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Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi

Nature volume 457, pages599–602(2009)Cite this article

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.

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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.

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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

  1. Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada

    Catherine D. Van Raamsdonk

  2. Department of Dermatology and Comprehensive Cancer Center,

    Vladimir Bezrookove, Gary Green, Jürgen Bauer, Lona Gaugler & Boris C. Bastian

  3. Department of Ophthalmology and Comprehensive Cancer Center, University of California, San Francisco, California 94143, USA

    Joan M. O’Brien

  4. Department of Dermatology, University of Tübingen, Tübingen D-72076, Germany

    Jürgen Bauer

  5. Centre for Molecular Medicine and Therapeutics and Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada

    Elizabeth M. Simpson

  6. Department of Genetics, Stanford University, Stanford, California 94305, USA.

    Gregory S. Barsh

Authors
  1. Catherine D. Van Raamsdonk
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  2. Vladimir Bezrookove
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  3. Gary Green
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  4. Jürgen Bauer
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  5. Lona Gaugler
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  6. Joan M. O’Brien
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  7. Elizabeth M. Simpson
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  8. Gregory S. Barsh
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  9. Boris C. Bastian
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Corresponding author

Correspondence to Boris C. Bastian.

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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

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