Mutation frequencies of GNAQ, GNA11, BAP1, SF3B1, EIF1AX and TERT in uveal melanoma: detection of an activating mutation in theTERT gene promoter in a single case of uveal melanoma.

Background: Uveal melanoma is the most frequent primary tumor of the eye. It is molecularly clearly distinct from cutaneous melanoma and shows a different pattern of driver mutations. The influence of sunlight UV-exposure on the aetiology of uveal melanoma is matter of debate. The recent identification of driver mutations in the promoter of the telomerase reverse transcriptase (TERT) gene with UV induced cytidine-to-thymidine transitions in cutaneous melanoma prompted us to investigate whether these mutations also occur in uveal melanoma. Methods: We analysed 50 cases of uveal melanoma obtained from enucleation surgery for mutations in the genes GNAQ, GNA11, BAP1, SF3B1, EIFAX1 and TERT, measured gene expression using microarrays and analysed gene copy numbers by SNP arrays. Results: We detected a TERT mutation in only one case of a 57-year old white male with clinical and histopathological features typical for uveal melanoma. The tumor showed mutations in GNA11 and EIF1AX that are typical for uveal melanoma and absent from cutaneous melanoma. No mutations were detected in GNAQ, BAP1, and SF3B1 that are frequently mutated in uveal melanoma. Both copies of chromosome 3 were retained. Several tumors among which the one carrying the TERT promoter mutation showed elevated TERT expression. Consistent with previous reports GNAQ is inversely associated with chromosome 3 monosomy and metastasis. BAP1 mutations are significantly associated with chromosome 3 monosomy but not with relapse. Conclusion: These data indicate that TERT mutations are rare in uveal melanoma. No conclusion can be drawn on their potential influence on tumor progression.