Repository logo
 

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

Published version
Peer-reviewed

Type

Article

Change log

Authors

Pleasance, Erin D 
Stephens, Philip J 
O'Meara, Sarah 
McBride, David J 
Meynert, Alison 

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.

Description

Keywords

Carcinogens, Cell Line, Tumor, DNA Copy Number Variations, DNA Damage, DNA Helicases, DNA Mutational Analysis, DNA Repair, DNA-Binding Proteins, Exons, Gene Expression Regulation, Neoplastic, Genome, Human, Humans, Lung Neoplasms, Mutagenesis, Insertional, Mutation, Promoter Regions, Genetic, Sequence Deletion, Small Cell Lung Carcinoma, Smoking, Nicotiana

Journal Title

Nature

Conference Name

Journal ISSN

0028-0836
1476-4687

Volume Title

463

Publisher

Springer Science and Business Media LLC