Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis
Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis
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DOI：
10.1016/j.cell.2019.02.012
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发表时间：
2019-03-07
期刊：
影响因子：
64.5
通讯作者：
Stratton, Michael R.
中科院分区：
文献类型：
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作者：
Petljak, Mia;Alexandrov, Ludmil B.;Stratton, Michael R.
已经在癌症基因组中鉴定了体细胞突变的多个特征。1，001个人类癌细胞系和577个异种移植物的外显子组序列揭示了最常见的突变特征，表明潜在过程的过去活动，通常在适当的癌症类型中。为了研究突变特征产生的持续模式，将细胞系培养延长的时间段，随后进行DNA测序。体外并未产生停止接触（包括烟草烟雾和紫外线）的特征。正常和有缺陷的DNA修复和复制的特征继续以大致稳定的突变率产生。APOBEC胞苷脱氨酶DNA编辑的特征表现出突变率随时间的大幅波动，伴有突变的间歇性爆发。爆发的起始因素尚不清楚，尽管反转录转座子动员可能有贡献。所检查的细胞系构成突变过程的活实验模型的资源，其潜在地保留在原发性人类癌症中操作的活性和调节模式。
Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed most common mutational signatures, indicating past activity of the underlying processes, usually in appropriate cancer types. To investigate ongoing patterns of mutational-signature generation, cell lines were cultured for extended periods and subsequently DNA sequenced. Signatures of discontinued exposures, including tobacco smoke and ultraviolet light, were not generated in vitro. Signatures of normal and defective DNA repair and replication continued to be generated at roughly stable mutation rates. Signatures of APOBEC cytidine deaminase DNA-editing exhibited substantial fluctuations in mutation rate over time with episodic bursts of mutations. The initiating factors for the bursts are unclear, although retrotransposon mobilization may contribute. The examined cell lines constitute a resource of live experimental models of mutational processes, which potentially retain patterns of activity and regulation operative in primary human cancers.