Activating cysteinyl leukotriene receptor 2 (CYSLTR2) mutations in blue nevi

Abstract

Blue nevi are common melanocytic tumors arising in the dermal layer of the skin. Similar to uveal melanomas, blue nevi frequently harbor GNAQ and GNA11 mutations. Recently, recurrent CYSLTR2 and PLCB4 mutations were identified in uveal melanomas not harboring GNAQ or GNA11 mutations. All four genes (GNAQ, GNA11, CYSLTR2, and PLCB4) code for proteins involved in the same signaling pathway, which is activated by mutations in these genes. Given the related functional consequences of these mutations and the known genetic similarities between uveal melanoma and blue nevi, we analyzed a cohort of blue nevi to investigate whether CYSLTR2 and PLCB4 mutations occur in tumors lacking GNAQ or GNA11 mutations (as in uveal melanoma). A targeted next-generation sequencing assay covering known activating mutations in GNAQ, GNA11, CYSLTR2, PLCB4, KIT, NRAS, and BRAF was applied to 103 blue nevi. As previously reported, most blue nevi were found to harbor activating mutations in GNAQ (59%, n = 61), followed by less frequent mutations in GNA11 (16%, n = 17). Additionally, one BRAF (1%) and three NRAS (3%) mutations were detected. In three tumors (3%) harboring none of the aforementioned gene alterations, CYSLTR2 mutations were identified. All three CYSLTR2 mutations were the same c.386T > A, L129Q mutation previously identified in uveal melanoma that has been shown to lead to increased receptor activation and signaling. In summary, our study identifies CYSLTR2 L129Q alterations as a previously unrecognized activating mutation in blue nevi, occuring in a mutually exclusive fashion with known GNAQ and GNA11 mutations. Similar to GNAQ and GNA11 mutations, CYSLTR2 mutations, when present, are likely defining pathogenetic events in blue nevi.

SF3B1 and BAP1 mutations in blue nevus-like melanoma

“…Similar to previous studies, 5,13,14,16 the overwhelming majority of blue nevi in our cohort were found to harbor activating mutations in GNAQ and GNA11 . CYSLTR2 L129 and PLCB4 D630 mutations were rare with a frequency of around 1% (4 and 3 cases, respectively).…”

“…Of these samples, approximately one third (103) of the cases were described in a previous publication. 16 The study was performed in accordance with the guidelines of the ethics committee of the University of Duisburg-Essen and approved under the IRB-number 16–6951-BO.…”

“…10–12 This is uncommon in blue nevi which frequently contain activating GNAQ, GNA11 and less frequently CYSLTR2 mutation. 13–16 All of these mutations were also identified in uveal melanoma. 13–15 Other genes mutated in uveal melanomas are BAP1 , EIF1AX , and SF3B1 .…”

Activating CYSLTR2 and PLCB4 Mutations in Primary Leptomeningeal Melanocytic Tumors

“…CYSLTR2 mutations have also been detected in blue nevi (Moller et al, 2016). These mutations always occurred in tumors lacking GNAQ and GNA11 mutations, and have not yet been reported in cutaneous melanomas (Cancer Genome Atlas, 2015).…”

“…These mutations always occurred in tumors lacking GNAQ and GNA11 mutations, and have not yet been reported in cutaneous melanomas (Cancer Genome Atlas, 2015). To determine whether CYSLTR2 and PLCB4 mutations also occur in PLMTs, we analyzed our previously published cohort of tumors (van de Nes et al, 2016a, van de Nes et al, 2016b), using a next-generation sequencing gene panel covering the mutational hot-spots in CYSLTR2 and PLCB4 as well as other gene mutations reported in uveal melanoma (described in Supplemental Material and previously reported (Moller et al, 2016)).…”