Mutations in GNAQ and GNA11 in Chinese patients with uveal melanoma

Abstract

Purpose : Uveal melanoma is the most common primary malignancy of the eye, yet our understanding of the molecular genetics and pathogenesis of the disease remains incomplete. The R138 and Q209 mutations in exons 4 and 5 of GNAQ and its paralogous gene GNA11 have been shown to be mutational hotspots in Caucasians. We tested the hypothesis that these mutations may also exhibit oncogenic potential in a Chinese population by analyzing DNA sequencing data from enucleated eyes with biopsy-proven uveal melanoma.

Methods : Somatic DNA was extracted from paraffin-embedded biopsies of 63 enucleated eyes from Chinese patients with uveal melanoma between 2005 and 2011. The average age of the patients was 51+/- 1.8 years, and 55.6% were male. DNA was amplified by polymerase chain reaction and sequenced with Genetic Analyzer 3130. Direct nucleotide sequence analysis was completed for the entire coding regions of exons 4 and 5 of both GNAQ and GNA11.

Results : Among 63 eyes of Chinese uveal melanoma patients, 7 (11.1%) had a Q209 mutation in GNAQ, and 14 (22.2%) had a Q209 mutation in GNA11. There was not a single R183 mutation in either GNAQ or GNA11 observed in this Chinese cohort. We identified seven novel missense somatic mutations in GNAQ (Y192C, F194L, P170S, D236N, L232F, V230A, and M227I) and four novel missense somatic mutations in GNA11 (R166C, I200T, S225F, and V206M). All of these novel mutations were located in evolutionarily conserved regions.

Conclusions : Exons 4 and 5 of GNAQ and GNA11 have been identified as mutational hotspots in Caucasian patients. Approximately one-third (33.3%) of eyes from Chinese uveal melanoma patients carried the Q209 mutation in GNAQ or GNA11. No Chinese patients carried the R183 mutation, although this may have been secondary to sample size. Multiple novel missense mutations were also identified in these exons in the Chinese cohort. These findings suggest that exons 4 and 5 of GNAQ and GNA11 may also be important for the pathogenesis of uveal melanoma in Chinese patients. Understanding the genetics of uveal melanoma in different patient populations may help shed light on the pathogenesis of the disease and ultimately aid in the development of effective clinical therapies.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.