title: A small-cell lung cancer genome with complex signatures of tobacco exposure.
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.
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
authors.forename: Erin D
authors.initials: ED
authors.lastname: Pleasance
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Stephens
authors.forename: Sarah
authors.initials: S
authors.lastname: O'Meara
authors.forename: David J
authors.initials: DJ
authors.lastname: McBride
authors.forename: Alison
authors.initials: A
authors.lastname: Meynert
authors.forename: David
authors.initials: D
authors.lastname: Jones
authors.forename: Meng-Lay
authors.initials: ML
authors.lastname: Lin
authors.forename: David
authors.initials: D
authors.lastname: Beare
authors.forename: King Wai
authors.initials: KW
authors.lastname: Lau
authors.forename: Chris
authors.initials: C
authors.lastname: Greenman
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.forename: Serena
authors.initials: S
authors.lastname: Nik-Zainal
authors.forename: Helen R
authors.initials: HR
authors.lastname: Davies
authors.forename: Gonzalo R
authors.initials: GR
authors.lastname: Ordoñez
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Mudie
authors.forename: Calli
authors.initials: C
authors.lastname: Latimer
authors.forename: Sarah
authors.initials: S
authors.lastname: Edkins
authors.forename: Lucy
authors.initials: L
authors.lastname: Stebbings
authors.forename: Lina
authors.initials: L
authors.lastname: Chen
authors.forename: Mingming
authors.initials: M
authors.lastname: Jia
authors.forename: Catherine
authors.initials: C
authors.lastname: Leroy
authors.forename: John
authors.initials: J
authors.lastname: Marshall
authors.forename: Andrew
authors.initials: A
authors.lastname: Menzies
authors.forename: Adam
authors.initials: A
authors.lastname: Butler
authors.forename: Jon W
authors.initials: JW
authors.lastname: Teague
authors.forename: Jonathon
authors.initials: J
authors.lastname: Mangion
authors.forename: Yongming A
authors.initials: YA
authors.lastname: Sun
authors.forename: Stephen F
authors.initials: SF
authors.lastname: McLaughlin
authors.forename: Heather E
authors.initials: HE
authors.lastname: Peckham
authors.forename: Eric F
authors.initials: EF
authors.lastname: Tsung
authors.forename: Gina L
authors.initials: GL
authors.lastname: Costa
authors.forename: Clarence C
authors.initials: CC
authors.lastname: Lee
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Adi
authors.initials: A
authors.lastname: Gazdar
authors.forename: Ewan
authors.initials: E
authors.lastname: Birney
authors.forename: Michael D
authors.initials: MD
authors.lastname: Rhodes
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: McKernan
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.forename: P Andrew
authors.initials: PA
authors.lastname: Futreal
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Campbell
mesh_terms: D002273:Carcinogens / Q000633:toxicity; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005091:Exons / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D015894:Genome, Human / Q000187:drug effects / Q000235:genetics; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology* / Q000235:genetics*; D016254:Mutagenesis, Insertional / Q000187:drug effects / Q000235:genetics; D009154:Mutation / Q000187:drug effects / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D017384:Sequence Deletion / Q000235:genetics; D055752:Small Cell Lung Carcinoma / Q000209:etiology* / Q000235:genetics*; D012907:Smoking / Q000009:adverse effects*; D014026:Nicotiana
chemical_list: D002273:Carcinogens; D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human