title: Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events.
abstract: Lung cancer is a highly heterogeneous disease in terms of both underlying genetic lesions and response to therapeutic treatments. We performed deep whole-genome sequencing and transcriptome sequencing on 19 lung cancer cell lines and three lung tumor/normal pairs. Overall, our data show that cell line models exhibit similar mutation spectra to human tumor samples. Smoker and never-smoker cancer samples exhibit distinguishable patterns of mutations. A number of epigenetic regulators, including KDM6A, ASH1L, SMARCA4, and ATAD2, are frequently altered by mutations or copy number changes. A systematic survey of splice-site mutations identified 106 splice site mutations associated with cancer specific aberrant splicing, including mutations in several known cancer-related genes. RAC1b, an isoform of the RAC1 GTPase that includes one additional exon, was found to be preferentially up-regulated in lung cancer. We further show that its expression is significantly associated with sensitivity to a MAP2K (MEK) inhibitor PD-0325901. Taken together, these data present a comprehensive genomic landscape of a large number of lung cancer samples and further demonstrate that cancer-specific alternative splicing is a widespread phenomenon that has potential utility as therapeutic biomarkers. The detailed characterizations of the lung cancer cell lines also provide genomic context to the vast amount of experimental data gathered for these lines over the decades, and represent highly valuable resources for cancer biology.
authors.affiliation: Department of Bioinformatics and Computational Biology.
authors.forename: Jinfeng
authors.initials: J
authors.lastname: Liu
authors.forename: William
authors.initials: W
authors.lastname: Lee
authors.forename: Zhaoshi
authors.initials: Z
authors.lastname: Jiang
authors.forename: Zhongqiang
authors.initials: Z
authors.lastname: Chen
authors.forename: Suchit
authors.initials: S
authors.lastname: Jhunjhunwala
authors.forename: Peter M
authors.initials: PM
authors.lastname: Haverty
authors.forename: Florian
authors.initials: F
authors.lastname: Gnad
authors.forename: Yinghui
authors.initials: Y
authors.lastname: Guan
authors.forename: Houston N
authors.initials: HN
authors.lastname: Gilbert
authors.forename: Jeremy
authors.initials: J
authors.lastname: Stinson
authors.forename: Christiaan
authors.initials: C
authors.lastname: Klijn
authors.forename: Joseph
authors.initials: J
authors.lastname: Guillory
authors.forename: Deepali
authors.initials: D
authors.lastname: Bhatt
authors.forename: Steffan
authors.initials: S
authors.lastname: Vartanian
authors.forename: Kimberly
authors.initials: K
authors.lastname: Walter
authors.forename: Jocelyn
authors.initials: J
authors.lastname: Chan
authors.forename: Thomas
authors.initials: T
authors.lastname: Holcomb
authors.forename: Peter
authors.initials: P
authors.lastname: Dijkgraaf
authors.forename: Stephanie
authors.initials: S
authors.lastname: Johnson
authors.forename: Julie
authors.initials: J
authors.lastname: Koeman
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Adi F
authors.initials: AF
authors.lastname: Gazdar
authors.forename: Howard M
authors.initials: HM
authors.lastname: Stern
authors.forename: Klaus P
authors.initials: KP
authors.lastname: Hoeflich
authors.forename: Thomas D
authors.initials: TD
authors.lastname: Wu
authors.forename: Jeff
authors.initials: J
authors.lastname: Settleman
authors.forename: Frederic J
authors.initials: FJ
authors.lastname: de Sauvage
authors.forename: Robert C
authors.initials: RC
authors.lastname: Gentleman
authors.forename: Richard M
authors.initials: RM
authors.lastname: Neve
authors.forename: David
authors.initials: D
authors.lastname: Stokoe
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Somasekar
authors.initials: S
authors.lastname: Seshagiri
authors.forename: David S
authors.initials: DS
authors.lastname: Shames
authors.forename: Zemin
authors.initials: Z
authors.lastname: Zhang
mesh_terms: D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics / Q000378:metabolism; D017398:Alternative Splicing; D045744:Cell Line, Tumor; D056915:DNA Copy Number Variations; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D057890:Epigenomics; D005091:Exons; D015972:Gene Expression Regulation, Neoplastic; D005819:Genetic Markers; D015894:Genome, Human / Q000235:genetics*; D006579:Heterozygote; D056466:Histone Demethylases / Q000235:genetics / Q000378:metabolism; D011495:Histone-Lysine N-Methyltransferase; D006801:Humans; D007621:Karyotyping / Q000379:methods; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome; D015854:Up-Regulation; D020830:rac1 GTP-Binding Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D005819:Genetic Markers; D009687:Nuclear Proteins; C107953:RAC1 protein, human; D014157:Transcription Factors; D056466:Histone Demethylases; C523998:KDM6A protein, human; C490911:ASH1L protein, human; D011495:Histone-Lysine N-Methyltransferase; D000251:Adenosine Triphosphatases; C084108:SMARCA4 protein, human; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D004265:DNA Helicases; D020830:rac1 GTP-Binding Protein