GNAQ and PMS1 Mutations Associated with Uveal Melanoma, Ocular Surface Melanosis, and Nevus of Ota

Abstract

G protein mutations are common in uveal melanomas, and the vast majority target amino acid residue Q209 in either GNAQ or GNA11. The GNAQ R183Q mutation is found in a small fraction of uveal melanomas. We report a patient with an unusual presentation of uveal melanoma arising at an early age in the setting of congenital skin and ocular surface melanosis. A 34-year-old Hispanic female with congenital bilateral nevus of Ota and ocular surface melanosis presented with progressive loss of visual acuity and was found to have a juxtapapillary uveal melanoma. She was treated with brachytherapy, but the tumor relapsed. She underwent enucleation that revealed mixed spindle and epithelioid uveal melanoma cells with no extraocular or lymphovascular spread. Next-generation sequencing performed on DNA isolated from the enucleation specimen identified a GNAQ R183Q mutation and a PMS1 truncation mutation. Cytogenetic profiling revealed no monosomy 3. These findings raise the possibility that uveal melanomas bearing G protein R183 mutations may have distinct clinicopathologic profiles compared to those with Q209 mutations. Furthermore, this is the first reported case of a mutation in the mismatch repair gene PMS1 associated with uveal melanoma.

Keywords: GNAQ/GNA11; Mismatch repair; Nevus of Ota; Ocular melanosis; Uveal melanoma.

Fig. 1

a External photograph demonstrating periocular dermal hyperpigmentation typical of nevus of Ota. b External photograph demonstrating episcleral pigmentation typical of ocular melanocytosis. c Color fundus image showing a large juxtapapillary choroidal lesion at the time of diagnosis. d B-scan ultrasound of the lesion measuring 9.5 × 8.1 × 4.1 mm.

Fig. 2

a, b Histopathology of the vitrectomy biopsy shows malignant, epithelioid, pigmented melanocytes at low (a) and high magnifications (b). c Histopathology of the uveal melanoma with overlying retina. d Higher magnification reveals uveal melanoma associated with ocular melanosis of choroid and sclera.