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 pathway. However, BRAF and NRAS mutations are absent in a number of other melanocytic neoplasms in which the equivalent oncogenic events are currently unknown. Here we report frequent somatic mutations in the heterotrimeric G protein alpha-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.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Apoptosis
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Biopsy
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Cell Proliferation
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Cell Transformation, Neoplastic
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Cells, Cultured
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Codon / genetics
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DNA Mutational Analysis
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Enzyme Activation
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GTP-Binding Protein alpha Subunits / chemistry
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GTP-Binding Protein alpha Subunits / deficiency
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GTP-Binding Protein alpha Subunits / genetics*
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GTP-Binding Protein alpha Subunits / metabolism
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Genes, Dominant / genetics
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Humans
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MAP Kinase Signaling System
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Melanocytes / enzymology
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Melanocytes / pathology
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Melanoma / enzymology
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Melanoma / genetics*
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Melanoma / pathology
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Mitogen-Activated Protein Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinases / metabolism
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Mutation / genetics*
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Nevus, Blue / enzymology
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Nevus, Blue / genetics*
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Nevus, Blue / pathology
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Oncogenes / genetics
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Protein Structure, Tertiary
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Skin Neoplasms / enzymology
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Skin Neoplasms / genetics*
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Skin Neoplasms / pathology
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Uveal Neoplasms / enzymology
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Uveal Neoplasms / genetics*
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Uveal Neoplasms / pathology
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ras Proteins / chemistry
Substances
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Codon
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GTP-Binding Protein alpha Subunits
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Mitogen-Activated Protein Kinases
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ras Proteins