Department of Microbiology and Molecular Genetics, IMRIC, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel.
Sharett Institute for Oncology, The Gaffin Center for Neuro-Oncology, Hebrew University-Hadassah Medical Center, Jerusalem, Israel.
Sci Rep. 2023 Aug 12;13(1):13143. doi: 10.1038/s41598-023-39463-1.
Cancer somatic mutations are the product of multiple mutational and repair processes, some of which are tightly associated with DNA replication. Mutation rates (MR) are known to be higher in late replication timing (RT) regions, but different processes can affect this association. Systematic analysis of the mutational landscape of 2787 tumors from 32 tumor types revealed that approximately one third of the tumor samples show weak association between replication timing and mutation rate. Further analyses revealed that those samples have unique mutational signatures and are enriched with mutations in genes involved in DNA replication, DNA repair and chromatin structure. Surprisingly, analysis of differentially expressed genes between weak and strong RT-MR association groups revealed that tumors with weak association are enriched with genes associated with cell-cell communication and the immune system, suggesting a non-autonomous response to DNA damage.
癌症体细胞突变是多种突变和修复过程的产物，其中一些过程与 DNA 复制密切相关。众所周知，复制时滞（RT）晚期的突变率（MR）更高，但不同的过程可能会影响这种关联。对来自 32 种肿瘤类型的 2787 个肿瘤的突变景观进行系统分析表明，大约三分之一的肿瘤样本显示 RT 与 MR 之间的弱相关性。进一步的分析表明，这些样本具有独特的突变特征，并富含与 DNA 复制、DNA 修复和染色质结构相关的基因突变。令人惊讶的是，对弱 RT-MR 关联组和强 RT-MR 关联组之间差异表达基因的分析表明，弱关联组的肿瘤富含与细胞间通讯和免疫系统相关的基因，表明对 DNA 损伤的非自主反应。
