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.

Clinicopathologic features and survival outcomes of ocular melanoma: a series of 31 cases from a tertiary university hospital

“…One UM patient had a single-nucleotide variation at codon 183 on exon 4 of the GNAQ gene, which triggered a substitution of arginine with glutamine. This particular mutation is rarely reported in UM [44]. GNAQ/GNA11 mutations induce abnormal activation of the mitogen-activated protein kinase (MAPK) pathway, making MAPK/MEK (MAPK kinase) signaling pathway inhibitors an impressive target for therapy [45].…”

Fatal GNAQ‐mutated CNS melanoma in an adolescent with nevus of Ota

“…Development of CNS melanoma in patients with nevus of Ota is exceedingly rare, arising later in life for the few affected 1 . Nevus of Ota is known to harbor GNAQ mutations, 2 but more commonly, these mutations are associated with approximately 85% of uveal melanomas, and up to 75% of blue nevi 3 . GNAQ mutations can also be found in some port wine stains and in CNS tissue affected by Sturge‐Weber syndrome 4 …”

Melanoma in the setting of nevus of Ota: a review for dermatologists

“…The most commonly offered treatment was enucleation or extirpation of the orbit, however multiple patients opted for plaque radiotherapy after declining the former options 23,29 . Interestingly, the majority of cases that received plaque radiotherapy saw no recurrences within the follow‐up periods provided, aside from one case that recurred 3 years later, necessitating enucleation at that time with no recurrences thereafter 32 . Two cases were found to have recurrences (one at 15 months and another at 13 years), both following orbitotomy as treatment 22,26 …”

“…Like the skin, melanomas developing from the ocular aspect of nevus of Ota appear to be more common in females (Table 2). Twelve of the 16 cases of ocular melanoma occurred in women, suggesting an estimated 3 : 1 female‐to‐male ratio 13,18‐32 . The melanomas were reported in adult patients, with no pediatric cases published.…”

“…Within the eye, melanoma progressing from nevus of Ota most commonly presents in one of two locations: retro‐orbital (within the intraconal space) or within the choroid layer (uveal tract). Most cases developed within a unilateral nevus of Ota, however, a few cases demonstrated bilateral involvement 19,23,32 . In cases with bilateral lesions, the melanoma developed only in one eye, and the contralateral eye was monitored vigilantly.…”