Frequent somatic mutations of GNAQ in uveal melanoma and intradermal melanocytic proliferations


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Boris Bastian

University of California, San Francisco, USA

Abstract

Frequent somatic mutations of GNAQ in uveal melanoma and intradermal melanocytic proliferations

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 MAP-kinase pathway. BRAF and NRAS mutations are absent in melanocytic neoplasms that arise without association to epithelial structures and the equivalent oncogenic events are currently unknown. We report somatic mutations in the heterotrimeric G protein alpha subunit, GNAQ, in 80% blue nevi, i.e. benign intradermal melanocytic neoplasms, and 50% of ocular melanoma of the uvea. The mutation was exclusively found in tumours without any mutations in the known melanoma oncogenes BRAF, NRAS, and KIT. Mutations in GNAQ exclusively occur in codon 209 in the ras-like domain and result in constitutive activation, turning GNAQ into a dominant acting. When transduced into immortalized human melanocytes, mutant, but not wild-type GNAQ induces anchorage independent growth and activation of MAP-kinase. Conversely, siRNA mediated knock-down in melanoma cell lines harbouring the mutation results in loss of MAP-kinase activation and subsequent apoptosis. Our results identify the pathway(s) downstream of GNAQ as an alternative route to MAP-kinase activation in melanocytic neoplasia providing new opportunities for therapeutic intervention.