Lung cancer remains one of the most common and deadly diseases worldwide, with a 5-year survival rate of 16%. It is still the leading cause of cancer-associated mortality among both men and women, despite a decreasing incidence rate over the past decade. MicroRNAs (miRNAs), a class of small non-coding RNAs, may regulate the expression of one third of all human genes and are related to carcinogenesis through their function as oncogenes or tumor suppressors. Circulating serum miRNAs that are differentially expressed between early stage lung cancer patients and controls could serve as non-invasive biomarkers for the early detection of lung cancer. In this study, we assessed a total of 89 candidate miRNAs using a quantitative Real-Time PCR method in 200 Caucasian, early stage lung cancer patients (stage I or II disease) and 200 Caucasian healthy controls. We used the rank sum test to assess differential serum miRNA expression levels between cases and controls. Odds ratios [OR] and 95% confidence intervals [CI] were calculated using multivariate logistic regression while adjusting for age, gender and smoking status. Of the 89 candidate miRNAs, 56 miRNAs were expressed in the serum of study subjects and 4 miRNAs (mir409_3p, mir223star, mir152, mir378) exhibited significant differential expression between cases and controls. The most significant association was observed for mir409_3p with a rank-sum test p-value at 0.008. In the stratified analysis, significant association was observed for mir409_3p in younger individuals less than or equal to 65 years of age, mir223star, mir152, and mir378 in older individuals greater than 65 years of age, mir409_3p and mir223star in males, mir152 in females, and mir378 in ever smokers. After dichotomizing serum miRNAs using the 1st quartile cut-off in the controls and comparing to the lowest quartile, we also observed significant associations for mir409_3p, mir223star, mir152, and mir378 with ORs (95% CI) of 0.47 (0.27-0.83), 2.00(1.03-3.88), 0.43(0.25-0.74), and 2.58(1.37-4.86), respectively. Risk score analysis using these 4 miRNAs showed significant increased risk of lung cancer with an increasing risk score (P = 1.64 X 10-6). Under Receiver Operating Characteristic curve analysis, the area under the curve (AUC) for age, gender, and smoking status is 0.76 while AUC increased to 0.81 with the addition of the serum miRNA data. We further downloaded the miRNA expression data from TCGA and found that mir378 and mir152 were available. These two miRNAs exhibited consistent associations (up-regulated for mi378 or down-regulated for mir152) while comparing tumor and normal tissues in lung patients with pathological stage I and II disease and comparing serum in lung cancer cases and controls. In conclusion, serum miRNAs exhibited differential expression between early stage lung cancer cases and controls and could be used for the early detection of lung cancer.

Citation Format: Yuanqing Ye, Yan Wang, Jack Roth, Xifeng Wu. Serum MicroRNAs as biomarkers in early stage non-small cell lung cancer. [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 298. doi:10.1158/1538-7445.AM2014-298