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

Nature. 2010 Jan 14;463(7278):184-90. doi: 10.1038/nature08629. Epub 2009 Dec 16.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens / toxicity
  • Cell Line, Tumor
  • DNA Copy Number Variations / drug effects
  • DNA Copy Number Variations / genetics
  • DNA Damage / genetics
  • DNA Helicases / genetics
  • DNA Mutational Analysis
  • DNA Repair / genetics
  • DNA-Binding Proteins / genetics
  • Exons / genetics
  • Gene Expression Regulation, Neoplastic / drug effects
  • Genome, Human / drug effects
  • Genome, Human / genetics
  • Humans
  • Lung Neoplasms / etiology*
  • Lung Neoplasms / genetics*
  • Mutagenesis, Insertional / drug effects
  • Mutagenesis, Insertional / genetics
  • Mutation / drug effects
  • Mutation / genetics*
  • Promoter Regions, Genetic / genetics
  • Sequence Deletion / genetics
  • Small Cell Lung Carcinoma / etiology*
  • Small Cell Lung Carcinoma / genetics*
  • Smoking / adverse effects*
  • Tobacco / adverse effects*

Substances

  • Carcinogens
  • DNA-Binding Proteins
  • DNA Helicases
  • CHD7 protein, human