<i>GNAQ</i> / <i>11</i> mutant nonuveal melanoma: same same but different
Authors: D. Rafei‐Shamsabadi
Journal: British Journal of Dermatology (2020)

Linked Article: Livingstone et al. Br J Dermatol 2020; 183:928–939. The work by Livingstone et al. published in this issue of the BJD draws attention to the rarely occurring but prognostically highly relevant GNAQ/11 mutations in nonuveal melanoma.1 Malignant melanoma harbours certain hotspot mutations in signalling pathways and the occurrence of these mutations differs according to the localization of the primary tumour.2 In cutaneous melanoma we frequently find mutations in the Ras-Raf-MEK-ERK mitogen-activated protein kinase pathway, most of which are BRAF (~40%) or NRAS (~20%) mutations that occur mutually exclusively, at least in the case of highly active BRAF oncoproteins.2, 3 These mutations are much less common in acral lentiginous melanoma (ALM), which accounts for 14–15% of BRAF and NRAS mutations.4 Small molecule drugs inhibiting BRAF-mutated melanoma have been proven effective, leading to a much improved overall survival (OS). Mutations in the proto-oncogene c-KIT can be found in ALM (~12%)4 and melanoma of the mucous membranes (~16%).5 Studies investigating the efficacy of KIT inhibitors such as imatinib have shown little to no effect on progression-free survival and OS.6 Finally, ocular melanoma, which most commonly occurs as uveal melanoma, normally lacks BRAF, NRAS or c-KIT mutations, but frequently (80% of somatic mutations) presents with mutations in GNAQ or GNA11, which are involved in signalling via G-protein-coupled receptors.7 Additional mutations typically occur in SF3B1, EIF1AX or BAP1 and have been shown to be of prognostic relevance.8 Metastasized uveal melanoma is known to have a bad prognosis with poor treatment response (e.g. to immunotherapy).9 In a large analysis of cutaneous melanomas from 331 patients, 52% (n = 166) harboured BRAF somatic mutations, 28% (n = 88) had NRAS somatic mutations and 14% of samples displayed mutations in NF1.10 Most notably, in the so-called triple wildtype subtype (n = 46), GNAQ (n = 1), GNA11 (n = 2) and KIT (n = 6) mutations were found.10 Van Raamsdonk et al. sequenced exon 5 of GNAQ and GNA11 in 713 melanocytic neoplasms and exon 4 of GNAQ and GNA11 in 453 of these samples and in all coding exons of GNAQ and GNA11 in 97 uveal melanomas and 45 blue naevi. Of the uveal melanomas analysed, 83% had somatic mutations in GNAQ or GNA11.7 Of the 273 extraocular melanomas sequenced, only one melanoma located on chronically sun-damaged skin showed a mutation in GNAQ, resulting in a frequency of 0.4%. Interestingly, there was no significant difference in outcome on the basis of mutational status (GNAQ, GNA11 or neither mutation) among 81 patients with primary uveal melanoma.7 Very little is known about GNAQ or GNA11 mutations in nonuveal melanoma. Livingstone et al. retrospectively characterized a cohort of 18 patients with metastasized nonuveal melanomas, all of whom harboured mutations in the GNAQ or GNA11 genes.1 Molecular characterization of tumour tissues included immunohistochemistry staining, targeted sequencing for known recurrent hotspot mutations and a 130-gene panel to determine tumour mutational burden (TMB). In addition to the GNAQ and GNA11 loci, six SF3B1, three EIF1AX and four BAP1 mutations were detected in this cohort, but had no impact on patient prognosis. The data were correlated with the clinical outcome of these patients.1 Interestingly, GNAQ/11 mutant nonuveal melanomas behave in a clinically different manner regarding the site of first metastases and show much more ultraviolet-derived mutations compared with uveal melanomas. The TMB was situated right between uveal (low) and cutaneous melanoma (high). However, nonuveal melanomas had a poor response to immune checkpoint inhibitor treatments (such as cytotoxic T-lymphocyte-associated protein 4 inhibitors and programmed cell death protein 1 inhibitors), similar to that seen in uveal melanomas.1 In conclusion, Livingstone et al. describe a distinct subtype of malignant melanoma that shares the clinical behaviour of the cutaneous and genetic alterations of uveal melanoma. The poor treatment responses render this subtype a candidate for intensive research on therapeutic targets.1 The author would like to thank Tilman Brummer from the Institute of Molecular Medicine and Cell Research, Faculty of Medicine, University of Freiburg, Freiburg, Germany for critically reviewing this commentary. David Rafei: Conceptualization (lead); Investigation (lead); Writing-original draft (lead). Tilman Brummer: Writing-review & editing (supporting).