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 1–3. 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 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.

The biology of uveal melanoma

“…The analysis of whole exome sequencing data in double wild-type UM has led to the identification of a L129G-activating mutation in the cysteinyl leukotriene receptor 2 (CYSLTR2) gene, coding for a G protein-coupled receptor. The mutation leads to constitutive activation of GNAQ signaling [169]. The D630Y mutation in the phospholipase Cβ4 (PLCB4) gene that has been observed in several GNAQ and GNA11 wild-type UM cases activates the same pathway acting downstream of GNAQ by catalyzing the formation of inositol 1,4,5-trisphosphate and diacylglycerol from phosphatidylinositol 4,5-bisphosphate [157].…”

“…2. Almost all UMs are characterized by mutations in either GNAQ, GNA11, PLCB4, or CYSLTR2 with few cases showing none of these mutations [27, 28, 157, 169]. These mutations are most likely not sufficient for the establishment of the tumor.…”

Co-targeting HGF/cMET Signaling with MEK Inhibitors in Metastatic Uveal Melanoma

“…Silencing BAP1 in primary UM cell lines results in a gain of stem-like properties with little/no effect on proliferation and invasion (14). Additional genes mutated in UM are SF3B1 and EIF1AX, which associate with a favorable prognosis (15–17), PLCB4 (18) and CYSLTR2 (19). …”

PD-L1 expression in tumor metastasis is different between uveal melanoma and cutaneous melanoma

“…Uveal melanoma tends to recur in approximately 50% of the cases despite successful therapy of the primary tumor, in particular those whose tumors have certain risk factors for metastasis, such as large tumor size, ciliary body location, epithelioid cell morphology, high mitotic count and chromosomal abnormalities (e.g., chromosome 3 loss, 8q gain) [4]. Compared with cutaneous melanoma, uveal melanoma is characterized by its distinct genetic profile and clinical presentation, where most metastases are detected in the liver [5][6][7][8][9][10]. Once uveal melanoma metastasizes, prognosis is poor because metastatic uveal melanoma (MUM) tends to be widespread within the liver and only surgically resectable in some cases [11,12].…”