(2012) Deep sequence analysis of on-small cell lung cancer : integrated analysis of gene expression, alternative splicing, and single nucleotide variations in lung adenocarcinomas with and without oncogenic KRAS mutations. Frontiers in Oncology, Volume 2 . Article number 12. doi:10.3389/fonc.2012.00012

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Abstract

KRAS mutations are highly prevalent in non-small cell lung cancer (NSCLC), and tumors harboring these mutations tend to be aggressive and resistant to chemotherapy. We used next-generation sequencing technology to identify pathways that are specifically altered in lung tumors harboring a KRAS mutation. Paired-end RNA-sequencing of 15 primary lung adenocarcinoma tumors (8 harboring mutant KRAS and 7 with wild-type KRAS) were performed. Sequences were mapped to the human genome, and genomic features, including differentially expressed genes, alternate splicing isoforms and single nucleotide variants, were determined for tumors with and without KRAS mutation using a variety of computational methods. Network analysis was carried out on genes showing differential expression (374 genes), alternate splicing (259 genes), and SNV-related changes (65 genes) in NSCLC tumors harboring a KRAS mutation. Genes exhibiting two or more connections from the lung adenocarcinoma network were used to carry out integrated pathway analysis. The most significant signaling pathways identified through this analysis were the NFκB, ERK1/2, and AKT pathways. A 27 gene mutant KRAS-specific sub network was extracted based on gene–gene connections from the integrated network, and interrogated for druggable targets. Our results confirm previous evidence that mutant KRAS tumors exhibit activated NFκB, ERK1/2, and AKT pathways and may be preferentially sensitive to target therapeutics toward these pathways. In addition, our analysis indicates novel, previously unappreciated links between mutant KRAS and the TNFR and PPARγ signaling pathways, suggesting that targeted PPARγ antagonists and TNFR inhibitors may be useful therapeutic strategies for treatment of mutant KRAS lung tumors. Our study is the first to integrate genomic features from RNA-Seq data from NSCLC and to define a first draft genomic landscape model that is unique to tumors with oncogenic KRAS mutations.

Item Type:	Journal Article
Subjects:	R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Divisions:	Faculty of Science > Statistics
Library of Congress Subject Headings (LCSH):	Small cell lung cancer, Lungs -- Cancer -- Diagnosis, Nucleotide sequence
Journal or Publication Title:	Frontiers in Oncology
Publisher:	Frontiers Research Foundation
ISSN:	2234-943X
Official Date:	10 February 2012
Dates:	Date Event 10 February 2012 Published 18 November 2011 Submitted
Volume:	Volume 2
Article Number:	Article number 12
DOI:	10.3389/fonc.2012.00012
Status:	Peer Reviewed
Publication Status:	Published
Access rights to Published version:	Open Access
Funder:	Florida. Department of Health and Rehabilitative Services (DHRS), National Cancer Institute (U.S.) (NCI), Eveleigh Family Foundation (EFF), Mayo Foundation (MF), 26.2 With Donna Foundation, National Marathon to Fight Breast Cancer, Mayo Clinic (MC)
Grant number:	1KG05 (DHRS), CA081436 (NCI), CA15083 (MC)

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