Stage- and smoking-associated microRNA expression in lung adenocarcinoma.

Background: Altered expression of microRNAs (miRNAs) is implicated in lung carcinogenesis, but little research has investigated the association of miRNA alterations with lung cancer stage or smoking status. To identify such alterations in lung adenocarcinoma, we conducted miRNA profiling. Methods: Lung adenocarcinoma specimens and paired nonneoplastic lung tissues from 58 patients who had received no preoperative therapy and underwent tumor resection from 1991 to 2006 were collected from tumor tissue banks. Thirty (52%) of the tumors were stage I and 28 (48%) stage II or higher. Twenty-five (43%) patients were nonsmokers and 33 (57%) were smokers. To identify miRNAs of which its expression was associated with disease stage and/or smoking status, we performed subgroup analyses based on disease stage and smoking status, alongside overall profiling of all samples. miRNA expression was profiled using a microarray kit in tumors and paired nonneoplastic lung tissues. We assessed the fold changes (FCs) and local false discovery rates (FDRs) for the intercept in addition to P values. Results: Of the 706 miRNAs examined, 64 had overall altered expression. Of these, 36 (56%) were associated with all stages of adenocarcinoma in both smokers and nonsmokers. In stage-based analysis, 20 altered miRNAs were associated with stage I disease and 38 with stage II or higher disease. Of the 20 miRNAs associated with stage I adenocarcinoma, 4 were miR-200 family members, and miR-200b was the most highly upregulated. Analysis based on smoking status identified 38 altered miRNAs in nonsmokers and 6 altered miRNAs in smokers. Three miR-200 family members were significantly altered in nonsmokers. Among the miRNA alterations associated with stage I adenocarcinoma in nonsmokers, we found alterations in all 5 miR-200 family members (miR-200b, miR-200a, miR-141, miR-429, and miR-200c). Conclusions: Our identification of miRNA alterations associated with early-stage lung adenocarcinoma in nonsmokers, especially alterations in the miR-200 family, suggests that these miRNAs may play a unique role in the early stages of lung carcinogenesis and progression in nonsmokers and that they may be useful as markers for the early detection of lung cancer.