Skip to main content
Article thumbnail
Location of Repository

Deep Sequence Analysis of Non-Small Cell Lung Cancer: Integrated Analysis of Gene Expression, Alternative Splicing, and Single Nucleotide Variations in Lung Adenocarcinomas with and without Oncogenic KRAS Mutations

By Krishna R. Kalari, David Rossell, Brian M. Necela, Yan W. Asmann, Asha Nair, Saurabh Baheti, Jennifer M. Kachergus, Curtis S. Younkin, Tiffany Baker, Jennifer M. Carr, Xiaojia Tang, Michael P. Walsh, High-Seng Chai, Zhifu Sun, Steven N. Hart, Alexey A. Leontovich, Asif Hossain, Jean-Pierre Kocher, Edith A. Perez, David N. Reisman, Alan P. Fields and E. Aubrey Thompson


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

Topics: Oncology
Publisher: Frontiers Research Foundation
OAI identifier:
Provided by: PubMed Central
Download PDF:
Sorry, we are unable to provide the full text but you may find it at the following location(s):
  • http://www.pubmedcentral.nih.g... (external link)
  • Suggested articles


    1. (2009). A gene expression signature associated with “K-Ras addiction” reveals regulators of EMT and tumor cell survival.
    2. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain.
    3. (2011). c-Raf, but not B-Raf, is essential for development of KRas oncogene-driven non-small cell lung carcinoma.
    4. (2008). Computing topological parameters of biological networks.
    5. (2011). Cytoscape 2.8: new features for data integration and network visualization.
    6. (2009). Fast and accurate short read alignment with Burrows-Wheeler transform.
    7. (2002). Geneexpression profiles predict survival of patients with lung adenocarcinoma.
    8. (1998). Increasingcomplexityof theRassignaling pathway.
    9. (2011). Integrated analysis of gene expression,CpG island methylation, andgenecopynumberinbreastcancer cells by deep sequencing.
    10. (2006). K-ras activation generates an inflammatory response in lung tumors.
    11. (2007). KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer.
    12. (2005). KRAS mutations and primary resistance of lung adenocarcinomas to gefitinib or erlotinib.
    13. (1977). Maximum likelihood from incomplete data via the EM algorithm.
    14. (1988). Most human carcinomasof theexocrinepancreascontain mutant c-K-ras genes.
    15. (2012). Next-generation sequencing of lung adenocarcinomas
    16. (2006). Oncogenic pathway signatures in human cancers as a guide to targeted therapies.
    17. (2010). Quantifying alternative splicing from paired end reads”,
    18. (2009). Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma.
    19. (2009). single-agentsorafenib in patients with relapsed or refractory, advanced non-small-cell lung cancer.J.Clin.Oncol.27,4274–4280.
    20. (2011). smoking and lung cancer on the airway transcriptome using RNA-Seq.
    21. (2010). SNVMix: predicting single nucleotide variants from nextgeneration sequencing of tumors.
    22. (2004). Suppression of polyamine catabolism by activated Ki-ras in human colon cancer cells.
    23. (2009). The sequence alignment/map format and SAM tools.
    24. (2011). The UCSC Genome Browser database: update 2011. Nucleic Acids Res.
    25. (2012). This is an open-access article distributed under the terms of the Creative Commons Attribution Non Commercial License, which permits noncommercial use, distribution, and reproduction in other forums, provided the original authors and source are credited.
    26. (2005). Transformation by oncogenic RAS sensitizes human colon cells to TRAIL-induced apoptosis by up-regulating death receptor 4 and death receptor 5 through a MEKdependent pathway.
    27. (2009). Ultrafast and memory-efficient alignment of short DNA sequences to the human genome.
    28. (2000). Understanding Ras: ‘it ain’t over ‘til it’s over’.
    29. Zhang,Y.R.,Seshagiri,S.,andHillan, K.J.(2005).Mutationsintheepidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with nonsmall-cell lung cancer treated with chemotherapy alone and in combination with erlotinib.

    To submit an update or takedown request for this paper, please submit an Update/Correction/Removal Request.