Abstract 1414: Race-associated variation in the airway transcriptome response to cigarette smoke
Authors: Tassinari Anna , Whitney Duncan , Porta Kate , Lenburg Marc , Spira Avrum , Beane Jennifer 
Published: May 2015

INTRODUCTION: Tobacco-induced lung cancer is the leading cause of cancer death. Lung cancer incidence is 15% higher in African Americans (AFA) than Caucasians (CAU) even after taking into account variations in smoking behavior and other environmental variables, and the reasons for this difference are unclear. As 90% of patients with lung cancer have a smoking history, we hypothesize that race-related differences in the response to tobacco smoke might contribute to the elevated lung cancer risk observed in AFA. To begin to test this hypothesis, we have used gene expression profiling to identify differences in the biologic response of the bronchial airway epithelium of AFA and CAU to tobacco smoke.

METHODS: Cytologically normal bronchial epithelial cells obtained during bronchoscopy from current (C) and former (F) smokers with and without lung cancer were hybridized to Affymetrix Human Gene 1.0 ST microarrays (n=885). After quality control, n=810 samples (from n=710 subjects) were selected for subsequent analysis. RMA-normalized gene expression levels were batch-corrected using ComBat. Genes whose expression is altered by smoking differently in the airway epithelium of AFA (n=155; nC=76, nF=79) as compared to CAU (n=655; nC=283, nF=372), were identified via ANOVA using a linear model including terms for self-reported race, smoking status, and the interaction between race and smoking status, as well as other covariates including gender, cancer status, COPD status, age, cumulative cigarette smoke exposure, and RIN. Smoking-associated race-dependent pathways were identified using Enrichr. An independent dataset of cytologically normal bronchial epithelial cells hybridized to the Affymetrix HGU133A microarrays (nCAU=154, nAFA=58) was analyzed as detailed above and relationships between the two datasets were established using GSEA for the genes associated with race, and the interaction between race and smoking status.

RESULTS: We identified 361 genes that displayed smoking-associated race-dependent patterns of expression (FDR&lt;0.05) and were linked to multiple biological processes, pathways, and phenotypes, including DNA damage response, membrane organization, endoplasmic reticulum stress, and abnormal lung morphology and respiration. In addition, 2771 genes were found to be associated with race (FDR&lt;0.01) and enriched in pathways related to metabolism of xenobiotics, integrin cell surface interactions, and response to chemical stimulus. (Enrichr; Fisher exact test p-value&lt;0.05). Both sets of genes were significantly concordantly enriched in the independent dataset by GSEA (FDR&lt;0.05).

CONCLUSIONS: These findings suggest that race influences the airway epithelial response to cigarette smoke at the level of individual genes and pathways. Our findings also suggest that gene expression profiling of the airway epithelium might be useful to understand the molecular basis of the elevated risk of lung cancer among African Americans.

Citation Format: Anna Tassinari, Duncan Whitney, Kate Porta, Marc Lenburg, Avrum Spira, Jennifer Beane. Race-associated variation in the airway transcriptome response to cigarette smoke. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1414. doi:10.1158/1538-7445.AM2014-1414