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Validating the concept of mutational signatures with isogenic cell models.

Published version
Peer-reviewed

Change log

Authors

Owusu, Michel 
Harris, Rebecca 
Jackson, Stephen P 
Loizou, Joanna I 

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.

Description

Keywords

Algorithms, CRISPR-Cas Systems, Cell Line, DNA Damage, DNA Repair, Humans, Models, Biological, Mutation, Neoplasms

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
Wellcome Trust (101126/Z/13/Z)
Cancer Research UK (18796)
Wellcome Trust (206388/Z/17/Z)
Cancer Research UK (23916)
Cancer Research UK (C6946/A24843)
Wellcome Trust (203144/Z/16/Z)