title: 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 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.
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada.
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Van Raamsdonk
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bezrookove
authors.forename: Gary
authors.initials: G
authors.lastname: Green
authors.forename: Jürgen
authors.initials: J
authors.lastname: Bauer
authors.forename: Lona
authors.initials: L
authors.lastname: Gaugler
authors.forename: Joan M
authors.initials: JM
authors.lastname: O'Brien
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Simpson
authors.forename: Gregory S
authors.initials: GS
authors.lastname: Barsh
authors.forename: Boris C
authors.initials: BC
authors.lastname: Bastian
mesh_terms: D017209:Apoptosis; D001706:Biopsy; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic; D002478:Cells, Cultured; D003062:Codon / Q000235:genetics; D004252:DNA Mutational Analysis; D004789:Enzyme Activation; D044385:GTP-Binding Protein alpha Subunits / Q000737:chemistry / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism; D005799:Genes, Dominant / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D008544:Melanocytes / Q000201:enzymology / Q000473:pathology; D008545:Melanoma / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009154:Mutation / Q000235:genetics*; D018329:Nevus, Blue / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes / Q000235:genetics; D017434:Protein Structure, Tertiary; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014604:Uveal Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D018631:ras Proteins / Q000737:chemistry
chemical_list: D003062:Codon; D044385:GTP-Binding Protein alpha Subunits; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins