Involvement of mutant and wild-type CYSLTR2 in the development and progression of uveal nevi and melanoma

Rogier J Nell,Mieke Versluis,Gregorius P M Luyten,Martine J Jager,Robert M Verdijk,Michele C Madigan,Pieter A Van Der Velden,Nino V Menger

doi:10.1186/s12885-021-07865-x

Rogier J Nell, Mieke Versluis + Show 6 more

Open Access

https://doi.org/10.1186/s12885-021-07865-x

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Abstract

BackgroundActivating Gαq signalling mutations are considered an early event in the development of uveal melanoma. Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLT2R) forms a rare alternative. The role of wild-type CysLT2R in uveal melanoma remains unknown.MethodsWe performed a digital PCR-based molecular analysis of benign choroidal nevi and primary uveal melanomas. Publicly available bulk and single cell sequencing data were mined to further study mutant and wild-type CYSLTR2 in primary and metastatic uveal melanoma.Results1/16 nevi and 2/120 melanomas carried the CYSLTR2 mutation. The mutation was found in a subpopulation of the nevus, while being clonal in both melanomas. In the melanomas, secondary, subclonal CYSLTR2 alterations shifted the allelic balance towards the mutant. The resulting genetic heterogeneity was confirmed in distinct areas of both tumours. At the RNA level, further silencing of wild-type and preferential expression of mutant CYSLTR2 was identified, which was also observed in two CYSLTR2 mutant primary melanomas and one metastatic lesion from other cohorts. In CYSLTR2 wild-type melanomas, high expression of CYSLTR2 correlated to tumour inflammation, but expression originated from melanoma cells specifically.ConclusionsOur findings suggest that CYSLTR2 is involved in both early and late development of uveal melanoma. Whereas the CYSLTR2 p.L129Q mutation is likely to be the initiating oncogenic event, various mechanisms further increase the mutant allele abundance during tumour progression. This makes mutant CysLT2R an attractive therapeutic target in uveal melanoma.

Highlights

Activating Gαq signalling mutations are considered an early event in the development of uveal melanoma
CYSLTR2 p.L129Q is subclonally present in a GNAQ/GNA11 wild-type nevus Previously, 16 choroidal nevi from 13 post-mortem collected eyes were analysed for GNAQ and GNA11 hotspot mutations
In nevus 12B, the only one being GNAQ and GNA11 wild-type, we identified this CYSLTR2 mutation, while only CYSLTR2 wild-type alleles were detected in other nevi (Fig. 1a and b)

Summary

Introduction

Activating Gαq signalling mutations are considered an early event in the development of uveal melanoma. Whereas most tumours harbour a mutation in GNAQ or GNA11, CYSLTR2 (encoding G-protein coupled receptor CysLT2R) forms a rare alternative. The role of wild-type CysLT2R in uveal melanoma remains unknown. Uveal melanoma is the most common primary tumour in the adult eye, with an annual incidence of 2–8 per million [1]. Uveal melanoma is usually fatal within a year [2]. The cancer originates from melanocytes in the uvea, the pigmented vascular layer of the eye. It is hypothesised that (epi)genetic alterations drive the transformation of these melanocytes into benign nevi and subsequently into malignant melanomas. It is rare to find histologically distinct pre-malignant lesions within or adjacent to a primary tumour [3]

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