GNAQ and GNA11 mutations and downstream YAP activation in choroidal nevi

Abstract

Background:Mutations in GNAQ/11 genes are considered an early event in the development of uveal melanoma that may derive from a pre-existing nevus. The Hippo pathway, by way of YAP activation, rather than MAP kinase, has a role in the oncogenic capacity of GNAQ/11 mutations.Methods:We investigated 16 nevi from 13 human eyes for driver GNAQ/11 mutations using droplet digital PCR and determined whether nevi are clonal by quantifying mutant nevus cell fractions. Immunohistochemistry was performed on 15 nevi to analyse YAP activation.Results:For 15 out of 16 nevi, a GNAQ/11 mutation was detected in the nevus cells albeit at a low frequency with a median of 13%. Nuclear YAP, a transcriptional co-activator in the Hippo tumour-suppressor pathway, was detected in 14/15 nevi.Conclusions:Our analysis suggests that a mutation in GNAQ/11 occurs in a subset of choroidal nevus cells. We hypothesise that GNAQ/11 mutant-driven extracellular mitogenic signalling involving YAP activation leads to accumulation of wild-type nevus cells.

Iris Colour and the Risk of Developing Uveal Melanoma

“…It is known that posterior UMs carry specific mutations: in 94% of all tumours, a mutation in either the GNAQ or GNA11 gene has been found [ 63 ]. These mutations are also found in choroidal nevi [ 64 ]. GNAQ and GNA11 occur in a mutually-exclusive fashion, in about equal numbers [ 28 , 41 , 65 ].…”

Genetic Biomarkers in Melanoma of the Ocular Region: What the Medical Oncologist Should Know

“…Mutations in GNAQ and GNA11 are mutually exclusive and can lead to the activation of multiple downstream pathways involved in proliferation and cell growth [ 20 ]. As both mutations are already observed in most uveal nevi [ 21 ], they are not suitable as a diagnostic biomarker and neither have they been shown to be of significant prognostic value, although GNA11 -mutated tumors might be slightly more aggressive than their GNAQ -mutated counterparts [ 22 , 23 ]. In contrast, some chromosomal aberrations and secondary driver mutations are strong prognostic genetic biomarkers.…”

YAP/TAZ: Drivers of Tumor Growth, Metastasis, and Resistance to Therapy

“…For the GPCR ligand PGE 2 , there is evidence that it contributes to YAP activation in vivo during intestinal regeneration, colitis, and colorectal cancer. [ 29 ] The GPCR pathway is also mutationally activated in some cancers, as activating mutations in G q ( GNAQ / GNA11 ) occur in 83% uveal melanoma [ 226,227 ] and the Kaposi sarcoma virus encodes a GPCR that activates YAP/TAZ. [ 228 ] As noted above, how Rho activation leads to inhibition of LATS1/2 is still unclear, but could involve increased tension on Integrin adhesions and thus FAK‐SRC signaling.…”