Genetic evidence for the role of ultraviolet radiation in the pathogenesis of uveal melanoma

Abstract

Purpose Recent advances in the understanding and treatments of metastatic cutaneous melanoma (CM) have not led to parallel improvements in the care of metastatic uveal melanoma (UM), and consequently, the two conditions are now often viewed as separate entities. One possible difference is the aetiological role of ultraviolet (UV) radiation, which although well‐established in CM, remains uncertain in UM. This study hypothesised that UV radiation is a pathogenic factor in UM development, evidenced by genetic changes consistent with UV‐related damage in UM. Methods We analysed data from 993 UM patient samples and 11803 CM patient samples available from the Catalogue of Somatic Mutations in Cancer (COSMIC) as well as 80 UM patient samples and 343 CM patient samples from the Broad Institute GDAC FireBrowse. UM samples were probed to identify the most frequently mutated genes, mutation types and specific nucleotide substitutions. Somatic mutation data was then cross‐correlated with CM samples from COSMIC and Broad Institute GDAC FireBrowse. Results The most common overlapping mutated genes were BRAF, PTEN, CDKN2A, TERT, NRAS, TP53 and ARID2, with four shared point mutations in BRAF (V600E (1799T>A)), NRAS (Q61R (182A>G)) and TP53 (R273C (817C>T)), R248Q (743G>A)). These gene mutations were found to be strongly associated with UV‐related damage in previous scientific reports. The proportion of samples with C>T substitutions (a marker of UV‐related damage) were similar between UM and CM on both DNA strands (20.35% vs 20.05%) and coding strand (11.3% vs 15.7%). Conclusions These findings support the hypothesis that the pathogenesis of UM is more dependent on UV radiation than previously thought.