GNAQ and GNA11 Genes: A Comprehensive Review on Oncogenesis, Prognosis and Therapeutic Opportunities in Uveal Melanoma

Abstract

The GNAQ and GNA11 genes are mutated in almost 80-90% of uveal melanomas in a mutually exclusive pattern. These genes encode the alpha subunits of the heterotrimeric G proteins, Gq and G₁₁; thus, mutations of these genes result in the activation of several important signaling pathways, including phospholipase C, and activation of the transcription factor YAP. It is well known that both of them act as driver genes in the oncogenic process and it has been assumed that they do not play a role in the prognosis of these tumours. However, it has been hypothesised that mutations in these genes could give rise to molecularly and clinically distinct types of uveal melanomas. It has also been questioned whether the type and location of mutation in the GNAQ and GNA11 genes may affect the progression of these tumours. All of these questions, except for their implications in carcinogenesis, remain controversial. Uveal melanoma has a distinctive genetic profile, and specific recurrent mutations, which make it a potential candidate for treatment with targeted therapy. Given that the most frequent mutations are those observed in the GNAQ and GNA11 genes, and that both genes are involved in oncogenesis, these molecules, as well as the downstream signalling pathways in which they are involved, have been proposed as promising potential therapeutic targets. Therefore, in this review, special attention is paid to the current data related to the possible prognostic implications of both genes from different perspectives, as well as the therapeutic options targeting them.

Keywords: GNA11; GNAQ; mutation; oncogenesis; prognostication; therapies; uveal melanoma.

Figure 1

Simplified view of heterotrimeric G protein Gαq/11 and its cellular downstream signalling pathways in UM. Targeted therapies studied only preclinically are shown in red, and those already tested in clinical trials are shown in blue. Created with BioRender.com (accessed on 1 February 2022).