title: Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism.
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.
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: de Lange
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Lubna
authors.initials: L
authors.lastname: Razzaq
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mieke
authors.initials: M
authors.lastname: Versluis
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Sven
authors.initials: S
authors.lastname: Verlinde
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Dogrusöz
authors.affiliation: Department of Medical Statistics, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Böhringer
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marina
authors.initials: M
authors.lastname: Marinkovic
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Gregorius P M
authors.initials: GP
authors.lastname: Luyten
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Rob J W
authors.initials: RJ
authors.lastname: de Keizer
authors.affiliation: Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Frank R
authors.initials: FR
authors.lastname: de Gruijl
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Martine J
authors.initials: MJ
authors.lastname: Jager
authors.affiliation: Department of Ophthalmology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: van der Velden
mesh_terms: D019943:Amino Acid Substitution; D005260:Female; D044385:GTP-Binding Protein alpha Subunits / Q000235:genetics*; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006801:Humans; D008297:Male; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D020125:Mutation, Missense; D009363:Neoplasm Proteins / Q000235:genetics*; D014466:Ultraviolet Rays / Q000009:adverse effects*; D014604:Uveal Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C554062:GNA11 protein, human; C554061:GNAQ protein, human; D044385:GTP-Binding Protein alpha Subunits; D009363:Neoplasm Proteins; D043802:GTP-Binding Protein alpha Subunits, Gq-G11