Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism

Mark J de Lange; Lubna Razzaq; Mieke Versluis; Sven Verlinde; Mehmet Dogrusöz; Stefan Böhringer; Marina Marinkovic; Gregorius P M Luyten; Rob J W de Keizer; Frank R de Gruijl; Martine J Jager; Pieter A van der Velden

doi:10.1371/journal.pone.0138002

Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism

PLoS One. 2015 Sep 14;10(9):e0138002. doi: 10.1371/journal.pone.0138002. eCollection 2015.

Affiliations

¹ Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
² Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands.
³ Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.

Abstract

Uveal melanomas (UM) originate from melanocytes in the interior wall of the eye, namely from the iris, ciliary body and the choroid with marked differences in light exposure (from dark anterior to illuminated posterior). In contrast to UV radiation, focused or converging visible light readily reaches the retina and can damage DNA which possibly contributes to UM development. In this report choroidal, ciliochoroidal and iridociliary melanomas were analyzed for GNAQ and GNA11 mutations which were subsequently correlated to the location of tumor origin. Hotspot mutations in GNAQ and GNA11 can be divided in A>T and in A>C mutation signatures. The GNAQ A626C mutation (Q209P) was almost exclusively observed in choroidal melanomas from the illuminated posterior side. On the other hand, ciliochoroidal UM from the dark anterior side with mostly A>T mutations were clearly associated with light-colored eyes. Combined these data suggest a light and a pigment dependent etiology in UM development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Amino Acid Substitution
Female
GTP-Binding Protein alpha Subunits / genetics*
GTP-Binding Protein alpha Subunits, Gq-G11
Humans
Male
Melanoma / genetics*
Melanoma / pathology
Mutation, Missense*
Neoplasm Proteins / genetics*
Ultraviolet Rays / adverse effects*
Uveal Neoplasms / genetics*
Uveal Neoplasms / pathology

Substances

GNA11 protein, human
GNAQ protein, human
GTP-Binding Protein alpha Subunits
Neoplasm Proteins
GTP-Binding Protein alpha Subunits, Gq-G11

Grants and funding

This work was supported by KWF kankerbestrijding grant no.: UL2011-4991, received by PAvdV. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.