Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution

Michelle Dietzen, Haoran Zhai, Olivia Lucas, Oriol Pich, Christopher Barrington, Wei-Ting Lu, Sophia Ward, Yanping Guo, Robert E. Hynds, Simone Zaccaria, Charles Swanton, Nicholas McGranahan () and Nnennaya Kanu ()
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Michelle Dietzen: University College London Cancer Institute
Haoran Zhai: University College London Cancer Institute
Olivia Lucas: University College London Cancer Institute
Oriol Pich: University College London Cancer Institute
Christopher Barrington: The Francis Crick Institute
Wei-Ting Lu: The Francis Crick Institute
Sophia Ward: University College London Cancer Institute
Yanping Guo: UCL Cancer Institute
Robert E. Hynds: University College London Cancer Institute
Simone Zaccaria: University College London Cancer Institute
Charles Swanton: University College London Cancer Institute
Nicholas McGranahan: University College London Cancer Institute
Nnennaya Kanu: University College London Cancer Institute

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: Abstract During each cell cycle, the process of DNA replication timing is tightly regulated to ensure the accurate duplication of the genome. The extent and significance of alterations in this process during malignant transformation have not been extensively explored. Here, we assess the impact of altered replication timing (ART) on cancer evolution by analysing replication-timing sequencing of cancer and normal cell lines and 952 whole-genome sequenced lung and breast tumours. We find that 6%–18% of the cancer genome exhibits ART, with regions with a change from early to late replication displaying an increased mutation rate and distinct mutational signatures. Whereas regions changing from late to early replication contain genes with increased expression and present a preponderance of APOBEC3-mediated mutation clusters and associated driver mutations. We demonstrate that ART occurs relatively early during cancer evolution and that ART may have a stronger correlation with mutation acquisition than alterations in chromatin structure.

Date: 2024
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DOI: 10.1038/s41467-024-50107-4

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