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Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature

Journal article
Authors Nils J Fredriksson
Kerryn Elliott
Stefan Filges
Jimmy Van den Eynden
Anders Ståhlberg
Erik Larsson
Published in Plos Genetics
Volume 13
Issue 5
ISSN 1553-7404
Publication year 2017
Published at Institute of Biomedicine, Department of Pathology
Sahlgrenska Cancer Center
Department of Chemistry and Molecular Biology
Institute of Biomedicine, Department of Medical Biochemistry and Cell Biology
Language en
Keywords human transcription factors, somatic mutations, cancer genomics, in-vivo, dna, binding, photoproducts, landscape, regions, search, Genetics & Heredity
Subject categories Genetics


Sequencing of whole tumor genomes holds the promise of revealing functional somatic regulatory mutations, such as those described in the TERT promoter. Recurrent promoter mutations have been identified in many additional genes and appear to be particularly common in melanoma, but convincing functional data such as influence on gene expression has been more elusive. Here, we show that frequently recurring promoter mutations in melanoma occur almost exclusively at cytosines flanked by a distinct sequence signature, TTCCG, with TERT as a notable exception. In active, but not inactive, promoters, mutation frequencies for cytosines at the 5' end of this ETS-like motif were considerably higher than expected based on a UV trinucleotide mutational signature. Additional analyses solidify this pattern as an extended context-specific mutational signature that mediates an exceptional position-specific vulnerability to UV mutagenesis, arguing against positive selection. We further use ultra-sensitive amplicon sequencing to demonstrate that cell cultures exposed to UV light quickly develop subclonal mutations specifically in affected positions. Our findings have implications for the interpretation of somatic mutations in regulatory regions, and underscore the importance of genomic context and extended sequence patterns to accurately describe mutational signatures in cancer.

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