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.

Development and validation of immunogenic cell death-related signature for predicting the prognosis and immune landscape of uveal melanoma

“…The genetic analysis of tumor samples in UM can help predict metastatic risk and manage patients. Monosomy 3 (M3) and BAP1 gene inactivation are strongly associated with poor prognosis ( 39 ), and patients with BAP1 inactivation are at high risk of metastasis ( 40 , 41 ). Among the four subtypes identified by Robert son AG et al., EIF1AX or SF3B1 alterations were associated with a lower risk of metastasis and a better prognosis ( 41 ).…”

“…Among the four subtypes identified by Robert son AG et al., EIF1AX or SF3B1 alterations were associated with a lower risk of metastasis and a better prognosis ( 41 ). Although there is no conclusive evidence that alterations in the GNAQ and GNA11 genes are relevant to UM prognosis and metastasis ( 39 ), a recent study reported a poorer prognosis for those with GNA11 mutations ( 42 ). In our results, the frequencies of GN A11 and BAP1 gene alterations were highest in the ICD high expression and high-risk groups, indicating a poor prognosis.…”

Review: The Key Factors to Melanomagenesis

“…4. GNAQ/GNA11 subtype: GNAQ/GNA11 mutations are found in 80–90% of uveal melanomas [ 38 ]. These genes encode the alpha subunits of the heterotrimeric G proteins (Gq/G11) and their mutations activate various signaling pathways, acting as driver genes in the oncogenic process [ 38 ].…”

“…GNAQ/GNA11 subtype: GNAQ/GNA11 mutations are found in 80–90% of uveal melanomas [ 38 ]. These genes encode the alpha subunits of the heterotrimeric G proteins (Gq/G11) and their mutations activate various signaling pathways, acting as driver genes in the oncogenic process [ 38 ]. Patients may be treated with MEK inhibitors since these genes’ activation leads to the activation of the MAPK pathway with MEK enzymes being one of its main effectors [ 26 ].…”

Detection of the Uveal Melanoma-Associated Mutation GNAQ Q209P from Liquid Biopsy Using CRISPR/Cas12a Technology

“…For example, GNAQ /11 mutations result in the constitutive activation of signaling cascades that promote cell proliferation and tumor progression in UM. The inhibition of these well-studied signaling pathways is a promising targeted therapeutic strategy , but requires prior knowledge of the patient’s mutational status.…”