Identification of Three Circular RNAs Cargo in Serum Exosomes as Diagnostic Biomarkers of Non-Small Cell Lung Cancer

Background: Recent discovery of tumor-special circRNAs in serum exosomes have suggested novel and worth considering biomarkers for cancer non-invasive diagnosis. There is not yet any research literature targeting this topic. Methods: We conducted RNA-seq analysis to characterize circRNA profiles of serum exosomes between 3 pairs of non-small cell lung cancer (NSCLC) patients and ruled-out cases of suspected lung cancer, and then assessed diagnostic value of differentially expressed circRNAs in a training set including 120 NSCLC patients and 46 tuberculosis plus 94 healthy controls and a validation set with a total of 63 NSCLC cases and 58 chronic obstructive pulmonary disease plus 95 healthy controls. Findings: We delineated the circRNA profile in serum exosomes of NSCLC and identified 46 abnormally expressional circRNAs. The circ_0047921, circ_0056285 and circ_0007761 were further found to exert a considerable accuracy for diagnosing NSCLC in both the training set (area under curve [AUC] = 0.806, 95% confidence interval [95%CI] = 0.753-0.859) and the validation set (AUC = 0.810, 95%CI = 0.772-0.844). Their panel also played a significant role in diagnosis of early-stage NSCLC (AUC = 0.773, 95%CI = 0.725-0.815). Furthermore, circ_0047921 and circ_0007761 expressions were recovered to normal level after treatment. Circ_0056285 expression was correlated with clinical stage and lymph node metastasis. Interpretation: These findings suggested the exosomal circRNAs, circ_0047921, circ_0056285 and circ_0007761 to be promising biomarkers for NSCLC diagnosis as well as early diagnosis. Funding Statement: This study was supported by the National Natural Scientific Foundation of China grants 81402753, 81672303 (L. Yang) and by 81473040, 81673267 (J. Lu). Guangzhou Science and Technology Program Pearl River Nova projects Grant 201710010049 (L. Yang) and Guangzhou Education Bureau Major Projects Grant 1201610122 (L. Yang). Declaration of Interests: The authors declare that they have no competing interests. Ethics Approval Statement: The study was approved by the institutional review board of Guangzhou Medical University