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, Chris; 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; Campbell, Peter J.

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

Erin D. Pleasance, Philip J. Stephens, Sarah O’Meara, David J. McBride, Alison Meynert, David Jones, Meng-Lay Lin, David Beare, King Wai Lau, Chris Greenman, Ignacio Varela, Serena Nik-Zainal, Helen R. Davies, Gonzalo R. Ordoñez, Laura J. Mudie, Calli Latimer, Sarah Edkins, Lucy Stebbings, Lina Chen, Mingming Jia, Catherine Leroy, John Marshall, Andrew Menzies, Adam Butler, Jon W. Teague, Jonathon Mangion, Yongming A. Sun, Stephen F. McLaughlin, Heather E. Peckham, Eric F. Tsung, Gina L. Costa, Clarence C. Lee, John D. Minna, Adi Gazdar, Ewan Birney, Michael D. Rhodes, Kevin J. McKernan, Michael R. Stratton, P. Andrew Futreal and Peter J. Campbell ()
Additional contact information
Erin D. Pleasance: Wellcome Trust Sanger Institute
Philip J. Stephens: Wellcome Trust Sanger Institute
Sarah O’Meara: Wellcome Trust Sanger Institute
David J. McBride: Wellcome Trust Sanger Institute
Alison Meynert: European Bioinformatics Institute
David Jones: Wellcome Trust Sanger Institute
Meng-Lay Lin: Wellcome Trust Sanger Institute
David Beare: Wellcome Trust Sanger Institute
King Wai Lau: Wellcome Trust Sanger Institute
Chris Greenman: Wellcome Trust Sanger Institute
Ignacio Varela: Wellcome Trust Sanger Institute
Serena Nik-Zainal: Wellcome Trust Sanger Institute
Helen R. Davies: Wellcome Trust Sanger Institute
Gonzalo R. Ordoñez: Wellcome Trust Sanger Institute
Laura J. Mudie: Wellcome Trust Sanger Institute
Calli Latimer: Wellcome Trust Sanger Institute
Sarah Edkins: Wellcome Trust Sanger Institute
Lucy Stebbings: Wellcome Trust Sanger Institute
Lina Chen: Wellcome Trust Sanger Institute
Mingming Jia: Wellcome Trust Sanger Institute
Catherine Leroy: Wellcome Trust Sanger Institute
John Marshall: Wellcome Trust Sanger Institute
Andrew Menzies: Wellcome Trust Sanger Institute
Adam Butler: Wellcome Trust Sanger Institute
Jon W. Teague: Wellcome Trust Sanger Institute
Jonathon Mangion: Life Technologies
Yongming A. Sun: Life Technologies, Foster City, California 94404, USA
Stephen F. McLaughlin: Life Technologies, Beverley, Massachusetts 01915, USA
Heather E. Peckham: Life Technologies, Beverley, Massachusetts 01915, USA
Eric F. Tsung: Life Technologies, Beverley, Massachusetts 01915, USA
Gina L. Costa: Life Technologies, Beverley, Massachusetts 01915, USA
Clarence C. Lee: Life Technologies, Beverley, Massachusetts 01915, USA
John D. Minna: University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Adi Gazdar: University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA
Ewan Birney: European Bioinformatics Institute
Michael D. Rhodes: Life Technologies, Foster City, California 94404, USA
Kevin J. McKernan: Life Technologies, Beverley, Massachusetts 01915, USA
Michael R. Stratton: Wellcome Trust Sanger Institute
P. Andrew Futreal: Wellcome Trust Sanger Institute
Peter J. Campbell: Wellcome Trust Sanger Institute

Nature, 2010, vol. 463, issue 7278, 184-190

Abstract: 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.

Date: 2010
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DOI: 10.1038/nature08629

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