TY - JOUR
T1 - Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events
AU - Liu, Jinfeng
AU - Lee, William
AU - Jiang, Zhaoshi
AU - Chen, Zhongqiang
AU - Jhunjhunwala, Suchit
AU - Haverty, Peter M.
AU - Gnad, Florian
AU - Guan, Yinghui
AU - Gilbert, Houston N.
AU - Stinson, Jeremy
AU - Klijn, Christiaan
AU - Guillory, Joseph
AU - Bhatt, Deepali
AU - Vartanian, Steffan
AU - Walter, Kimberly
AU - Chan, Jocelyn
AU - Holcomb, Thomas
AU - Dijkgraaf, Peter
AU - Johnson, Stephanie
AU - Koeman, Julie
AU - Minna, John D.
AU - Gazdar, Adi F.
AU - Stern, Howard M.
AU - Hoeflich, Klaus P.
AU - Wu, Thomas D.
AU - Settleman, Jeff
AU - De Sauvage, Frederic J.
AU - Gentleman, Robert C.
AU - Neve, Richard M.
AU - Stokoe, David
AU - Modrusan, Zora
AU - Seshagiri, Somasekar
AU - Shames, David S.
AU - Zhang, Zemin
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
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U2 - 10.1101/gr.140988.112
DO - 10.1101/gr.140988.112
M3 - Article
C2 - 23033341
AN - SCOPUS:84870495530
SN - 1088-9051
VL - 22
SP - 2315
EP - 2327
JO - Genome Research
JF - Genome Research
IS - 12
ER -