Validating the concept of mutational signatures with isogenic cell models

Xueqing Zou, Michel Owusu, Rebecca Harris, Stephen P. Jackson, Joanna I. Loizou () and Serena Nik-Zainal ()
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Xueqing Zou: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Michel Owusu: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Rebecca Harris: Wellcome Trust Sanger Institute, Wellcome Genome Campus
Stephen P. Jackson: University of Cambridge
Joanna I. Loizou: CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences
Serena Nik-Zainal: Wellcome Trust Sanger Institute, Wellcome Genome Campus

Nature Communications, 2018, vol. 9, issue 1, 1-16

Abstract: 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.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-04052-8

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DOI: 10.1038/s41467-018-04052-8

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