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, Ruban M. Drews, Ailith Ewing, Vera B. Kaiser, Ava Khamseh, Erika Lopez-Arribillaga, Aisling M. RedmondJavier Santoyo-Lopez, Inés Sentís, Lana Talmane, Andrew D. Yates, Colin A. Semple, Núria López-Bigas, Paul Flicek, Duncan T. Odom, Martin S. Taylor

Research output: Contribution to journalArticlepeer-review

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.
Original languageEnglish
Pages (from-to)265–270
Number of pages6
JournalNature
Volume583
Early online date24 Jun 2020
DOIs
Publication statusPublished - 9 Jul 2020

Keywords

  • Cancer genomics
  • DNA adducts
  • Nucleotide excision repair
  • Tumour heterogeneity

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