Abstract 2181: Differential expression of genes related to autoimmunity and metabolism in Stage I NSCLC from patients with COPD

Abstract

Abstract Chronic obstructive pulmonary disease increases lung cancer risk 3-fold, but individuals with COPD may not qualify for lung cancer screening if their age or smoking histories do not meet eligibility criteria. Genomics might reveal genes differentially active in lung tumors from COPD patients, identifying pathways associated with lung cancer in the COPD setting. We used mRNA profiling to identify differences in Stage I non-small cell lung cancers (NSCLC) from patients with and without COPD. COPD was determined by pre-surgery Pulmonary Function Tests (PFTs); the GOLD score was calculated from FEV1 and FVC measurements. Stage I cases were chosen to minimize effect of tumor burden on PFTs. After extraction of mRNA from frozen tumor specimens (71 adenocarcinoma and 24 squamous cell carcinoma), the Illumina HT-12 v4 BeadChip was used to measure mRNA expression. All cases passed RNA quality checks, had not received neo-adjuvant therapy, and had pre-surgical PFT results. 44% of cases were GOLD II-IV (COPD positive) and 56% were GOLD 0-I (COPD negative). In an unbiased examination using the limma R package, 5,789 probes showed expression above background and variation in expression. These probes were compared in COPD positive and negative tumors; no probes were significantly different after multiple comparisons adjustment. In an examination of KEGG pathways by gene set enrichment analysis (GSEA) using a t-test or a linear model that adjusted for age, race, sex and smoking status, 31 pathways (17 in squamous cell and 14 in adenocarcinoma) were identified that were differentially expressed between COPD positive and negative tumors (p value < 0.025 in a 2-tailed test). There was no overlap in significant KEGG Pathways between the two histologies. In squamous cell carcinoma, DNA Replication and Mismatch Repair were repressed in COPD positive tumors, while many Autoimmunity and Infection pathways were activated. In adenocarcinoma, COPD positive tumors showed repression of metabolic pathways including P450, fatty acid, and pentose metabolism. Ingenuity pathway analysis predicted upstream regulators that are reported to control differentially expressed genes contained in the significant KEGG pathways. In squamous cell lung carcinoma, IL27 (p = 2.96 E-36, activation score 3.00), interferon gamma (p = 1.65 E-58, activation score 5.57), and tumor necrosis factor (p = 2.01 E-44, activation score 3.92) were the three top upstream regulators. In adenocarcinoma, PPAR alpha/RXRA (p = 4.83 E -15, inhibition score -2.84), TP53 (p = 3.63 E-08, inhibition score -2.06), and HNF1A (p = 3.88 -08, inhibition score -2.59) were the top three upstream regulators. Results show that distinct pathways are affected by COPD in lung squamous cell and adenocarcinoma, and identify potential biomarkers such as IL27 that may drive squamous cell carcinoma development, while loss of PPAR activity may drive adenocarcinoma, in smokers with COPD. Supported by P50 CA090440. Citation Format: Jill M. Siegfried, Kan Shang, Cavan Reilly, Laura P. Stabile. Differential expression of genes related to autoimmunity and metabolism in Stage I NSCLC from patients with COPD. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2181. doi:10.1158/1538-7445.AM2015-2181