Abstract
Circulating microRNAs are potential diagnostic and predictive biomarkers, but have not been investigated for patients with anaplastic lymphoma kinase (ALK)-positive lung cancer. In this exploratory study, we sought to identify potential plasma biomarkers for ALK-positive non-small cell lung cancer (NSCLC). A microRNA microarray was used to select ALK-related microRNAs in ALK-positive NSCLC (n = 3), ALK-negative NSCLC (n = 3), and healthy subjects (n = 3). Plasma levels of 21 microRNAs were differentially expressed for ALK-positive and ALK-negative NSCLC, including 14 down-regulated and 7 up-regulated microRNAs. We also identified 5s rRNA as the most stable endogenous control gene using geNorm and NormFinder algorithms. Candidate microRNAs in plasma from ALK-positive (n = 41) and ALK-negative NSCLC patients (n = 32) were quantified using real-time reverse transcriptase quantitative polymerase chain reaction. The expression levels of miR-28-5p, miR-362-5p, and miR-660-5p were all down-regulated in ALK-positive NSCLC, compared with ALK-negative NSCLC. The areas under the receiver operating characteristic curves of miR-28-5p, miR-362-5p, miR-660-5p, and 3-microRNAs panel were 0.873, 0.673, 0.760, and 0.876, respectively. The positive predictive values of miR-28-5p, miR-362-5p, and miR-660-5p were 96.43%, 80.77%, and 83.87%, respectively. Increased plasma levels of miR-660-5p after crizotinib treatment predicted good tumor response (p = 0.012). The pre-crizotinib levels of miR-362-5p were significantly associated with progression-free survival (p = 0.015). Thus, in this preliminary investigation, we identified a potential panel of 3 microRNAs for distinguishing between patients with ALK-positive and ALK-negative NSCLC. We also identified miR-660-5p and miR-362-5p as potential predictors for response to crizotinib treatment.
Highlights
In 2007, investigators in Japan identified anaplastic lymphoma kinase (ALK) as a novel potential target in non-small cell lung cancer (NSCLC)
We evaluated the potential of circulating microRNAs as novel biomarkers of ALK status and response to crizotinib in patients with NSCLC
Our report is the first to describe a prospective analysis of circulating microRNAs as diagnostic or prognostic biomarkers for ALK-positive lung cancer that is treated with crizotinib
Summary
In 2007, investigators in Japan identified anaplastic lymphoma kinase (ALK) as a novel potential target in NSCLC. Most ALK-positive lung cancer patients are characterized by younger ages, no history of smoking or a history of light smoking, and adenocarcinoma histology [1, 2]. It is sometimes difficult to collect tumor tissues from patients with advanced-stage NSCLC. It has been shown that circulating biomarkers are present in plasma and other body fluids, and may have potential as novel, non-invasive biomarkers [6,7,8]. Recent findings indicate that circulating microRNAs are useful as non-invasive biomarkers for different tumor types, including lung cancer [9,10,11,12,13,14,15,16]
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