Guanine nucleotide binding proteins (G proteins) are a family of heterotrimeric proteins which couple seven transmembrane domain receptors to intracellular cascades, including neurotransmitter, growth factor, and hormone signaling pathways (for review, see Neves, Ram, and Iyengar 2002 and Rosenbaum, Rasmussen, and Kobilka 2009). Heterotrimeric G proteins are composed of three subunits, Gα, Gß, and Gγ (Figure 1); each of the subunits has many different family members. The GNAQ gene encodes the Gq alpha subunit (Gαg). Receptor activation catalyzes the exchange of GDP (guanosine diphosphate) to GTP (guanosine triphosphate) on the Gα subunit, resulting in the dissociation of the Gα subunit from Gßγ. Both Gα and Gßγ can then activate downstream cellular signaling pathways. The signal is terminated when GTP is hydrolyzed to GDP by the intrinsic GTPase activity of the Gα subunit. Oncogenic mutations result in a loss of this intrinsic GTPase activity, resulting in a constitutively active Gα subunit (Kalinec et al. 1992; Landis et al. 1989).
Figure 1. Schematic of heterotrimeric G protein signaling. Activation of a 7 transmembrane G-protein coupled receptor results in exchange of GDP for GTP on the Gα subunit. The GTP bound form of Gα then dissociates from Gßγ. Multiple downstream cellular effector pathways can be activated by G protein signaling.
Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2014. GNAQ. My Cancer Genome http://www.mycancergenome.org/content/disease/melanoma/gnaq/?tab=0 (Updated August 20).
Last Updated: August 20, 2014
GNAQ in Melanoma
Somatic mutations in GNAQ have been found in ~50% of primary uveal melanomas and up to 28% of uveal melanoma metastases (Onken et al. 2008; Van Raamsdonk et al. 2009; van Raamsdonk et al. 2010). In all malignant melanoma, GNAQ mutations are found in about 1.3% of samples (COSMIC). GNAQ mutations are rare in extraocular melanoma (Van Raamsdonk et al. 2009).
The majority of melanoma-associated mutations in GNAQ have been detected at codon 209 within exon 5 of the gene, a region within the catalytic (GTPase) domain of GNAQ. Mutation at this site inactivates the GTPase domain, resulting in a constitutively active GNAQ protein, which is 'locked' in the GTP bound form (Kalinec et al. 1992; Landis et al. 1989). Expression of GNAQ Q209L in mice results in melanocyte transformation and increased signaling through the MAPK pathway (Van Raamsdonk et al. 2009).
In the vast majority of cases, GNAQ mutations are non-overlapping with other oncogenic mutations found in melanoma (e.g., BRAF mutations, KIT mutations, etc.). Currently, there are no direct anti-GNAQ therapies available.
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. GNAQ in Melanoma. My Cancer Genome http://www.mycancergenome.org/content/disease/melanoma/gnaq/ (Updated June 18).
Last Updated: June 18, 2015
GNAQ c.626A>C (Q209P) Mutation in Melanoma
|Location of mutation
|Frequency of GNAQ mutations in primary uveal melanoma
||~50% (Onken et al. 2008; Van Raamsdonk et al. 2009; van Raamsdonk et al. 2010)
|Frequency of Q209P mutation among GNAQ-mutated primary uveal melanoma
|Implications for Targeted Therapeutics|
|Response to BRAF inhibitors
||Unknown at this time
|Response to MEK inhibitors
||Unknown at this timea
|Response to KIT inhibitors
||Unknown at this time
The Q209P mutation results in an amino acid substitution at position 209 in GNAQ, from a glutamine (Q) to a proline (P). This mutation occurs within the catalytic (GTPase) domain of GNAQ and results in a constitutively active GNAQ protein (Kalinec et al. 1992; Landis et al. 1989). GNAQ mutations are usually found in tumors with no driver mutations detected in NRAS, BRAF, KIT, and other genes. Currently, there are no direct anti-GNAQ therapies available.
a In a phase II trial, no significant difference in efficacy was reported in a subset of uveal melanoma patients whose tumors harbored GNAQ or GNA11 Exon 5 mutations treated with the MEK1/2 inhibitor selumetinib compared with chemotherapy (Carvajal et al. 2014).
Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. GNAQ c.626A>C (Q209P) Mutation in Melanoma. My Cancer Genome http://www.mycancergenome.org/content/disease/melanoma/gnaq/102/ (Updated June 16).
Last Updated: June 16, 2015