A small-cell lung cancer genome with complex signatures of tobacco exposure.
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.
Pleasance
Erin D
ED
Wellcome Trust Sanger Institute, Hinxton CB10 1SA, UK.
Stephens
Philip J
PJ
O'Meara
Sarah
S
McBride
David J
DJ
Meynert
Alison
A
Jones
David
D
Lin
Meng-Lay
ML
Beare
David
D
Lau
King Wai
KW
Greenman
Chris
C
Varela
Ignacio
I
Nik-Zainal
Serena
S
Davies
Helen R
HR
Ordoñez
Gonzalo R
GR
Mudie
Laura J
LJ
Latimer
Calli
C
Edkins
Sarah
S
Stebbings
Lucy
L
Chen
Lina
L
Jia
Mingming
M
Leroy
Catherine
C
Marshall
John
J
Menzies
Andrew
A
Butler
Adam
A
Teague
Jon W
JW
Mangion
Jonathon
J
Sun
Yongming A
YA
McLaughlin
Stephen F
SF
Peckham
Heather E
HE
Tsung
Eric F
EF
Costa
Gina L
GL
Lee
Clarence C
CC
Minna
John D
JD
Gazdar
Adi
A
Birney
Ewan
E
Rhodes
Michael D
MD
McKernan
Kevin J
KJ
Stratton
Michael R
MR
Futreal
P Andrew
PA
Campbell
Peter J
PJ
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
D002273:Carcinogens; D004268:DNA-Binding Proteins; D004265:DNA Helicases; C491434:CHD7 protein, human