Frequent somatic mutations of GNAQ in uveal melanoma and blue naevi

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Abstract
Mutations in BRAF and NRAS that lead to constitutive activation of MAPK signalling have been found at high frequencies in many melanomas, both benign and malignant. However, they have not been found in uveal melanomas (arising from in the cells that give colour to the eye) or in blue naevi melanomas (a type of benign blue–black mole). Now a genetic screen of biopsy samples shows that these melanoma subtypes instead show frequent activating mutations in the G protein α-subunit GNAQ, also leading to the activation of the MAPK pathway. This identifies signalling components downstream of GNAQ as potential therapeutic targets. Mutations in BRAF and NRAS that lead to constitutive activation of MAP kinase signalling have been found at high frequencies in many melanomas. However, they have not been found in the uveal melanomas and blue nevi subtypes of melanoma. This paper shows that these subtypes instead show frequent activating mutations in the G protein α-subunit GNAQ, also leading to the activation of the MAP kinase pathway. 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.