Presence and prevalence of UV related genetic mutations in uveal melanoma: similarities with cutaneous melanoma

Abstract

Ultraviolet (UV) radiation is an accepted etiological factor in cutaneous melanoma (CM), however its role in Uveal Melanoma (UM) is controversial. Partly as a consequence, CM and UM are often considered to be separate conditions, and advances in the treatment of CM have not led to joint clinical trials or parallel improvements in survival of UM. This study hypothesized that a subset of UM tumors display evidence of genetic changes consistent with UV-related damage similar to that shown in CM. Analysis of the Broad Institute Firebrowse depository of 80 UM samples and 343 CM samples, together with the Sanger Ins cer depository of 995 UM and 12,447 CM samples was undertaken to identify the most frequently mutated genes, mutation types and specific nucleotide variants (SNVs) in each condition. Somatic mutation data was cross-correlated and shared mutations assessed against known effects of UV radiation. The proportion of samples with C>T substitutions (a classic genetic marker of UV-related damage) was higher in UM than CM on both DNA strands (17.0% vs 13.1% , p = 0.038). The most frequently encountered cross-correlated mutated genes between UM and CM were, in order, BRAF, NRAS, TP53, CDKN2A, TERT, PTEN, ARID2 and KMT2C, with multiple common BRAF point mutations. Each cross-correlated mutation, and each common point mutation in BRAF, was associated with UV-related mechanistic changes. These findings support the hypothesis that the etiology of a substantial minority of UMs may be more UV dependent than previously recognized. Key words: uveal melanoma, cutaneous melanoma, ultraviolet radiation Cutaneous melanoma (CM) is the most common type of melanoma, accounting for more than 90% of melanomas worldwide. In comparison, the uveal tract gives rise to only 5% of melanomas, despite being the second most common site of origin. As a considerably more prevalent and studied disease,

The Impact of Ultraviolet Radiation on the Aetiology and Development of Uveal Melanoma

“…Aberrant BRAF -driven MAPK pathway activity is the dominant oncogenic driver in CMs [ 74 ] and is a mutation considered to be associated with UVR damage [ 75 ]. This same BRAF mutation has sometimes been observed in as high as 40% of UM samples including those arising from the choroid [ 6 , 76 , 77 ]. On the other hand, 80–96% of UMs possess GNAQ or GNA11 mutations in a mutually exclusive fashion [ 78 , 79 , 80 , 81 ], while this occurs in CM approximately 20% of the time [ 82 ].…”

“…The C to T changes seen in ~35% of the 12 UMs investigated were conversely not enriched at the 3′ position of pyrimidine dimers and therefore UVR was not thought to be involved [ 71 ]. Meanwhile, Goh et al compared over 1000 UM mutations and over 12,000 CM samples and found that the proportion of samples with C to T substitutions was higher in UM (17.0%) than CM (13.1%), suggesting a substantial number of UMs are related to UVR damage [ 6 ]. A further 103 whole-genome sequencing analyses found that a significant subset of UM characterised by UVR-damage mutations was restricted to those originating from the iris [ 7 ], the most anterior structure of the uveal tract and therefore with the greatest exposure to UVR.…”

“…The quality and quantity of melanin presents as different eye colours and skin colours [ 4 ] and provide varying levels of protection from ultraviolet radiation (UVR) [ 5 ]. This protection is important because UVR can cause physical or genomic damage to cells [ 6 , 7 , 8 ]. In their role as light receptors for producing the input for vision, the eyes spend many hours exposed to environmental UVR.…”

“…Indeed, it has been demonstrated that wavelengths of the UVR spectrum cannot even penetrate the adult crystalline lens and cornea to reach the posterior eye where the choroid is located [ 11 , 12 ], and yet, the posterior choroid is the most common uveal melanoma origin (85–95%) compared to the iris (3–5% and ciliary body (5–8%) [ 13 ]. Despite this, it has recently been demonstrated that a proportion of UMs possess molecular signatures reflective of UVR damage even in those originating from the choroid [ 6 , 7 , 8 ], suggesting that UVR may, in some cases, be involved in the aetiology of UM.…”

Iris Colour and the Risk of Developing Uveal Melanoma

“…UV radiation may damage DNA in different ways, such as by creating the main promutagenic DNA adduct cyclobutene pyrimide dimer or through the formation of reactive oxygen species (ROS) [ 87 , 88 ]. In a recent study, the C > T substitute in DNA (associated with UV light) was even higher in UM than in cutaneous melanoma [ 44 ]. Because the iris is directly exposed to UV light, UV light may especially play an important role in the development of iris melanoma.…”