Gene expression differences in current versus former smokers lung squamous preneoplasia.

Abstract

10575 Background: The study of the molecular biology of the lung carcinogenesis would help finding biomarkers for early diagnosis and targets for chemoprevention. The present study aim to characterize genomic profiles between current and formers smokers in lung squamous carcinogenesis. Methods: 122 bronchial biopsies (67/55 from current/former smokers) at successive stages of lung squamous carcinogenesis (normal, hyperplasia, metaplasia, mild, moderate and severe dysplasia, carcinoma in situ and invasive carcinoma) obtained by fluorescence bronchoscopy in 74 high risk individuals (40/34 current/former smokers) were analyzed by gene expression microarrays (Mascaux, J Thorac Oncol 2009 4(9) S282). Results: 740 genes were significantly differentially expressed (FDR 0.05) between biopsies from current versus former smokers in bronchial pre-invasive lesions. The most significantly associated pathways was metabolism of xenobiotic by cytochrome CP450 eg CYP1A1, CYP2A6, ALDH1L1, but genes related to cancer pathways were also found, ie metallopeptidases, IGF binding proteins, cell growth and proliferation (ie EGF), or apoptosis (ie survivin). Our findings in lung preneoplasia were consistent by gene set enrichement analyses. (GSEA) with data previously reported on normal bronchial epithelial cells (Spira, PNAS 2004 101(27) 10143). Association between gene expression differences observed between the early steps of lung carcinogenesis in our study and between current and former smokers in normal bronchial epithelial cells in Spira study were analysed by GSEA. Some associations were observed: genes down-regulated in current smokers were also down-regulated in transition to squamous metaplasia including cancer genes like eg BCL2, FGF2, AKT3 and eicosanoid signaling eg PTGDR, PLA2G5. Conclusions: Genes discriminating current and former smokers during lung carcinogenesis include genes involved in metabolism of xenobiotic by cytochrome CP450, cell proliferation and apoptosis. Cigarette smoke exposure effects on normal epithelial cells and on preneoplasia from different data sets are related. Genes related to current smoking like eicosanoid signaling genes are involved in the early steps of carcinogenesis. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration AstraZeneca, Bristol-Myers Squibb/ImClone, Boehringer Ingelheim, Lilly, Merck Serono, OSI/Genentech/ Roche, Pfizer, Syndax AstraZeneca, Biogen Idec, Genentech, Genmab, Merck, OSI, Syndax, Ventana-Roche Abbott Laboratories