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Nat Commun. 2018 May 1;9(1):1744. doi: 10.1038/s41467-018-04052-8.

Validating the concept of mutational signatures with isogenic cell models.

Author information

1
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK.
2
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria.
3
The Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, CB2 1QN, UK.
4
CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Lazarettgasse 14, AKH BT 25.3, 1090, Vienna, Austria. jloizou@cemm.oeaw.ac.at.
5
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, CB10 1SA, UK. snz@sanger.ac.uk.
6
Department of Medical Genetics, The Clinical School, University of Cambridge, Cambridge, CB2 0QQ, UK. snz@sanger.ac.uk.

Abstract

The diversity of somatic mutations in human cancers can be decomposed into individual mutational signatures, patterns of mutagenesis that arise because of DNA damage and DNA repair processes that have occurred in cells as they evolved towards malignancy. Correlations between mutational signatures and environmental exposures, enzymatic activities and genetic defects have been described, but human cancers are not ideal experimental systems-the exposures to different mutational processes in a patient's lifetime are uncontrolled and any relationships observed can only be described as an association. Here, we demonstrate the proof-of-principle that it is possible to recreate cancer mutational signatures in vitro using CRISPR-Cas9-based gene-editing experiments in an isogenic human-cell system. We provide experimental and algorithmic methods to discover mutational signatures generated under highly experimentally-controlled conditions. Our in vitro findings strikingly recapitulate in vivo observations of cancer data, fundamentally validating the concept of (particularly) endogenously-arising mutational signatures.

PMID:
29717121
PMCID:
PMC5931590
DOI:
10.1038/s41467-018-04052-8
[Indexed for MEDLINE]
Free PMC Article

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