
Kalinec, G., Nazarali, A. J., Hermouet, S., Xu, N. & Gutkind, J. S. Mutated alpha subunit of the Gq protein induces malignant transformation in NIH 3T3 cells. Mol. Cell. Biol. 12, 4687–4693 (1992)
Lyons, J. et al. Two G protein oncogenes in human endocrine tumors. Science 249, 655–659 (1990)
Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005)
Hubbard, K. B. & Hepler, J. R. Cell signalling diversity of the Gqα family of heterotrimeric G proteins. Cell. Signal. 18, 135–150 (2006)
Zuidervaart, W. et al. Activation of the MAPK pathway is a common event in uveal melanomas although it rarely occurs through mutation of BRAF or RAS. Br. J. Cancer 92, 2032–2038 (2005)
Shin, M. K., Levorse, J. M., Ingram, R. S. & Tilghman, S. M. The temporal requirement for endothelin receptor-B signalling during neural crest development. Nature 402, 496–501 (1999)
Dissanayake, S. K. et al. The Wnt5A/protein kinase C pathway mediates motility in melanoma cells via the inhibition of metastasis suppressors and initiation of an epithelial to mesenchymal transition. J. Biol. Chem. 282, 17259–17271 (2007)
Sheldahl, L. C., Park, M., Malbon, C. C. & Moon, R. T. Protein kinase C is differentially stimulated by Wnt and Frizzled homologs in a G-protein-dependent manner. Curr. Biol. 9, 695–698 (1999)
Marin, Y. E. et al. Stimulation of oncogenic metabotropic glutamate receptor 1 in melanoma cells activates ERK1/2 via PKCε. Cell. Signal. 18, 1279–1286 (2006)
Mizushima, J., Nogita, T., Higaki, Y., Horikoshi, T. & Kawashima, M. Dormant melanocytes in the dermis: do dermal melanocytes of acquired dermal melanocytosis exist from birth? Br. J. Dermatol. 139, 349–350 (1998)
Chang, A. E., Karnell, L. H. & Menck, H. R. The National Cancer Data Base report on cutaneous and noncutaneous melanoma: a summary of 84,836 cases from the past decade. The American College of Surgeons Commission on Cancer and the American Cancer Society. Cancer 83, 1664–1678 (1998)
Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005)
Bennett, D. C., Cooper, P. J. & Hart, I. R. A line of non-tumorigenic mouse melanocytes, syngeneic with the B16 melanoma and requiring a tumour promoter for growth. Int. J. Cancer 39, 414–418 (1987)
We thank W. Harbour for providing additional DNA samples from uveal melanomas and P. Viciana-Rodriguez and A. Balmain for providing advice. hTERT/CDK4R24C/p53DD melanocytes were a gift from D. Fisher, Dana Farber Cancer Institute13, normal human melanocytes from foreskin were a gift from M. Herlyn, and OMM1.3 and Mel202 cells were originally from B. Ksander. The melan-a cells were a gift from D. Bennett, St George’s University, London23.This work was supported by grants from the National Cancer Institute (P01 CA025874 Project 2 to B.C.B.) the Melanoma Research Alliance, the Canadian Institutes of Health Research (MOP-79511 to C.D.V.R.), and the National Institutes of Health (G.S.B.).
About this article
Cite this article
Van Raamsdonk, C., Bezrookove, V., Green, G. et al. Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi. Nature 457, 599–602 (2009). https://doi.org/10.1038/nature07586
Primary intra‐abdominal melanoma arising in association with extracutaneous blue naevus: a report of two cases
Clinical Cancer Research (2021)
Integrated differential DNA methylation and gene expression of formalin-fixed paraffin-embedded uveal melanoma specimens identifies genes associated with early metastasis and poor prognosis
Experimental Eye Research (2021)
Pigment Cell & Melanoma Research (2021)
Transcriptional analysis of metastatic uveal melanoma survival nominates NRP1 as a therapeutic target
Melanoma Research (2021)