Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events

Jinfeng Liu, William Lee, Zhaoshi Jiang, Zhongqiang Chen, Suchit Jhunjhunwala, Peter M. Haverty, Florian Gnad, Yinghui Guan, Houston N. Gilbert, Jeremy Stinson, Christiaan Klijn, Joseph Guillory, Deepali Bhatt, Steffan Vartanian, Kimberly Walter, Jocelyn Chan, Thomas Holcomb, Peter Dijkgraaf, Stephanie Johnson, Julie KoemanJohn D. Minna, Adi F. Gazdar, Howard M. Stern, Klaus P. Hoeflich, Thomas D. Wu, Jeff Settleman, Frederic J. De Sauvage, Robert C. Gentleman, Richard M. Neve, David Stokoe, Zora Modrusan, Somasekar Seshagiri, David S. Shames, Zemin Zhang

Research output: Contribution to journalArticle

131 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)2315-2327
Number of pages13
JournalGenome Research
Volume22
Issue number12
DOIs
Publication statusPublished - Dec 2012

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ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Liu, J., Lee, W., Jiang, Z., Chen, Z., Jhunjhunwala, S., Haverty, P. M., ... Zhang, Z. (2012). Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events. Genome Research, 22(12), 2315-2327. https://doi.org/10.1101/gr.140988.112