Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution
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Michelle Dietzen Haoran Zhai Olivia Lucas Oriol Pich Christopher Barrington Wei-Ting Lu Sophie Ward Yanping Guo Rob Hynds Simone Zaccaria Charles Swanton Nicholas McGranahan Nnennaya KanuAbstract
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.
Journal details
Journal
Nature Communications
Volume
15
Issue number
1
Pages
6039
Available online
Publication date
Full text links
Publisher website (DOI)
10.1038/s41467-024-50107-4
Europe PubMed Central
39019871
Pubmed
39019871
