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PMID: 22980976 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

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

Cell ·Vol. 150 ·No. 6 ·2012-09-14 ·Pages 1121-34

Govindan R, Ding L, Griffith M, Subramanian J, Dees ND, Kanchi KL, Maher CA, Fulton R, Fulton L, Wallis J, Chen K, Walker J, McDonald S, Bose R, Ornitz D, Xiong D, You M, Dooling DJ, Watson M, Mardis ER, Wilson RK

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.

MeSH Terms
Carcinoma, Non-Small-Cell Lung/genetics,pathology,therapy Chromosome Aberrations Female Gene Expression Profiling Genome-Wide Association Study High-Throughput Nucleotide Sequencing Humans INDEL Mutation Lung Neoplasms/genetics,pathology,therapy Male Molecular Targeted Therapy Point Mutation Reelin Protein Smoking/genetics,pathology
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Govindan Ramaswamy
Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Ding Li
Griffith Malachi
Subramanian Janakiraman
Dees Nathan D
Kanchi Krishna L
Maher Christopher A
Fulton Robert
Fulton Lucinda
Wallis John
Chen Ken
Walker Jason
McDonald Sandra
Bose Ron
Ornitz David
Xiong Donghai
You Ming
Dooling David J
Watson Mark
Mardis Elaine R
Wilson Richard K
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2012.08.024
Published
2012-09-14
Pages
1121-34
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC3656590
Subset
IM
Grants
NCI NIH HHS · P30 CA016672 · United States
NCI NIH HHS · R00 CA149182 · United States
NHGRI NIH HHS · U54 HG003079 · United States
External Links
PubMed source DOI: 10.1016/j.cell.2012.08.024 PMC Full Text View journal details
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