PDF(Pubmed)
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.
摘要：
在每个细胞周期中,DNA复制的时间受到严格调控，以确保基因组的准确复制。在恶性转化过程中，这一过程中改变的程度和意义尚未得到广泛探讨。这里,我们通过分析癌症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和乳腺肿瘤,评估了复制时间改变(ART)对癌症进化的影响.我们发现6%-18%的癌症基因组表现出ART，从早期到晚期复制变化的区域显示出增加的突变率和不同的突变特征。而从晚期到早期复制改变的区域包含表达增加的基因，并呈现出APOBEC3介导的突变簇和相关的驱动突变的优势。我们证明了ART在癌症进化过程中相对较早发生，并且ART与染色质结构改变相比，与突变获得具有更强的相关性。
