TY - JOUR
T1 - Genomic landscape of non-small cell lung cancer in smokers and never-smokers
AU - Govindan, Ramaswamy
AU - Ding, Li
AU - Griffith, Malachi
AU - Subramanian, Janakiraman
AU - Dees, Nathan D.
AU - Kanchi, Krishna L.
AU - Maher, Christopher A.
AU - Fulton, Robert
AU - Fulton, Lucinda
AU - Wallis, John
AU - Chen, Ken
AU - Walker, Jason
AU - McDonald, Sandra
AU - Bose, Ron
AU - Ornitz, David
AU - Xiong, Donghai
AU - You, Ming
AU - Dooling, David J.
AU - Watson, Mark
AU - Mardis, Elaine R.
AU - Wilson, Richard K.
N1 - Funding Information:
We thank the following groups at The Genome Institute for their dedicated efforts in this work: the Production group for sequence data production and processing, the Technology Development group for formulation of methods and troubleshooting, the Analysis Pipeline group for developing the automated sequence analysis pipelines, the LIMS group for developing tools and software to manage samples and sequencing, and the Systems group for providing the IT infrastructure and HPC solutions required for sequencing and analysis. We thank Daniel C. Koboldt for his help on tumor clonality analysis, Mike Wendl for help with pathway analysis, Josh Peck for help with manuscript preparation, and Joshua McMichael for help with figure preparation. We also thank the Washington University Cancer Genome Initiative and Siteman Cancer Center for their support. This work was funded by grants to R.K.W. from Washington University in St. Louis and the National Human Genome Research Institute (NHGRI U54 HG003079).
PY - 2012/9/14
Y1 - 2012/9/14
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84866434919&partnerID=8YFLogxK
U2 - 10.1016/j.cell.2012.08.024
DO - 10.1016/j.cell.2012.08.024
M3 - Article
C2 - 22980976
AN - SCOPUS:84866434919
SN - 0092-8674
VL - 150
SP - 1121
EP - 1134
JO - Cell
JF - Cell
IS - 6
ER -