Journal Article

Elevated pyrimidine dimer formation at distinct genomic bases underlies promoter mutation hotspots in UV-exposed cancers

Filges, Stefan, Clausen, Anders R., Lindberg, Markus, Elliott, Kerryn, Boström, Martin, Van den Eynden, Jimmy, Ståhlberg, Anders, Larsson, Erik

2018

Overview

Sequencing of whole cancer genomes has revealed an abundance of recurrent mutations in gene-regulatory promoter regions, in particular in melanoma where strong mutation hotspots are observed adjacent to ETS-family transcription factor (TF) binding sites. While sometimes interpreted as functional driver events, these mutations are commonly believed to be due to locally inhibited DNA repair. Here, we first show that low-dose UV light induces mutations preferably at a known ETS promoter hotspot in cultured cells even in the absence of global or transcription-coupled nucleotide excision repair (NER). Further, by genome-wide mapping of cyclobutane pyrimidine dimers (CPDs) shortly after UV exposure and thus before DNA repair, we find that ETS-related mutation hotspots exhibit strong increases in CPD formation efficacy in a manner consistent with tumor mutation data at the single-base level. Analysis of a large whole genome cohort illustrates the widespread contribution of this effect to recurrent mutations in melanoma. While inhibited NER underlies a general increase in somatic mutation burden in regulatory elements including ETS sites, our data supports that elevated DNA damage formation at specific genomic bases is at the core of the prominent promoter mutation hotspots seen in skin cancers, thus explaining a key phenomenon in whole-genome cancer analyses.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Base Sequence / Binding Sites - genetics / Biochemistry / Bioinformatics / Biology and Life Sciences / Cancer / Cancer genetics / Cell and Molecular Biology / Cell Line, Tumor / Cell- och molekylärbiologi / Cyclobutane pyrimidine dimers / Deoxyribonucleic acid / DNA / DNA Damage / DNA repair / DNA sequencing / DNA, Neoplasm - genetics / ETS protein / Gene mapping / Gene mutation / Gene regulation / Genes / Genetic aspects / Genetics and Genomics / Genetik och genomik / Genomes / Humans / Medical Genetics and Genomics / Medicine and Health Sciences / Medicinsk genetik och genomik / Melanoma / Melanoma - etiology / Melanoma - genetics / Melanoma - metabolism / Methods / Molecular Biology / Molekylärbiologi / Mutagenesis / Mutation / Mutation hot spots / Neoplasms, Radiation-Induced - etiology / Neoplasms, Radiation-Induced - genetics / Neoplasms, Radiation-Induced - metabolism / Nucleotide excision repair / Pathology / Physical Sciences / Promoter Regions, Genetic / Proto-Oncogene Proteins c-ets - metabolism / Pyrimidine Dimers - biosynthesis / Pyrimidine Dimers - genetics / Pyrimidine Dimers - radiation effects / Regulatory sequences / Research and Analysis Methods / Skin cancer / Skin Neoplasms - etiology / Skin Neoplasms - genetics / Skin Neoplasms - metabolism / Supervision / Transcription factors / Tumors / Ultraviolet radiation / Ultraviolet Rays - adverse effects / Whole Genome Sequencing