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A COPD-related gene expression signature in squamous cell lung cancer

ABSTRACT: Chronic obstructive pulmonary disease (COPD) and squamous cell lung carcinoma (SCC) are both smoking-related diseases. Interestingly, COPD itself is a risk factor for SCC, and this is independent of smoking history. Inferring from this knowledge, it is plausible to assume that patients with COPD may have a different gene expression profile in normal bronchial epithelium and in SCC. To test this hypothesis, we compared gene expression profiles in bronchial epithelium and in SCC from patients with and without COPD. Gene expression profiles were generated using whole human genome oligo microarrays for 28 laser microdissected histologically normal bronchial epithelium samples (10 without COPD, 18 with COPD) and 35 laser microdissected SCC samples (17 without COPD, 18 with COPD). We found no significant differences in gene expression levels between normal bronchial epithelium from patients with and without COPD. Remarkably, 374 genes were differentially expressed in SCC obtained from patients with or without COPD; 295 showed a higher expression level in SCC from patients with COPD and 79 genes showed higher expression levels in SCC from patients without COPD. Genes related to mitochondrial localization (n=44) and genes located on chromosomal arm 5q (n=34) were significantly overrepresented. For both categories, all genes showed a higher expression level in SCC from patients with COPD than from those without COPD. In conclusion, SCC from patients with COPD show a different gene expression profile compared to SCC from patients without COPD. This suggests that COPD related factors affect the gene expression signature in SCC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE12472 | GEO | 2009/02/01

SECONDARY ACCESSION(S): PRJNA112943

REPOSITORIES: GEO

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Project description:Cystatin A (gene: CSTA), is up-regulated in non-small-cell lung cancer (NSCLC) and dysplastic vs normal human bronchial epithelium. In the context that chronic obstructive pulmonary disease (COPD), a small airway epithelium (SAE) disorder, is independently associated with NSCLC (especially squamous cell carcinoma, SCC), but only occurs in a subset of smokers, we hypothesized that genetic variation, smoking and COPD modulate CSTA gene expression levels in SAE, with further up-regulation in SCC. Gene expression was assessed by microarray in SAE of 178 individuals [healthy nonsmokers (n=60), healthy smokers (n=82), and COPD smokers (n=36)], with corresponding large airway epithelium (LAE) data in a subset (n=52). Blood DNA was genotyped by SNP microarray. Twelve SNPs upstream of the CSTA gene were all significantly associated with CSTA SAE gene expression (p<0.04 to 5 x 10-4). CSTA gene expression levels in SAE were higher in COPD smokers (28.4 Â± 2.0) than healthy smokers (19.9 Â± 1.4, p<10-3), who in turn had higher levels than nonsmokers (16.1 Â± 1.1, p<0.04). CSTA LAE gene expression was also smoking-responsive (p<10-3). Using comparable publicly available NSCLC expression data, CSTA was up-regulated in SCC vs LAE (p<10-2) and down-regulated in adenocarcinoma vs SAE (p<10-7). All phenotypes were associated with significantly different proportional gene expression of CSTA to cathepsins. The data demonstrate that regulation of CSTA expression in human airway epithelium is influenced by genetic variability, smoking, and COPD, and is further up-regulated in SCC, all of which should be taken into account when considering the role of CSTA in NSCLC pathogenesis. CSTA gene expression was assessed in the small airway epithelium obtained by bronchoscopy from 178 individuals, including healthy nonsmokers (n= 60) and healthy smokers (n= 118) and the large airway epithelium from healthy nonsmokers (n=21) and healthy smokers(n=31). *** Processed data not provided for all gene expression records. *** Blood DNA from the majority of these individuals was genotyped and an association analysis of gene expression with genotypes of all 48 SNPs within 100 kb of CSTA was performed in PLINK, and tested for significance following 103 permutations within ancestral clusters. Supplementary file (linked below) reports genotypes of all 48 SNPs within 100 kb of the CSTA gene for the 112 genotyping Samples.

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A COPD-related gene expression signature in squamous cell lung cancer

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