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Updated: Mar 22, 2026
Spatial and Temporal Control of Murine Melanoma Initiation from Mutant Melanocyte Stem Cells
Published on: June 7, 2019
Recurrent activating mutations of G-protein-coupled receptor CYSLTR2 in uveal melanoma
Amanda R Moore1,2, Emilie Ceraudo3, Jessica J Sher1
1Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York, USA.
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.
Insights
Uveal melanomas have unique genetic drivers. A novel mutation in cysteinyl leukotriene receptor 2 (CYSLTR2) acts as an oncogene, promoting tumor growth through Gαq signaling.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Uveal melanomas (UM) are distinct from cutaneous melanomas, lacking common mutations like BRAF and NRAS.
- UM are characterized by mutations in GNAQ/GNA11 and PLCB4, activating Gαq signaling.
- The genetic landscape of UM lacking these canonical mutations requires further elucidation.
Purpose of the Study:
- To identify novel genetic drivers in uveal melanomas that lack GNAQ, GNA11, and PLCB4 mutations.
- To investigate the functional role of identified mutations in uveal melanoma pathogenesis.
Main Methods:
- Genomic analysis of 136 uveal melanoma samples.
- Identification and characterization of mutations in CYSLTR2.
- Functional studies using melanocyte cell lines and in vivo tumorigenesis models.
Main Results:
- A recurrent CYSLTR2 mutation (p.Leu129Gln) was identified in 4 out of 9 UM samples lacking GNAQ, GNA11, and PLCB4 mutations.
- The Leu129Gln mutant CysLT2R protein constitutively activates Gαq signaling.
- Expression of the mutant receptor in melanocytes promoted lineage signature, anchorage-independent growth, and tumorigenesis.
Conclusions:
- CYSLTR2 is implicated as a novel oncogene in uveal melanoma.
- Constitutive Gαq pathway activation is a critical mechanism in UM pathogenesis.
- Targeting the Gαq pathway may offer therapeutic strategies for UM.
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