Molecular Pathology
Melanoma mutations
GNAQ

Author: Joshua Bradish, M.D. (see Authors page)

Editor: Liang Cheng, M.D.

Revised: 18 December 2015, last major update April 2014

Copyright: (c) 2003-2015, PathologyOutlines.com, Inc.

PubMed Search: GNAQ
Cite this page: GNAQ. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/molecularpathGNAQ.html. Accessed December 5th, 2016.
Definition / General
  • G proteins encode guanine nucleotide binding proteins, a group of heterotrimeric proteins (composed of α, β and γ subunits) involved in intracellular cascades (Science 2002;296:1636, Nature 2009;459:356)
  • GNAQ specifically encodes the alpha subunit, which binds GTP for activation and is hydrolyzed to GDP for inactivation
  • Hydrolysis is intrinsically mediated by the alpha subunit
  • The binding of GTP causes disassociation of the alpha subunit from the beta subunit
  • Both alpha and beta subunits are able to propagate cellular signaling pathways (Mol Cell Biol 1992;12:4687)
Diagrams / Tables

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G protein signaling

Frequency of GNAQ mutations



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GNAQ pathway

Molecular / Cytogenetics Description
  • GNAQ mutations appear to mainly occur in codon 209, a RAS-like domain necessary for GTPase activity
  • This mutation results in constitutive activation of the GNAQ protein, which causes it to behave as a dominant acting oncogene (Nature 2009;457:599)
  • GNAQ mutations in exon 5, at codon 209 are most common and include Q209P >> Q209L > Q209R (Br J Cancer 2009;101:813)
  • Less common mutations in exon 4, at codon 183 have also been described (N Engl J Med 2010;363:2191)
  • Specific mutations are detected using PCR-based DNA Sanger sequencing
Clinical Features
  • GNAQ mutations:
    • Found frequently in uveal melanoma (46%), malignant blue nevus (50%), and blue nevus (83%) (Nature 2009;457:599); very rare in other types of melanoma
    • Mostly mutually exclusive with other mutations (BRAF, KIT, etc.)
    • Alone are insufficient for full progression to melanoma; appears to be an early mutation in its development (Nature 2009;457:599)
    • Do not correlate with disease free survival in uveal melanoma (Br J Cancer 2009;101:813)
Treatment
  • Although not currently available, GNAQ is an attractive target for inhibitor development:
    • Preclinical data suggests that a melanoma cell line harboring the GNAQ Q209L is sensitive to MEK inhibition
    • A few ongoing phase I and phase II clinical trials may help elucidate the effectiveness of various therapies in patients with metastatic melanoma of the eye (My Cancer Genome)
Mechanisms of Resistance
  • None yet described
Resistance Therapies
  • None yet evaluated