Circulating microRNAs as novel biomarkers of ALK-positive non-small cell lung cancer and predictors of response to crizotinib therapy
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Liang-Liang Li1,2,*, Li-Li Qu1,*, Han-Jiang Fu3, Xiao-Fei Zheng3, Chuan-Hao Tang4, Xiao-Yan Li1, Jian Chen5, Wei-Xia Wang1, Shao-Xing Yang1, Lin Wang1, Guan-Hua Zhao1, Pan-Pan Lv1, Min Zhang1, Yang-Yang Lei1, Hai-Feng Qin1, Hong Wang1, Hong-Jun Gao1 and Xiao-Qing Liu1
1Department of Lung Cancer, Affiliated Hospital of Academy of Military Medical Sciences, Beijing, China
2Department of Oncology, 309th Hospital of PLA, Beijing, China
3Department of Biochemistry and Molecular Biology, Beijing Institute of Radiation Medicine, Beijing, China
4Department of Oncology, Peking University International Hospital, Beijing, China
5Department of Respiratory, Affiliated Hospital of Aviation Medicine, Beijing, China
*These authors contributed equally to this work and are co-first authors
Xiao-Qing Liu, email: [email protected]
Keywords: microRNA, plasma, biomarker, non-small cell lung cancer, ALK
Received: January 26, 2017 Accepted: April 12, 2017 Published: April 30, 2017
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.
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