Somatic mutations induced by UV radiation contribute to melanoma through affecting gene splicing

Authors

• V Gotea
• Y Samuels
• J Mullikin
• L Elnitski

Abstract

Skin cutaneous melanoma is a cancer type that predominantly affects people with prolonged exposure to ultraviolet (UV) radiation, which determines a high mutational load dominated by cytosine to thymine substitutions (C->T). Recent sequencing efforts revealed several high-frequency driver gene mutations (e.g. BRAF V600E) that led to specific treatments (e.g. the RAF inhibitor vemurafenib). However, the search for additional lower frequency driver mutations is ongoing because they could explain the frequent tumor relapse after treatment, as well as the lack of high-frequency drivers from many samples. Based on a growing body of evidence, we hypothesized that somatic mutations in melanoma could act as drivers through interfering with gene splicing. For this study, we analyzed more than 500,000 somatic mutations from more than 600 samples. We evaluated their impact on splicing with three computational tools (Skippy, SPANR, SplicePort) and found that recurrent mutations are associated with a higher likelihood of exon skipping (PT mutations. Based on these findings, we defined a set of 145 genes that are specifically enriched in recurrent mutations that increase the likelihood of exon skipping. These genes are enriched in tumor suppressor and other cancer-related genes (P=0.02), indicative of their relevance for melanoma onset and progression. We then used RNA-Seq data from TCGA to validate the predicted impact on gene splicing of relevant mutations. Overall, we propose novel candidate driver genes in melanoma and reveal a cellular mechanism affected by UV-induced mutations.

Scientific Focus Area: Computational Biology

This page was last updated on Friday, March 26, 2021