Genomic landscape of non-small cell lung cancer in smokers and never-smokers

Ramaswamy Govindan, Li Ding, Malachi Griffith, Janakiraman Subramanian, Nathan D. Dees, Krishna L. Kanchi, Christopher A. Maher, Robert Fulton, Lucinda Fulton, John Wallis, Ken Chen, Jason Walker, Sandra McDonald, Ron Bose, David Ornitz, Donghai Xiong, Ming You, David J. Dooling, Mark Watson, Elaine R. MardisRichard K. Wilson

Research output: Contribution to journalArticle

736 Scopus citations

Abstract

We report the results of whole-genome and transcriptome sequencing of tumor and adjacent normal tissue samples from 17 patients with non-small cell lung carcinoma (NSCLC). We identified 3,726 point mutations and more than 90 indels in the coding sequence, with an average mutation frequency more than 10-fold higher in smokers than in never-smokers. Novel alterations in genes involved in chromatin modification and DNA repair pathways were identified, along with DACH1, CFTR, RELN, ABCB5, and HGF. Deep digital sequencing revealed diverse clonality patterns in both never-smokers and smokers. All validated EFGR and KRAS mutations were present in the founder clones, suggesting possible roles in cancer initiation. Analysis revealed 14 fusions, including ROS1 and ALK, as well as novel metabolic enzymes. Cell-cycle and JAK-STAT pathways are significantly altered in lung cancer, along with perturbations in 54 genes that are potentially targetable with currently available drugs.

Original languageEnglish
Pages (from-to)1121-1134
Number of pages14
JournalCell
Volume150
Issue number6
DOIs
StatePublished - Sep 14 2012

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    Govindan, R., Ding, L., Griffith, M., Subramanian, J., Dees, N. D., Kanchi, K. L., Maher, C. A., Fulton, R., Fulton, L., Wallis, J., Chen, K., Walker, J., McDonald, S., Bose, R., Ornitz, D., Xiong, D., You, M., Dooling, D. J., Watson, M., ... Wilson, R. K. (2012). Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell, 150(6), 1121-1134. https://doi.org/10.1016/j.cell.2012.08.024