Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi

Abstract

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.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: GNAQ Q209L transforms melanocytes.
Figure 2: GNAQ Q209L induces MAP kinase activation.
Figure 3: Knockdown of GNAQ in OMM1.3 cells results in MAP kinase inhibition, reduced growth and apoptosis.

References

  1. 1

    Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949–954 (2002)

    ADS  CAS  Article  Google Scholar 

  2. 2

    Pollock, P. M. et al. High frequency of BRAF mutations in nevi. Nature Genet. 25, 25 (2002)

    Google Scholar 

  3. 3

    Saldanha, G. et al. High BRAF mutation frequency does not characterize all melanocytic tumor types. Int. J. Cancer 111, 705–710 (2004)

    CAS  Article  Google Scholar 

  4. 4

    Horsman, D. E. & White, V. A. Cytogenetic analysis of uveal melanoma. Consistent occurrence of monosomy 3 and trisomy 8q. Cancer 71, 811–819 (1993)

    CAS  Article  Google Scholar 

  5. 5

    Singh, A. D., Bergman, L. & Seregard, S. Uveal melanoma: epidemiologic aspects. Ophthalmol. Clin. North Am. 18, 75–84 (2005)

    Article  Google Scholar 

  6. 6

    Zembowicz, A. & Mihm, M. C. Dermal dendritic melanocytic proliferations: an update. Histopathology 45, 433–451 (2004)

    CAS  Article  Google Scholar 

  7. 7

    Singh, A. D. et al. Lifetime prevalence of uveal melanoma in white patients with oculo(dermal) melanocytosis. Ophthalmology 105, 195–198 (1998)

    CAS  Article  Google Scholar 

  8. 8

    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)

    CAS  Article  Google Scholar 

  9. 9

    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)

    ADS  CAS  Article  Google Scholar 

  10. 10

    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)

    ADS  CAS  Article  Google Scholar 

  11. 11

    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)

    CAS  Article  Google Scholar 

  12. 12

    Lyons, J. et al. Two G protein oncogenes in human endocrine tumors. Science 249, 655–659 (1990)

    ADS  CAS  Article  Google Scholar 

  13. 13

    Garraway, L. A. et al. Integrative genomic analyses identify MITF as a lineage survival oncogene amplified in malignant melanoma. Nature 436, 117–122 (2005)

    ADS  CAS  Article  Google Scholar 

  14. 14

    Hubbard, K. B. & Hepler, J. R. Cell signalling diversity of the Gqα family of heterotrimeric G proteins. Cell. Signal. 18, 135–150 (2006)

    CAS  Article  Google Scholar 

  15. 15

    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)

    CAS  Article  Google Scholar 

  16. 16

    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)

    ADS  CAS  Article  Google Scholar 

  17. 17

    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)

    CAS  Article  Google Scholar 

  18. 18

    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)

    CAS  Article  Google Scholar 

  19. 19

    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)

    CAS  Article  Google Scholar 

  20. 20

    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)

    CAS  Article  Google Scholar 

  21. 21

    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)

    CAS  Article  Google Scholar 

  22. 22

    Curtin, J. A. et al. Distinct sets of genetic alterations in melanoma. N. Engl. J. Med. 353, 2135–2147 (2005)

    CAS  Article  Google Scholar 

  23. 23

    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)

    CAS  Article  Google Scholar 

Download references

Acknowledgements

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.).

Author information

Affiliations

Authors

Corresponding author

Correspondence to Boris C. Bastian.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-3 with Legends and Supplementary Tables 1-4. (PDF 1563 kb)

PowerPoint slides

Rights and permissions

Reprints and Permissions

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

Download citation

Further reading

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing