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Impact of viral presence in tumor on gene expression in non-small cell lung cancer.

ABSTRACT: BACKGROUND:In our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. However, their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors. METHODS:Gene expression microarrays of 30 primary and 9 metastatic NSCLC patients were preprocessed through a series of quality control analyses. Linear Models for Microarray Analysis and Gene Set Enrichment Analysis were used to assess differential expression. RESULTS:Various genes and gene sets had significantly altered expressions between virus-infected and uninfected NSCLC tumors. Notably, 22 genes on the viral carcinogenesis pathway were significantly overexpressed in virus-infected primary tumors, along with three oncogenic gene sets. A total of 12 genes, as well as seven oncogenic and 133 immunologic gene sets, were differentially altered in squamous cell carcinomas, depending on the virus. In adenocarcinoma, 14 differentially expressed genes (DEGs) were identified, but no oncogenic and immunogenic gene sets were significantly altered. In bronchioloalveolar carcinoma, several genes were highly overexpressed in virus-infected specimens, but not statistically significant. Only five of 69 DEGs (7.2%) from metastatic tumor analysis overlapped with 1527 DEGs from the primary tumor analysis, indicating differences in host cellular targets and the viral impact between primary and metastatic NSCLC. CONCLUSIONS:The differentially expressed genes and gene sets were distinctive among infected viral types, histological subtypes, and metastatic disease status of NSCLC. These results support the hypothesis that tumor viruses play a role in NSCLC by regulating host genes in tumor cells during NSCLC differentiation and progression.

SUBMITTER: Kim Y

PROVIDER: S-EPMC6106745 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Impact of viral presence in tumor on gene expression in non-small cell lung cancer.

Kim Youngchul Y Pierce Christine M CM Robinson Lary A LA

BMC cancer 20180822 1

<h4>Background</h4>In our recent study, most non-small-lung cancer (NSCLC) tumor specimens harbored viral DNA but it was absent in non-neoplastic lung. However, their targets and roles in the tumor cells remain poorly understood. We analyzed gene expression microarrays to identify genes and pathways differentially altered between virus-infected and uninfected NSCLC tumors.<h4>Methods</h4>Gene expression microarrays of 30 primary and 9 metastatic NSCLC patients were preprocessed through a series ...[more]

PMID: 30134863

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Project description:Background:The immune cells in the local environments surrounding non-small cell lung cancer (NSCLC) implicate the balance of pro- and antitumor immunity; however, their transcriptomic profiles remain poorly understood. Methods:A transcriptomic microarray study of bronchoalveolar lavage (BAL) cells harvested from tumor-bearing lung segments was performed in a discovery group. The findings were validated (1) in published microarray datasets, (2) in an independent group by RT-qPCR, and (3) in non-diseased and tumor adjacent non-neoplastic lung tissue by immunohistochemistry and in BAL cell lysates by immunoblotting. Result:The differential expression of 129 genes was identified in the discovery group. These genes revealed functional enrichment in Fc gamma receptor-dependent phagocytosis and circulating immunoglobulin complex among others. Microarray datasets analysis (n?=?607) showed that gene expression of BAL cells of tumor-bearing lung segment was also the unique transcriptomic profile of tumor adjacent non-neoplastic lung of early stage NSCLC and a significantly gradient increase of immunoglobulin genes' expression for non-diseased lungs, tumor adjacent non-neoplastic lungs, and tumors was identified (ANOVA, p?<?2?×?10-16). A 53-gene signature was determined with significant correlation with inhibitory checkpoint PDCD1 (r?=?0.59, p?=?0.0078) among others, where the nine top genes including IGJ and IGKC were RT-qPCR validated with high diagnostic performance (AUC: 0.920, 95% CI: 0.831-0.985, p?=?2.98?×?10-7). Increased staining and expression of IGKC revealed by immunohistochemistry and immunoblotting in tumor adjacent non-neoplastic lung tissues (Wilcoxon signed-rank test, p?<?0.001) and in BAL cell lysates (p?<?0.01) of NSCLC, respectively, were noted. Conclusion:The BAL cells of tumor-bearing lung segments and tumor adjacent non-neoplastic lung tissues present a unique gene expression characterized by IGKC in relation to inhibitory checkpoints. Further study of humoral immune responses to NSCLC is warranted.

Project description:BackgroundAminopeptidase N (CD13) is a zinc-binding protease that has functional effects on both cancerogenesis and tumor angiogenesis. Since CD13 is an antigen suitable for molecular targeted therapies (e.g. tTF-NGR induced tumor vascular infarction), we evaluated its impact in NSCLC patients, and tested the effects of the CD13-targeted fusion protein tTF-NGR (truncated tissue factor (tTF) containing the NGR motif: asparagine-glycine-arginine) in vivo in nude mice.MethodsExpression of both CD13 and CD31 was studied in 270 NSCLC patients by immunohistochemistry. Clinical correlations and prognostic effects of the expression profiles were analyzed using univariate and multivariate analyses. In addition, a microarray-based analysis on the basis of the KM plotter database was performed. The in vivo effects of the CD13-targeted fusion protein tTF-NGR on tumor growth were tested in CD1 nude mice carrying A549 lung carcinoma xenotransplants.ResultsCD13 expression in tumor endothelial and vessel associated stromal cells was found in 15% of the investigated samples, while expression in tumor cells was observed in 7%. Although no significant prognostic impact was observed in the full NSCLC study cohort, both univariate and multivariate models identified vascular CD13 protein expression to correlate with poor overall survival in stage III and pN2+ NSCLC patients. Microarray-based mRNA analysis for either adenocarcinomas or squamous cell carcinomas did not reveal any significant effect. However, the analysis of CD13 mRNA expression for all lung cancer histologies demonstrated a positive prognostic effect. In vivo, systemic application of CD13-targeted tissue factor tTF-NGR significantly reduced CD13+ A549 tumor growth in nude mice.ConclusionsOur results contribute a data basis for prioritizing clinical testing of tTF-NGR and other antitumor molecules targeted by NGR-peptides in NSCLC. Because CD13 expression in NSCLC tissues was found only in a specific subset of NSCLC patients, rigorous pre-therapeutic testing will help to select patients for these studies.

Dataset Information

Impact of viral presence in tumor on gene expression in non-small cell lung cancer.

Publications

Impact of viral presence in tumor on gene expression in non-small cell lung cancer.

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