Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis

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 o...

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Bibliographic Details
Published in:Cell Vol. 176; no. 6; p. 1282
Main Authors: Petljak, Mia, Alexandrov, Ludmil B, Brammeld, Jonathan S, Price, Stacey, Wedge, David C, Grossmann, Sebastian, Dawson, Kevin J, Ju, Young Seok, Iorio, Francesco, Tubio, Jose M C, Koh, Ching Chiek, Georgakopoulos-Soares, Ilias, Rodríguez-Martín, Bernardo, Otlu, Burçak, O'Meara, Sarah, Butler, Adam P, Menzies, Andrew, Bhosle, Shriram G, Raine, Keiran, Jones, David R, Teague, Jon W, Beal, Kathryn, Latimer, Calli, O'Neill, Laura, Zamora, Jorge, Anderson, Elizabeth, Patel, Nikita, Maddison, Mark, Ng, Bee Ling, Graham, Jennifer, Garnett, Mathew J, McDermott, Ultan, Nik-Zainal, Serena, Campbell, Peter J, Stratton, Michael R
Format: Journal Article
Language:English
Published: United States 07.03.2019
Subjects:
APOBEC Deaminases - genetics
APOBEC Deaminases - metabolism
Cell Line
Cell Line, Tumor
Databases, Genetic
DNA - metabolism
DNA Mutational Analysis - methods
Exome
Genome, Human - genetics
Heterografts
Humans
Mutagenesis
Mutation - genetics
Mutation Rate
Neoplasms - genetics
Retroelements
Whole Exome Sequencing - methods
APOBEC deaminases
cancer cell lines
episodic mutagenesis
xenografts
mutational signatures
ISSN:1097-4172, 1097-4172
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Summary: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.
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ISSN:1097-4172
1097-4172
DOI:10.1016/j.cell.2019.02.012