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

Krishna R Kalari, David Rossell, Brian M. Necela, Yan 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 D Sun, Steven Hart, Alexey A. Leontovich, Asif Hossain, Jean-Pierre Kocher, Edith A. Perez, David N. Reisman & 2 others Alan P Fields, E Aubrey Thompson

Research output: Contribution to journalArticle

31 Citations (Scopus)

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.

Original languageEnglish (US)
Article number00012
JournalFrontiers in Oncology
Volume2
Issue numberFEB
DOIs
StatePublished - 2012

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Alternative Splicing
Non-Small Cell Lung Carcinoma
Sequence Analysis
Nucleotides
Gene Expression
Mutation
Genes
Neoplasms
Peroxisome Proliferator-Activated Receptors
MAP Kinase Signaling System
RNA Sequence Analysis
Lung
Adenocarcinoma of lung
Human Genome
Protein Isoforms
Therapeutics
RNA
Technology
Drug Therapy

Keywords

  • Bioinformatics
  • Data integration and computational methods
  • KRAS mutation
  • Network analysis
  • NSCLC
  • RNA-Seq
  • Transcriptome sequencing

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

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

In: Frontiers in Oncology, Vol. 2, No. FEB, 00012, 2012.

Research output: Contribution to journalArticle

Kalari, Krishna R ; Rossell, David ; Necela, Brian M. ; Asmann, Yan ; Nair, Asha ; Baheti, Saurabh ; Kachergus, Jennifer M. ; Younkin, Curtis S. ; Baker, Tiffany ; Carr, Jennifer M. ; Tang, Xiaojia ; Walsh, Michael P. ; Chai, High Seng ; Sun, Zhifu D ; Hart, Steven ; Leontovich, Alexey A. ; Hossain, Asif ; Kocher, Jean-Pierre ; Perez, Edith A. ; Reisman, David N. ; Fields, Alan P ; Thompson, E Aubrey. / 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. In: Frontiers in Oncology. 2012 ; Vol. 2, No. FEB.
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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.",
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AU - Necela, Brian M.

AU - Asmann, Yan

AU - Nair, Asha

AU - Baheti, Saurabh

AU - Kachergus, Jennifer M.

AU - Younkin, Curtis S.

AU - Baker, Tiffany

AU - Carr, Jennifer M.

AU - Tang, Xiaojia

AU - Walsh, Michael P.

AU - Chai, High Seng

AU - Sun, Zhifu D

AU - Hart, Steven

AU - Leontovich, Alexey A.

AU - Hossain, Asif

AU - Kocher, Jean-Pierre

AU - Perez, Edith A.

AU - Reisman, David N.

AU - Fields, Alan P

AU - Thompson, E Aubrey

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