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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.

SUBMITTER: Pleasance ED

PROVIDER: S-EPMC2880489 | biostudies-literature | 2010 Jan

REPOSITORIES: biostudies-literature

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

Pleasance Erin D ED 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

Nature 20091216 7278

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 ...[more]

PMID: 20016488

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Project description:Current paradigms hold that lung carcinomas arise from pleuripotent stem cells capable of differentiation into one or several histological types. These paradigms suggest lung tumor cell ontogeny is determined by consequences of gene expression that recapitulate events important in embryonic lung development. Using oligonucleotide microarrays, we acquired gene profiles from 32 microdissected non-small-cell lung tumors. We determined the 100 top-ranked marker genes for adenocarcinoma, squamous cell, large cell, and carcinoid using nearest neighbor analysis. Results were validated by immunostaining for 11 selected proteins using a tissue microarray representing 80 tumors. Gene expression data of lung development were accessed from a publicly available dataset generated with the murine Mu11k genome microarray. Self-organized mapping identified two temporally distinct clusters of murine orthologues. Supervised clustering of lung development data showed large-cell carcinoma gene orthologues were in a cluster expressed in pseudoglandular and canalicular stages whereas adenocarcinoma homologues were predominantly in a cluster expressed later in the terminal sac and alveolar stages of murine lung development. Representative large-cell genes (E2F3, MYBL2, HDAC2, CDK4, PCNA) are expressed in the nucleus and are associated with cell cycle and proliferation. In contrast, adenocarcinoma genes are associated with lung-specific transcription pathways (SFTPB, TTF-1), cell adhesion, and signal transduction. In sum, non-small-cell lung tumors histology gene profiles suggest mechanisms relevant to ontogeny and clinical course. Adenocarcinoma genes are associated with differentiation and glandular formation whereas large-cell genes are associated with proliferation and differentiation arrest. The identification of developmentally regulated pathways active in tumorigenesis provides insights into lung carcinogenesis and suggests early steps may differ according to the eventual tumor morphology.

Dataset Information

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

Publications

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

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