Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma

Yu Chen and colleagues describe a new constitutively activating mutation in the G-protein-coupled receptor CYSLTR2 in patients with uveal melanoma lacking mutations in the G-protein-encoding genes GNAQ and GNA11 . They find that expression of the mutant leads to increased expression of melanocyte-lineage signature genes and promotes tumorigenesis in vivo . Uveal melanomas are molecularly distinct from cutaneous melanomas and lack mutations in BRAF , NRAS , KIT , and NF1 . Instead, they are characterized by activating mutations in GNAQ and GNA11 , two highly homologous α subunits of G αq/11 heterotrimeric G proteins, and in PLCB4 (phospholipase C β4), the downstream effector of G αq signaling 1 , 2 , 3 . We analyzed genomics data from 136 uveal melanoma samples and found a recurrent mutation in CYSLTR2 (cysteinyl leukotriene receptor 2) encoding a p.Leu129Gln substitution in 4 of 9 samples that lacked mutations in GNAQ , GNA11 , and PLCB4 but in 0 of 127 samples that harbored mutations in these genes. The Leu129Gln CysLT 2 R mutant protein constitutively activates endogenous G αq and is unresponsive to stimulation by leukotriene. Expression of Leu129Gln CysLT 2 R in melanocytes enforces expression of a melanocyte-lineage signature, drives phorbol ester–independent growth in vitro , and promotes tumorigenesis in vivo . Our findings implicate CYSLTR2 as a uveal melanoma oncogene and highlight the critical role of G αq signaling in uveal melanoma pathogenesis.