title: Genomic landscape of non-small cell lung cancer in smokers and never-smokers.
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.
authors.affiliation: Department of Internal Medicine, Division of Oncology, Washington University School of Medicine, St. Louis, MO 63110, USA.
authors.forename: Ramaswamy
authors.initials: R
authors.lastname: Govindan
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.forename: Malachi
authors.initials: M
authors.lastname: Griffith
authors.forename: Janakiraman
authors.initials: J
authors.lastname: Subramanian
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Dees
authors.forename: Krishna L
authors.initials: KL
authors.lastname: Kanchi
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Maher
authors.forename: Robert
authors.initials: R
authors.lastname: Fulton
authors.forename: Lucinda
authors.initials: L
authors.lastname: Fulton
authors.forename: John
authors.initials: J
authors.lastname: Wallis
authors.forename: Ken
authors.initials: K
authors.lastname: Chen
authors.forename: Jason
authors.initials: J
authors.lastname: Walker
authors.forename: Sandra
authors.initials: S
authors.lastname: McDonald
authors.forename: Ron
authors.initials: R
authors.lastname: Bose
authors.forename: David
authors.initials: D
authors.lastname: Ornitz
authors.forename: Donghai
authors.initials: D
authors.lastname: Xiong
authors.forename: Ming
authors.initials: M
authors.lastname: You
authors.forename: David J
authors.initials: DJ
authors.lastname: Dooling
authors.forename: Mark
authors.initials: M
authors.lastname: Watson
authors.forename: Elaine R
authors.initials: ER
authors.lastname: Mardis
authors.forename: Richard K
authors.initials: RK
authors.lastname: Wilson
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D002869:Chromosome Aberrations; D005260:Female; D020869:Gene Expression Profiling; D055106:Genome-Wide Association Study; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D054643:INDEL Mutation; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology* / Q000628:therapy; D008297:Male; D058990:Molecular Targeted Therapy; D017354:Point Mutation; D000091042:Reelin Protein; D012907:Smoking / Q000235:genetics* / Q000473:pathology*