Pervasive lesion segregation shapes cancer genome evolution

Sarah J. Aitken, Craig J. Anderson, Frances Connor, Oriol Pich, Vasavi Sundaram, Christine Feig, Tim F. Rayner, Margus Lukk, Stuart Aitken, Juliet Luft, Elissavet Kentepozidou, Claudia Arnedo-Pac, Sjoerd V. Beentjes, Susan E. Davies, Ruben M. Drews, Ailith Ewing, Vera B. Kaiser, Ava Khamseh, Erika López-Arribillaga, Aisling M. Redmond, Javier Santoyo-Lopez, Inés Sentís, Lana Talmane, Andrew D. Yates, Colin A. Semple, Núria López-Bigas, Paul Flicek, Duncan T. Odom () and Martin S. Taylor ()
Additional contact information
Sarah J. Aitken: University of Cambridge
Craig J. Anderson: University of Edinburgh
Frances Connor: University of Cambridge
Oriol Pich: The Barcelona Institute of Science and Technology
Vasavi Sundaram: University of Cambridge
Christine Feig: University of Cambridge
Tim F. Rayner: University of Cambridge
Margus Lukk: University of Cambridge
Stuart Aitken: University of Edinburgh
Juliet Luft: University of Edinburgh
Elissavet Kentepozidou: European Bioinformatics Institute
Claudia Arnedo-Pac: The Barcelona Institute of Science and Technology
Sjoerd V. Beentjes: University of Edinburgh
Susan E. Davies: Cambridge University Hospitals NHS Foundation Trust
Ruben M. Drews: University of Cambridge
Ailith Ewing: University of Edinburgh
Vera B. Kaiser: University of Edinburgh
Ava Khamseh: University of Edinburgh
Erika López-Arribillaga: The Barcelona Institute of Science and Technology
Aisling M. Redmond: University of Cambridge
Javier Santoyo-Lopez: The University of Edinburgh
Inés Sentís: The Barcelona Institute of Science and Technology
Lana Talmane: University of Edinburgh
Andrew D. Yates: European Bioinformatics Institute
Colin A. Semple: University of Edinburgh
Núria López-Bigas: The Barcelona Institute of Science and Technology
Paul Flicek: University of Cambridge
Duncan T. Odom: University of Cambridge
Martin S. Taylor: University of Edinburgh

Nature, 2020, vol. 583, issue 7815, 265-270

Abstract: Abstract Cancers arise through the acquisition of oncogenic mutations and grow by clonal expansion1,2. Here we reveal that most mutagenic DNA lesions are not resolved into a mutated DNA base pair within a single cell cycle. Instead, DNA lesions segregate, unrepaired, into daughter cells for multiple cell generations, resulting in the chromosome-scale phasing of subsequent mutations. We characterize this process in mutagen-induced mouse liver tumours and show that DNA replication across persisting lesions can produce multiple alternative alleles in successive cell divisions, thereby generating both multiallelic and combinatorial genetic diversity. The phasing of lesions enables accurate measurement of strand-biased repair processes, quantification of oncogenic selection and fine mapping of sister-chromatid-exchange events. Finally, we demonstrate that lesion segregation is a unifying property of exogenous mutagens, including UV light and chemotherapy agents in human cells and tumours, which has profound implications for the evolution and adaptation of cancer genomes.

Date: 2020
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DOI: 10.1038/s41586-020-2435-1

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