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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Veröffentlicht in:	Cell Jg. 176; H. 6; S. 1282
Hauptverfasser:	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
Sprache:	Englisch
Veröffentlicht:	United States 07.03.2019
Schlagworte:	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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Abstract	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.
AbstractList	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. 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.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.
Author	Ju, Young Seok Petljak, Mia O'Neill, Laura Menzies, Andrew O'Meara, Sarah Patel, Nikita Stratton, Michael R Garnett, Mathew J Ng, Bee Ling Campbell, Peter J Wedge, David C McDermott, Ultan Georgakopoulos-Soares, Ilias Price, Stacey Dawson, Kevin J Jones, David R Anderson, Elizabeth Graham, Jennifer Nik-Zainal, Serena Teague, Jon W Maddison, Mark Zamora, Jorge Otlu, Burçak Beal, Kathryn Iorio, Francesco Raine, Keiran Rodríguez-Martín, Bernardo Brammeld, Jonathan S Latimer, Calli Butler, Adam P Koh, Ching Chiek Alexandrov, Ludmil B Tubio, Jose M C Grossmann, Sebastian Bhosle, Shriram G
Author_xml	– sequence: 1 givenname: Mia surname: Petljak fullname: Petljak, Mia organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 2 givenname: Ludmil B surname: Alexandrov fullname: Alexandrov, Ludmil B organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Cellular and Molecular Medicine and Department of Bioengineering, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA – sequence: 3 givenname: Jonathan S surname: Brammeld fullname: Brammeld, Jonathan S organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 4 givenname: Stacey surname: Price fullname: Price, Stacey organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 5 givenname: David C surname: Wedge fullname: Wedge, David C organization: Oxford Big Data Institute, Old Road Campus, Oxford OX3 7LF, UK; Oxford NIHR Biomedical Research Centre, Oxford, OX4 2PG, UK – sequence: 6 givenname: Sebastian surname: Grossmann fullname: Grossmann, Sebastian organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 7 givenname: Kevin J surname: Dawson fullname: Dawson, Kevin J organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 8 givenname: Young Seok surname: Ju fullname: Ju, Young Seok organization: Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology, Daejeon 305-701, Republic of Korea – sequence: 9 givenname: Francesco surname: Iorio fullname: Iorio, Francesco organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; European Molecular Biology Laboratory - European Bioinformatics Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 10 givenname: Jose M C surname: Tubio fullname: Tubio, Jose M C organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Mobile Genomes and Disease, Molecular Medicine and Chronic Diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain; Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain; The Biomedical Research Centre (CINBIO), Universidade de Vigo, Vigo 36310, Spain – sequence: 11 givenname: Ching Chiek surname: Koh fullname: Koh, Ching Chiek organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 12 givenname: Ilias surname: Georgakopoulos-Soares fullname: Georgakopoulos-Soares, Ilias organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 13 givenname: Bernardo surname: Rodríguez-Martín fullname: Rodríguez-Martín, Bernardo organization: Mobile Genomes and Disease, Molecular Medicine and Chronic Diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain; Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain; The Biomedical Research Centre (CINBIO), Universidade de Vigo, Vigo 36310, Spain – sequence: 14 givenname: Burçak surname: Otlu fullname: Otlu, Burçak organization: Department of Cellular and Molecular Medicine and Department of Bioengineering, Moores Cancer Center, University of California, San Diego, La Jolla, CA 92093, USA – sequence: 15 givenname: Sarah surname: O'Meara fullname: O'Meara, Sarah organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 16 givenname: Adam P surname: Butler fullname: Butler, Adam P organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 17 givenname: Andrew surname: Menzies fullname: Menzies, Andrew organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 18 givenname: Shriram G surname: Bhosle fullname: Bhosle, Shriram G organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 19 givenname: Keiran surname: Raine fullname: Raine, Keiran organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 20 givenname: David R surname: Jones fullname: Jones, David R organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 21 givenname: Jon W surname: Teague fullname: Teague, Jon W organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 22 givenname: Kathryn surname: Beal fullname: Beal, Kathryn organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 23 givenname: Calli surname: Latimer fullname: Latimer, Calli organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 24 givenname: Laura surname: O'Neill fullname: O'Neill, Laura organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 25 givenname: Jorge surname: Zamora fullname: Zamora, Jorge organization: Mobile Genomes and Disease, Molecular Medicine and Chronic Diseases Centre (CIMUS), Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain; Department of Zoology, Genetics and Physical Anthropology, Universidade de Santiago de Compostela, Santiago de Compostela 15706, Spain; The Biomedical Research Centre (CINBIO), Universidade de Vigo, Vigo 36310, Spain – sequence: 26 givenname: Elizabeth surname: Anderson fullname: Anderson, Elizabeth organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 27 givenname: Nikita surname: Patel fullname: Patel, Nikita organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 28 givenname: Mark surname: Maddison fullname: Maddison, Mark organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 29 givenname: Bee Ling surname: Ng fullname: Ng, Bee Ling organization: Cytometry Core Facility, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 30 givenname: Jennifer surname: Graham fullname: Graham, Jennifer organization: Cytometry Core Facility, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 31 givenname: Mathew J surname: Garnett fullname: Garnett, Mathew J organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 32 givenname: Ultan surname: McDermott fullname: McDermott, Ultan organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 33 givenname: Serena surname: Nik-Zainal fullname: Nik-Zainal, Serena organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK; Department of Medical Genetics, The Clinical School, University of Cambridge, Cambridge, CB2 0QQ, UK – sequence: 34 givenname: Peter J surname: Campbell fullname: Campbell, Peter J organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK – sequence: 35 givenname: Michael R surname: Stratton fullname: Stratton, Michael R email: mrs@sanger.ac.uk organization: Cancer, Ageing and Somatic Mutation, Wellcome Sanger Institute, Hinxton, Cambridgeshire CB10 1SA, UK. Electronic address: mrs@sanger.ac.uk
BackLink	https://www.ncbi.nlm.nih.gov/pubmed/30849372$$D View this record in MEDLINE/PubMed
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Keywords	APOBEC deaminases cancer cell lines episodic mutagenesis xenografts mutational signatures
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Snippet	Multiple signatures of somatic mutations have been identified in cancer genomes. Exome sequences of 1,001 human cancer cell lines and 577 xenografts revealed...
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SubjectTerms	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
Title	Characterizing Mutational Signatures in Human Cancer Cell Lines Reveals Episodic APOBEC Mutagenesis
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