A mutation in the CYCLTR2 G-protein–coupled receptor promotes tumorigenesis in uveal melanomas.

  • Major finding: A mutation in the CYCLTR2 G-protein–coupled receptor promotes tumorigenesis in uveal melanomas.

  • Concept:CYCLTR2 mutations constitutively activate Gαq in tumors lacking GNAQ, GNA11, and PLCB4 mutations.

  • Impact:CYCLTR2 is an uveal melanoma oncogene, and CYCLTR2 mutations may be actionable targets.

Uveal melanomas are eye tumors arising from melanocytes in the uveal tract. These tumors harbor frequent activating mutations in two subunits of Gαq heterotrimeric G proteins (GNAQ and GNA11), and in PLCB4, a downstream effector of Gαq signaling. To identify additional mutations driving uveal melanoma, Moore and colleagues analyzed whole-genome and whole-exome sequencing data from 136 patients with uveal melanoma from multiple cohorts. Using a mutation analysis algorithm to detect hotspot mutations in oncogenes, a previously undescribed mutation in cysteinyl leukotriene receptor 2 (CYSLTR2) was identified only in samples lacking mutations in GNAQ, GNA11, and PLCB4 (4 of 9 samples), suggesting that these mutations activate the same pathway. CYSLTR2 encodes a G-protein–coupled receptor, CysLT2R, involved in leukotriene-mediated signaling in inflammation and fibrosis. The identified mutation results in a Leu129Gln substitution in transmembrane helix 3, which associates with the extracellular ligand, intracellular Gα subunit, and other transmembrane helices. Leu129Gln CysLT2R was coupled to Gαq and was constitutively active, as evidenced by increased calcium mobilization and insensitivity to the CysLT2R agonist leukotriene D4. Leu129Gln CysLT2R had melanocyte lineage–specific effects, as it allowed melan-a melanocytes to grow in the absence of 12-O-tetradecanoylphorbol-13-acetate (TPA), which is usually required for melanosome growth and pigmentation. Moreover, Leu129Gln CysLT2R rescued pigmentation of Melan-a cells withdrawn from TPA, and enhanced expression of melanocyte lineage–specific genes. Subcutaneously engrafted melan-a cells expressing Leu129Gln CysLT2R were able to form tumors more rapidly than wild-type cells, indicating that the mutation enhances melanoma tumorigenesis in vivo. Further, CYSLTR2 knockdown suppressed the growth of Leu129Gln CysLT2R cells, and reduced expression of melanocyte-lineage genes. Taken together, these findings reveal an oncogenic role for CYSLTR2 in in uveal melanoma through activation of Gαq signaling, and further suggest that Leu129Gln CysLT2R may be a potential therapeutic target in uveal melanoma.

Moore AR, Ceraudo E, Sher JJ, Guan Y, Shoushtari AN, Chang MT, et al. Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma. Nat Genet 2016 April 18 [Epub ahead of print].

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