Cancer somatic mutations are the product of multiple mutational and repair processes, both of which are tightly associated with DNA replication. Distinctive patterns of somatic mutation accumulation, termed mutational signatures, are indicative of processes sustained within tumors. However, the association of various mutational processes with replication timing (RT) remains an open question. In this study, we systematically analyzed the mutational landscape of 2,787 tumors from 32 tumor types separately for early and late replicating regions using sequence context normalization and chromatin data to account for sequence and chromatin accessibility differences. To account for sequence differences between various genomic regions, an artificial genome–based approach was developed to expand the signature analyses to doublet base substitutions and small insertions and deletions. The association of mutational processes and RT was signature specific: Some signatures were associated with early or late replication (such as SBS7b and SBS7a, respectively), and others had no association. Most associations existed even after normalizing for genome accessibility. A focused mutational signature identification approach was also developed that uses RT information to improve signature identification; this approach found that SBS16, which is biased toward early replication, is strongly associated with better survival rates in liver cancer. Overall, this novel and comprehensive approach provides a better understanding of the etiology of mutational signatures, which may lead to improved cancer prevention, diagnosis, and treatment. Significance: Many mutational processes associate with early or late replication timing regions independently of chromatin accessibility, enabling development of a focused identification approach to improve mutational signature detection.

中文翻译：

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癌症突变过程与复制时间和染色质可及性的关系各不相同

癌症体细胞突变是多种突变和修复过程的产物，两者都与 DNA 复制密切相关。体细胞突变积累的独特模式，称为突变特征，表明肿瘤内持续存在的过程。然而，各种突变过程与复制时间 (RT) 的关联仍然是一个悬而未决的问题。在这项研究中，我们使用序列上下文标准化和染色质数据系统地分析了来自 32 种肿瘤类型的 2,787 个肿瘤的突变景观，分别用于早期和晚期复制区域，以解释序列和染色质可及性差异。为了解释不同基因组区域之间的序列差异，开发了一种基于人工基因组的方法，将特征分析扩展到双重碱基替换和小插入和缺失。突变过程和 RT 的关联是特定于特征的：一些特征与早期或晚期复制相关（分别如 SBS7b 和 SBS7a），而另一些则没有关联。即使在基因组可访问性标准化之后，大多数关联仍然存在。还开发了一种集中的突变特征识别方法，该方法使用 RT 信息来改进特征识别；这种方法发现，偏向于早期复制的 SBS16 与更好的肝癌存活率密切相关。总体而言，这种新颖而全面的方法可以更好地理解突变特征的病因，这可能会改善癌症的预防、诊断和治疗。意义：许多突变过程与早期或晚期复制时间区域相关，独立于染色质可及性，从而能够开发一种集中的识别方法来改善突变特征检测。