• What is GNA11?
  • GNA11 in Melanoma
  • GNA11 c.546_547delCCinsTT (R183C)
  • Clinical Trials

GNA11

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 a recent review, see 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 GNA11 gene encodes the alpha-11 subunit (Gα11). 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).

heterotrimeric-g-protein.png

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.

Related Pathways

Contributors: Christine M. Lovly, M.D., Ph.D., Jeff Sosman, M.D., William Pao, M.D., Ph.D. (through April 2014)

Suggested Citation: Lovly, C., J. Sosman, W. Pao. 2015. GNA11. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/gna11/?tab=0 (Updated December 4).

Last Updated: December 4, 2015

GNA11 in Melanoma

Somatic mutations in GNA11 have been found in up to 34% of primary uveal melanomas and up to 63% of uveal melanoma metastases (Van Raamsdonk et al. 2010). In all malignant melanoma, GNA11 mutations are found in about 1.2% of samples (COSMIC​). GNA11 mutations have not been detected in extraocular melanoma (Van Raamsdonk et al. 2010).

The majority of melanoma-associated mutations in GNA11 have been detected at codon 209 within exon 5 of the gene, a region within the catalytic (GTPase) domain of GNA11. Mutation at this site inactivates the GTPase domain, resulting in a constitutively active GNA11 protein which is 'locked' in the GTP bound form (Kalinec et al. 1992; Landis et al. 1989). Expression of GNA11 Q209L in mice results in melanocyte transformation and increased signaling through the MAPK pathway (Van Raamsdonk et al. 2010).

In the vast majority of cases, GNA11 mutations are non-overlapping with other oncogenic mutations found in melanoma (e.g., BRAF mutations, KIT mutations, etc.). Currently, there are no direct anti-GNA11 therapies available.

Contributors: Christine M. Lovly, M.D., Ph.D., William Pao, M.D., Ph.D. (through April 2014), Jeff Sosman, M.D.

Suggested Citation: Lovly, C., W. Pao, J. Sosman. 2015. GNA11 in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/gna11/ (Updated June 18).

Last Updated: June 18, 2015

GNA11 c.546_547delCCinsTT (R183C) Mutation in Melanoma

Properties
Location of mutation Exon 4
Frequency of GNA11 mutations in primary uveal melanoma 34% (van Raamsdonk et al. 2010​)
Frequency of R183C mutation in GNA11-mutated primary uveal melanoma 2.1–5.2% (COSMIC​; van Raamsdonk et al. 2010​)
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 R183C mutation results in an amino acid substitution at position 183 in GNA11, from an arginine (R) to a cysteine (C). This mutation occurs within the catalytic (GTPase) domain of GNA11 and results in a constitutively active GNA11 protein (Kalinec et al. 1992; Landis et al. 1989). GNA11 mutations are usually found in tumors with no driver mutations detected in NRAS, BRAF, KIT, and other genes. Currently, there are no direct anti-GNA11 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).

Contributors: Christine M. Lovly, M.D., Ph.D., Douglas Johnson, M.D., Jeff Sosman, M.D.

Suggested Citation: Lovly, C., D. Johnson, J. Sosman. 2015. GNA11 c.546_547delCCinsTT (R183C) Mutation in Melanoma. My Cancer Genome https://www.padiracinnovation.org/content/disease/melanoma/gna11/335/ (Updated June 16).

Last Updated: June 16, 2015

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