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.

Dietzen, M., Zhai, H., Lucas, O., Pich, O., Barrington, C., Lu, W., et al. (2024). Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution. NATURE COMMUNICATIONS, 15(1) [10.1038/s41467-024-50107-4].

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

Zaccaria S.;
2024

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.
Articolo in rivista - Articolo scientifico
APOBEC Deaminases; Breast Neoplasms; Cell Line, Tumor; DNA Replication; DNA Replication Timing; Female; Genome, Human; Humans; Lung Neoplasms; Mutation; Mutation Rate
English
18-lug-2024
2024
15
1
6039
open
Dietzen, M., Zhai, H., Lucas, O., Pich, O., Barrington, C., Lu, W., et al. (2024). Replication timing alterations are associated with mutation acquisition during breast and lung cancer evolution. NATURE COMMUNICATIONS, 15(1) [10.1038/s41467-024-50107-4].
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/508419
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