Dietzen Michelle, Zhai Haoran, Lucas Olivia, Pich Oriol, Barrington Christopher, Lu Wei-Ting, Ward Sophia, Guo Yanping, Hynds Robert E, Zaccaria Simone, Swanton Charles, McGranahan Nicholas, Kanu Nnennaya
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
Nat Commun. 2024 Jul 18;15(1):6039. doi: 10.1038/s41467-024-50107-4.
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.
在每个细胞周期中，DNA复制时间过程受到严格调控，以确保基因组的准确复制。在恶性转化过程中，这一过程改变的程度和意义尚未得到广泛探索。在这里，我们通过分析癌症细胞系和正常细胞系的复制时间测序以及952个全基因组测序的肺癌和乳腺癌肿瘤，评估复制时间改变（ART）对癌症演变的影响。我们发现6%-18%的癌症基因组表现出ART，从早期复制转变为晚期复制的区域显示出更高的突变率和独特的突变特征。而从晚期复制转变为早期复制的区域包含表达增加的基因，并呈现出大量载脂蛋白B编辑酶催化多肽样3（APOBEC3）介导的突变簇和相关的驱动突变。我们证明ART在癌症演变过程中相对较早发生，并且与突变获得的相关性可能比染色质结构改变更强。
