Genome and transcriptome sequencing of lung cancers reveal diverse mutational and splicing events
- Jinfeng Liu1,
- William Lee1,
- Zhaoshi Jiang1,
- Zhongqiang Chen1,
- Suchit Jhunjhunwala1,
- Peter M Haverty1,
- Florian Gnad1,
- Yinghui Guan1,
- Houston Gilbert1,
- Jeremy Stinson1,
- Christiaan Klijn1,
- Joseph Guillory1,
- Deepali Bhatt1,
- Steffan Vartanian1,
- Kimberly Walter1,
- Jocelyn Chan1,
- Thomas Holcomb1,
- Peter Dijkgraaf1,
- Stephanie Johnson1,
- Julie Koeman2,
- John D Minna3,
- Adi F Gazdar3,
- Howard M Stern1,
- Klaus P Hoeflich1,
- Thomas D Wu1,
- Jeff Settleman1,
- Frederic J de Sauvage1,
- Robert C Gentleman1,
- Richard M Neve1,
- David Stokoe1,
- Zora Modrusan1,
- Somasekar Seshagiri1,
- David S Shames1 and
- Zemin Zhang1,4
- ↵* Corresponding author; email: zemin{at}gene.com
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 3 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.
- Received March 26, 2012.
- Accepted September 24, 2012.
- © 2012, Published by Cold Spring Harbor Laboratory Press
This manuscript is Open Access.
This article is distributed exclusively by Cold Spring Harbor Laboratory Press for the first six months after the full-issue publication date (see http://genome.cshlp.org/site/misc/terms.xhtml). After six months, it is available under a Creative Commons License (Attribution-NonCommercial 3.0 Unported License), as described at http://creativecommons.org/licenses/by-nc/3.0/.
