Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi.
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.
Van Raamsdonk
Catherine D
CD
Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia V6T1Z3, Canada.
Bezrookove
Vladimir
V
Green
Gary
G
Bauer
Jürgen
J
Gaugler
Lona
L
O'Brien
Joan M
JM
Simpson
Elizabeth M
EM
Barsh
Gregory S
GS
Bastian
Boris C
BC
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
D003062:Codon; D044385:GTP-Binding Protein alpha Subunits; D020928:Mitogen-Activated Protein Kinases; D018631:ras Proteins