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Recurrent promoter mutations in melanoma are defined by an extended context-specific mutational signature
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine,The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.ORCID iD: 0000-0002-5763-6777
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine,The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.ORCID iD: 0000-0001-9238-7879
Sahlgrenska Cancer Center, Department of Pathology and Genetics, Institute of Biomedicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.ORCID iD: 0000-0002-5994-6699
Department of Medical Biochemistry and Cell Biology, Institute of Biomedicine,The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.ORCID iD: 0000-0003-0002-5614
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2017 (English)In: PLOS Genetics, ISSN 1553-7390, E-ISSN 1553-7404, Vol. 13, no 5, article id e1006773Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
Public Library of Science , 2017. Vol. 13, no 5, article id e1006773
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:oru:diva-78919DOI: 10.1371/journal.pgen.1006773ISI: 000402884800025PubMedID: 28489852Scopus ID: 2-s2.0-85020171023OAI: oai:DiVA.org:oru-78919DiVA, id: diva2:1383919
Funder
Knut and Alice Wallenberg FoundationSwedish Foundation for Strategic Research Swedish Cancer SocietyÅke Wiberg FoundationSwedish Childhood Cancer Foundation
Note

Funding Agencies:

Swedish Medical Research Council (SMRC)

Sahlgrenska Academy-ALF

Wallenberg Centre for Molecular and Translational Medicine  

SNIC through Uppsala Multidisciplinary Center for Advanced Computational Science (UPPMAX)  b2012108

Available from: 2020-01-09 Created: 2020-01-09 Last updated: 2022-09-13Bibliographically approved

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Fredriksson, Nils Johan

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