title: Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma.
abstract: 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 Gαq/11 heterotrimeric G proteins, and in PLCB4 (phospholipase C β4), the downstream effector of Gαq signaling. 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 CysLT2R mutant protein constitutively activates endogenous Gαq and is unresponsive to stimulation by leukotriene. Expression of Leu129Gln CysLT2R 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 Gαq signaling in uveal melanoma pathogenesis.
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.
authors.forename: Amanda R
authors.initials: AR
authors.lastname: Moore
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.
authors.forename: Emilie
authors.initials: E
authors.lastname: Ceraudo
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jessica J
authors.initials: JJ
authors.lastname: Sher
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Youxin
authors.initials: Y
authors.lastname: Guan
authors.affiliation: Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Alexander N
authors.initials: AN
authors.lastname: Shoushtari
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Matthew T
authors.initials: MT
authors.lastname: Chang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Jenny Q
authors.initials: JQ
authors.lastname: Zhang
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Edward G
authors.initials: EG
authors.lastname: Walczak
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.
authors.forename: Manija A
authors.initials: MA
authors.lastname: Kazmi
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
authors.forename: Barry S
authors.initials: BS
authors.lastname: Taylor
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Huber
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Chi
authors.affiliation: Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.|Department of Neurobiology, Care Sciences and Society, Division for Neurogeriatrics, Center for Alzheimer Research, Karolinska Institutet, Huddinge, Sweden.
authors.forename: Thomas P
authors.initials: TP
authors.lastname: Sakmar
authors.affiliation: Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Weill Cornell Graduate School of Medical Sciences, Cornell University, New York, New York, USA.|Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.|Department of Medicine, Weill Cornell Medical College, New York, New York, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Chen
mesh_terms: D000818:Animals; D002118:Calcium / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D006801:Humans; D008545:Melanoma / Q000235:genetics*; D051379:Mice; D016513:Mice, SCID; D009154:Mutation; D018077:Receptors, Leukotriene / Q000235:genetics*; D014604:Uveal Neoplasms / Q000235:genetics*
chemical_list: D018077:Receptors, Leukotriene; C412375:cysteinyl leukotriene receptor 2; D002118:Calcium