Abstract 3021: MicroRNA expression profile of CT screening detected lung cancer

Abstract

Abstract The benefits of lung cancer screening by spiral CT are still controversial and ongoing randomized trials will demonstrate the real impact of early detection on mortality of high risk individuals. Since the nature and life-threatening potential of CT-detected nodules is currently debated due to the potential issue of overdiagnosis, the study of molecular features of these tumors would allow for a better definition of those genetic signatures that are associated with invasiveness and metastatic potential. MicroRNAs (miRNAs), small regulatory non-coding molecules that silence gene expression by either cleaving target mRNAs or inhibiting their translation, offered new insight into the biology of tumors and miRNA expression profiles have been shown to be potential tools for cancer diagnosis, prognosis and therapeutic strategy. In this study we explored miRNA expression profile of 28 lung tumors detected in the 5 years of our pilot spiral-CT screening trial on 1035 heavy smokers, and compared the miRNAs signatures of the tumors with those of the paired normal lung tissues using a miRNA microarray platform and validation of the differentially expressed miRNAs using quantitative real-time PCR. Possible association of microRNA expression profiles with clinical-pathological characteristics of the patients were also investigated. 5 µg of total RNA was used for labeling and hybridization on miRNA microarray chip (Ohio State microRNA microarray version 2.0) containing 460 probes in quadruplicate. By class comparison analyses of paired and unpaired normal/tumor samples 54-66 miRNAs were significant at the nominal 0.001 level of the univariate test. The top ten deregulated miRNAs that discriminate normal lung versus early lung cancer were: mir-7, mir-21, mir-200, mir-210, mir-219, mir-324 (upregulated) and mir-451, mir-486, mir-126 (downregulated). This list included miRNAs previously identified (i.e. miR-21, mir-200 family known to be involved in specific pathways such as survival, apoptosis, epithelial-mesenchymal transition) and unidentified (i.e. downregulation of miR-486 and miR-451) in symptomatic lung cancer patients. Two miRNAs (mir-205, mir-106) significantly discriminated adenocarcinoma from squamous carcinoma histotypes. The miRNA expression profile of tumors detected in the first two years of the trial, including mainly Stage Ia adenocarcinoma with excellent survival, and that detected in the more advanced stage and lethal tumors found after the second year, showed nine differentially expressed miRNAs between the two groups: mir-128, mir-129, mir-369-3p, mir-193, mir-339-3p, mir-185, mir-346, mir-340, mir-206. Functional studies are ongoing to establish the role of these miRNas in the invasive phenotype of lung tumors in order to use them as biomarkers for molecular prediction of subjects at higher risk for tumors with worse prognosis and as potential therapeutic targets. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3021.