Characterization of mutational signatures in human cancer cell lines reveals episodic APOBEC mutagenesis

Multiple signatures of somatic mutations have been identified in human cancer genomes. To investigate whether mutational signatures continue to be generated, and if so their temporal patterns of activity, subsets of cell lines were cultured in vitro for extended periods and subjected to single cell cloning and whole genome or exome sequencing or directly to single cell whole genome sequencing. As expected, signatures of past exogenous exposures, such as tobacco smoke and ultraviolet light, were not generated in vitro. In contrast, signatures of normal and defective DNA repair and replication continued to be generated at essentially constant mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing activity exhibited a distinctive pattern with substantial fluctuations in mutation rate over time and episodic bursts of mutations. The initiating factors for these bursts are unclear although retrotransposon mobilisation may play a role. This cell line set now constitutes a comprehensive resource of live experimental models of mutational processes of both known and unknown aetiologies potentially retaining the patterns of activity and regulatory influences operative in human cells in vivo.

在人类癌症基因组中，已识别出多种体细胞突变的特征。为探究突变特征是否持续产生，以及其活动的时序模式，选取细胞系子集在体外长期培养，并进行了单细胞克隆以及全基因组或外显子测序，或直接进行单细胞全基因组测序。正如预期，过去的外源性暴露（如烟草烟雾和紫外线）的特征在体外并未产生。相反，正常与缺陷的DNA修复和复制的特征持续以基本恒定的突变率产生。APOBEC胞嘧啶脱氨酶DNA编辑活动的特征呈现了一种独特的模式，其突变率随时间波动显著，并伴有突变的间歇性爆发。尽管这些爆发的起始因素尚不明确，但反转录转座子的活化可能发挥了作用。该细胞系集合现已成为一个全面的资源，包含了已知和未知病因的突变过程活性和体内人类细胞中起作用的调节影响的活体实验模型。