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PMID: 27089179 Published · ppublish English Journal Article

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

Nature genetics ·Vol. 48 ·No. 6 ·2016-00-00 ·Pages 675-80

Moore AR, Ceraudo E, Sher JJ, Guan Y, Shoushtari AN, Chang MT, Zhang JQ, Walczak EG, Kazmi MA, Taylor BS, Huber T, Chi P, Sakmar TP, Chen Y

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.

MeSH Terms
Animals Calcium/metabolism Female Genetic Predisposition to Disease HEK293 Cells Humans Melanoma/genetics Mice Mice, SCID Mutation Receptors, Leukotriene/genetics Uveal Neoplasms/genetics
Chemicals
Receptors, Leukotriene cysteinyl leukotriene receptor 2 Calcium
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Moore Amanda R
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.
Ceraudo Emilie
Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.
Sher Jessica J
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Guan Youxin
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Shoushtari Alexander N
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.
Chang Matthew T
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.
Zhang Jenny Q
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Walczak Edward G
Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
Kazmi Manija A
Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.
Taylor Barry S
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.
Huber Thomas
Laboratory of Chemical Biology and Signal Transduction, Rockefeller University, New York, New York, USA.
Chi Ping
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.
Sakmar Thomas P
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.
Chen Yu
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.
Conflict of Interest

The authors declare no competing financial interests.

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Article Info
Journal
Nature genetics
Abbr.
Nat Genet
ISSN
1546-1718
DOI
10.1038/ng.3549
Published
2016-00-00
Epub
2016-00-18
Pages
675-80
Language
English
Region
United States
NLM ID
9216904
PMCID
PMC5032652
Subset
IM
Grants
NCI NIH HHS · R01 CA193837 · United States
NCI NIH HHS · DP2 CA174499 · United States
NCI NIH HHS · K08 CA151660 · United States
NCI NIH HHS · P50 CA140146 · United States
NCI NIH HHS · P30 CA008748 · United States
NCI NIH HHS · K08 CA140946 · United States
External Links
PubMed source DOI: 10.1038/ng.3549 PMC Full Text View journal details
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