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The recent discovery of circular RNAs (circRNAs) in serum exosomes suggests a novel and potentially useful tool for noninvasive cancer diagnosis. However, there are currently no substantial studies addressing this topic. RNA-sequencing analysis was performed between three pairs of non-small-cell lung cancer (NSCLC) patients and controls. The diagnostic values of exosomal circRNAs were assessed in a training set, validation set 1, and validation set 2. A total of 46 abnormally expressed circRNAs were identified. Among these, circ_0047921, circ_0056285, and circ_0007761 were found to display significant diagnostic validity for NSCLC. In distinguishing NSCLC cases from healthy controls, the panel of aforementioned circRNAs exhibited area under the curve (AUC) values of 0.926 (95% CI, 0.895-0.956) in the training set and 0.919 (95% CI, 0.877-0.962) in validation set 1. Circ_0047921 could distinguish NSCLC cases from chronic obstructive pulmonary disease controls (AUC, 0.890; 95%CI, 0.831-0.948), whereas the circ_0056285 and circ_0007761 combination could distinguish NSCLC cases from tuberculosis controls (AUC, 0.820; 95% CI, 0.739-0.902). For an early NSCLC diagnosis, similar results were observed for these circRNAs in distinguishing early-stage NSCLC cases from healthy controls, chronic obstructive pulmonary disease controls, or tuberculosis controls. Circ_0056285 expression was correlated with clinical stages and lymph node metastasis. The exosomal circRNAs, circ_0047921, circ_0056285, and circ_0007761, are promising biomarkers for NSCLC diagnosis in the Chinese population.

Germline copy number variant (gCNV) has been studied as a genetic determinant for prognosis of several types of cancer, but little is known about how it affects non-small cell lung cancer (NSCLC) prognosis. We aimed to develop a prognostic nomogram for NSCLC based on gCNVs. Promising gCNVs that are associated with overall survival (OS) of NSCLC were sorted by analyzing the TCGA data and were validated in a small Chinese population. Then the successfully verified gCNVs were determined in a training cohort (n = 570) to develop a prognostic nomogram, and in a validation cohort (n = 465) to validate the nomogram. Thirty-five OS-related gCNVs were sorted and were reduced to 15 predictors by the Lasso regression analysis. Of them, only CNVR395.1 and CNVR2239.1 were confirmed to be associated with OS of NSCLC in the Chinese population. High polygenic risk score (PRS), which was calculated by the hazard effects of CNVR395.1 and CNVR2239.1, exerted a significantly higher death rate in the training cohort (HR = 1.41, 95%CI: 1.16–1.74) and validation cohort (HR = 1.42, 95%CI: 1.13–1.77) than low PRS. The nomogram incorporating PRS and surrounding factors, achieved admissible concordance indexes of 0.678 (95%CI: 0.664–0.693) and 0.686 (95%CI: 0.670–0.702) in predicting OS in the training and validation cohorts, respectively, and had well-fitted calibration curves. Moreover, an interaction between PRS and asbestos exposure was observed on affecting OS (Pinteraction = 0.042). Our analysis developed a nomogram that achieved an admissible prediction of NSCLC survival, which would be beneficial to the personalized intervention of NSCLC.

A non-invasive method to distinguish potential lung cancer patients would improve lung cancer prevention. We employed the RNA-sequencing analysis to profile serum exosomal long non-coding RNAs (lncRNAs) from non-small cell lung cancer (NSCLC) patients and pneumonia controls, and then determined the diagnostic and prognostic value of a promising lncRNA in four datasets. We identified 90 dysregulated lncRNAs for NSCLC and found the most significant lncRNA was a novel isoform of linc01125. Serum exosomal linc01125 could distinguish NSCLC cases from disease-free and tuberculosis controls, with the area under the curve values as 0.662 [95% confidence interval (CI) = 0.614–0.711] and 0.624 (95% CI = 0.522–0.725), respectively. High expression of exosomal linc01125 was also correlated with an unfavorable overall survival of NSCLC (hazard ratio = 1.48, 95% CI = 1.05–2.08). Clinic treatment decreased serum exosomal linc01125 in NSCLC patients (P = 0.036). Linc01125 functions to inhibit cancer growth and metastasis via acting as a competing endogenous RNA to up-regulate tumor necrosis factor alpha-induced protein 3 (TNFAIP3) expression by sponging miR-19b-3p. Notably, the oncogenic transformation of 16HBE led to decreased linc01125 in cells but increased linc01125 in cell-derived exosomes. The expression of linc01125 in total exosomes was highly correlated with that in tumor-associated exosomes in serum. Moreover, lung cancer cells were capable of releasing linc01125 into exosomes in vitro and in vivo. Our analyses suggest serum exosomal linc01125 as a promising biomarker for non-invasively diagnosing NSCLC and predicting the prognosis of NSCLC.

Background: A non-invasive method to distinguish potential lung cancer patients would improve lung cancer prevention. Methods: We employed RNA-Seq analysis to profile serum exosomal long non-coding RNAs (lncRNAs) from non-small cell lung cancer (NSCLC) patients and pneumonia controls, and then determined diagnostic and prognostic value of a promising lncRNA in four datasets. Findings: We identified several dysregulated lncRNAs and found that those up-regulated lncRNAs in NSCLC were mostly tumor-suppressive, while down-regulated lncRNAs were most oncogenic. The most significant lncRNA was a novel isoform of linc01125. Serum exosomal linc01125 could distinguish NSCLC cases from disease-free and tuberculosis controls, and its expression was also correlated with prognosis. Clinic treatment decreased serum exosomal linc01125 in NSCLC patients. Linc01125 functions to inhibit cancer growth and metastasis. Acting as a competing endogenous RNA, linc01125 sponges several microRNAs (miRs) to regulate gene expression such as TNFAIP3 via binding miR-19b-3p. Notably, oncogenic transformation of 16HBE leads to decreased linc01125 in cells but increased linc01125 in cells-derived exosomes. Linc01125 expression in exosomes was also highly correlated with that in tumor-associated exosomes. Linc01125 could be loaded into exosomes in vitro and in vivo, which did not dampen tumor development. Interpretation: Our analyses suggest serum exosomal linc01125 as a promising biomarker for non-invasively diagnosing NSCLC and predicting prognosis of NSCLC. Funding: National Natural Scientific Foundation of China, Guangzhou Science and Technology Program Pearl River Nova projects, The National Key Research and Development Program of China, Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program. Declaration of Interest: None to declare. Ethical Approval: The study was approved by the institutional review board of Guangzhou Medical University.

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