A small-cell lung cancer genome with complex signatures of tobacco exposure

Pleasance, Erin D., Stephens, Philip J., O’Meara, Sarah, McBride, David J., Meynert, Alison, Jones, David, Lin, Meng-lay, Beare, David, Lau, King Wai, Greenman, Christopher, Varela, Ignacio, Nik-Zainal, Serena, Davies, Helen R., Ordoñez, Gonzalo R., Mudie, Laura J., Latimer, Calli, Edkins, Sarah, Stebbings, Lucy, Chen, Lina, Jia, Mingming, Leroy, Catherine, Marshall, John, Menzies, Andrew, Butler, Adam, Teague, Jon W., Mangion, Jonathon, Sun, Yongming A., Mclaughlin, Stephen F., Peckham, Heather E., Tsung, Eric F., Costa, Gina L., Lee, Clarence C., Minna, John D., Gazdar, Adi, Birney, Ewan, Rhodes, Michael D., Mckernan, Kevin J., Stratton, Michael R., Futreal, P. Andrew and Campbell, Peter J. (2010) A small-cell lung cancer genome with complex signatures of tobacco exposure. Nature, 463 (7278). pp. 184-190. ISSN 1476-4687

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Abstract

Cancer is driven by mutation. Worldwide, tobacco smoking is the principal lifestyle exposure that causes cancer, exerting carcinogenicity through >60 chemicals that bind and mutate DNA. Using massively parallel sequencing technology, we sequenced a small-cell lung cancer cell line, NCI-H209, to explore the mutational burden associated with tobacco smoking. A total of 22,910 somatic substitutions were identified, including 134 in coding exons. Multiple mutation signatures testify to the cocktail of carcinogens in tobacco smoke and their proclivities for particular bases and surrounding sequence context. Effects of transcription-coupled repair and a second, more general, expression-linked repair pathway were evident. We identified a tandem duplication that duplicates exons 3-8 of CHD7 in frame, and another two lines carrying PVT1-CHD7 fusion genes, indicating that CHD7 may be recurrently rearranged in this disease. These findings illustrate the potential for next-generation sequencing to provide unprecedented insights into mutational processes, cellular repair pathways and gene networks associated with cancer.

Item Type: Article
Faculty \ School: Faculty of Science > School of Computing Sciences
Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Christopher Greenman
Date Deposited: 22 Jun 2011 12:03
Last Modified: 19 Dec 2018 16:30
URI: https://ueaeprints.uea.ac.uk/id/eprint/30588
DOI: 10.1038/nature08629

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