GNAQ R183Q Mutation Identified in a Young Patient with Uveal Melanoma, Ocular Surface Melanosis, and Nevus of Ota

Abstract

Purpose : Uveal melanomas typically arise in aged patients and are associated with Guanine nucleotide-binding protein Ga subunit (GNAQ) mutations. The vast majority of GNAQ mutations in uveal melanomas target glutamine (Q) at position 209 to introduce oncogenic missense changes. A GNAQ R183Q (arginine to glutamine) mutation is found in 1-2% of uveal melanoma, while GNAQ Q209 is found in 20-45%. The clinicopathologic differences between uveal melanomas expressing GNAQ mutations at residue 183 vs 209 are unclear. Interestingly, the GNAQ R183Q mutation, but not the GNAQ Q209 mutation, is reported in disorders associated with melanocytic proliferations, including Sturge-Weber Syndrome (SWS) and Phacomatosis pigmentovascularis (PPV).

Methods : We identified a 34 year-old female with congenital bilateral nevus of Ota and ocular surface melanosis who presented with progressive loss of visual acuity in the right eye and was found to have a juxtapapillary uveal melanoma. She was treated with brachytherapy but the tumor relapsed in 2017. During attempt at internal resection by vitrectomy instrumentation, invasion of the optic nerve head was found. After enucleation, tumor DNA was extracted and analyzed for genetic mutations and chromosomal rearrangements.

Results : Gross and histological examination of the eye showed extensive choroidal melanosis and a uveal melanoma arising adjacent to the optic nerve head. There was no evidence of extraocular or vascular spread. SNP-based cytogenetic testing revealed no chromosomal 3 deletions. Next-generation sequencing identified a GNAQ R183Q mutation with a variant allele fraction of 70%.

Conclusions : SWS, PPV, and a subset of uveal melanomas involve the GNAQ R183Q mutation. The natural history of this patient’s presentation illustrates an unusual case of uveal melanoma arising at an early age in a background of bilateral nevus of Ota with ocular melanosis. Our findings in this patient raise the possibility that uveal melanomas with the rare GNAQ R183Q mutation may have a distinct clinical-pathologic profile on the spectrum of an ocular melanocytic disorder compared to conventional uveal melanomas with GNAQ 209 mutations.

This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.