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ISSN 0028-2685
ISSN 1338-4317 (online)

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neo_2020_190815N768

Title: Presence and prevalence of UV related genetic mutations in uveal melanoma: similarities with cutaneous melanoma
Author: A.Y. GOH, C.A. RAMLOGAN-STEEL, K.S. JENKINS, J.C. STEEL, C.J. LAYTON

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’s Firebrowse depository of 80 UM samples and 343 CM samples, together with the Sanger Institute’s Catalogue of Somatic Mutations in Cancer 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.

Keywords: uveal melanoma, cutaneous melanoma, ultraviolet radiation
Published online: 16-Apr-2020
Year: , Volume: , Issue: Page From: , Page To:
doi:10.4149/neo_2020_190815N768


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