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Background  Activating Gα q  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 CysLT 2 R) forms a rare alternative. The role of wild-type CysLT 2 R in uveal melanoma remains unknown.    Methods  We 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.    Results  1/16 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.    Conclusions  Our 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 CysLT 2 R an attractive therapeutic target in uveal melanoma.    Supplementary Information  The online version contains supplementary material available at 10.1186/s12885-021-07865-x.

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