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. Ordõez, Laura J. Mudie, Calli Latimer, Sarah Edkins, Lucy Stebbings, Lina Chen, Mingming JiaCatherine 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, Peter J. Campbell

Research output: Contribution to journalArticle

790 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)184-190
Number of pages7
JournalNature
Volume463
Issue number7278
DOIs
StatePublished - Jan 14 2010

ASJC Scopus subject areas

  • General

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