Distribution of GNAQ and GNA11 Mutation Signatures in Uveal Melanoma Points to a Light Dependent Mutation Mechanism

Abstract

Uveal melanomas (UM) originate from melanocytes in the interior wall of the eye, namely from the iris, ciliary body and the choroid with marked differences in light exposure (from dark anterior to illuminated posterior). In contrast to UV radiation, focused or converging visible light readily reaches the retina and can damage DNA which possibly contributes to UM development. In this report choroidal, ciliochoroidal and iridociliary melanomas were analyzed for GNAQ and GNA11 mutations which were subsequently correlated to the location of tumor origin. Hotspot mutations in GNAQ and GNA11 can be divided in A>T and in A>C mutation signatures. The GNAQ A626C mutation (Q209P) was almost exclusively observed in choroidal melanomas from the illuminated posterior side. On the other hand, ciliochoroidal UM from the dark anterior side with mostly A>T mutations were clearly associated with light-colored eyes. Combined these data suggest a light and a pigment dependent etiology in UM development.

Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential

“…Some studies suggest that mutations in uveal and iris melanoma might be associated with ultraviolet exposure. 25,34 However, in a whole-genome sequencing study of uveal melanoma, no UV-induced mutation signature was found. 35 In the current study, it is doubtful whether the mutations that we identified in NRAS, BRAF, PTEN, c-KIT and TP53 are related to ultraviolet light exposure since the primary tumors were located in different quadrants of the eye.…”

Sunbeds and Melanoma Risk: Many Open Questions, Not Yet Time to Close the Debate

“…A large body of evidence from epidemiological and animal studies demonstrates no increase in melanoma risk after chronic (moderate) UV exposure (24)(25)(26)(27)(28)(29)(30)(31). Many studies show that suberythemal chronic exposure to the sun may even be protective and that outdoor workers may have a reduced risk of melanoma (18,(27)(28)(29)(30).…”

“…Many studies show that suberythemal chronic exposure to the sun may even be protective and that outdoor workers may have a reduced risk of melanoma (18,(27)(28)(29)(30). Driver mutations in the B-rapidly accelerated fibrosarcoma (BRAF) gene or in other important drivers of melanomagenesis do not carry the specific UV signature [mutations in BRAF are similar to those found in guanine nucleotide-binding protein subunit alpha-11 (GNA11) and GNAQ driver genes in uveal melanomas from UV-protected parts of the inner eye (31) A recent analysis of the economic burden Indoor tanning represents a major Calculations presented are based on data that of sunbed use. economic burden in terms of the costs are speculative, because they are based on of medical care and lost productivity.…”

“…volunteers showed that UVA and UVB are (a) many melanomas arise in UV-shielded skin areas carcinogens; and sunbeds emit UVA and UVB (b) many epidemiological and laboratory findings (summarized by IARC)." demonstrate no increased melanoma risk after suberythemal chronic exposure to UV radiation (18,(24)(25)(26)(27)(28)(29)(30)(31). (c) Driver mutations in the BRAF gene and in other important drivers of melanomagenesis do not carry the specific UV signature [mutations in BRAF are similar to those found in GNA11 and GNAQ driver genes in uveal melanomas from UV-protected parts of the inner eye (31)].…”

“…epidemiological studies, summarized in chronic exposure to UV radiation (18,(24)(25)(26)(27)(28)(29)(30)(31), meta-analyses, is coherent with the laboratory increases the likelihood of no causal effect findings. For these reasons, the whole for the association between moderate solarium spectrum of UV radiation is now classified use and melanoma risk.…”