Circulating Exosomal Gastric Cancer–Associated Long Noncoding RNA1 as a Biomarker for Early Detection and Monitoring Progression of Gastric Cancer
Authors: Xin Guo, Xiaohui Lv, Yi Ru, Fuxing Zhou, Ning Wang, Hongqing Xi, Kecheng Zhang, Jiyang Li, Rongyan Chang, Tianyu Xie, Xinxin Wang, Baohai Li, Yong Chen, Yanling Yang, Lubin Chen, Lin Chen
Journal: JAMA Surgery (2020)

<h3>Importance</h3> The gastric cancer (GC)–associated long noncoding RNA1 (lncRNA-GC1) plays an important role in gastric carcinogenesis. However, exosomal lncRNA-GC1 and its potential role in GC are poorly understood. <h3>Objective</h3> To evaluate the diagnostic value of circulating exosomal lncRNA-GC1 for early detection and monitoring progression of GC. <h3>Design, Setting, and Participants</h3> We performed a multiphase investigation of circulating exosomal lncRNA-GC1 for early detection of GC involving consecutive patients with GC (n = 522), patients with gastric precancerous lesions (n = 85), and healthy donor individuals (HDs; n = 219) from December 2016 to February 2019 at Chinese People’s Liberation Army General Hospital, China. LncRNA-GC1 was measured by reverse transcription–polymerase chain reaction by independent researchers who had no access to patients’ information. Receiver operating characteristic curves were used to calculate diagnostic efficiency in comparison between lncRNA-GC1 and 3 traditional biomarkers (carcinoembryonic antigen [CEA], cancer antigen 72-4 [CA72-4], and CA19-9). <h3>Main Outcomes and Measures</h3> Assessment of diagnostic efficiency on the basis of area under curve (AUC), specificity, and sensitivity. <h3>Results</h3> Of the 826 patients included in the study, 508 were men (61.5%), and the median age of all patients was 60 years (range, 28-82 years). In the test phase, lncRNA-GC1 achieved better diagnostic performance than the standard biomarkers CEA, CA72-4, and CA19-9 (AUC = 0.9033) for distinguishing between the patients with GC and HDs. Additionally, exosomal lncRNA-GC1 levels were significantly higher in culture media from GC cells compared with those of normal gastric epithelial cells (<i>t</i> = 5.310;<i>P</i> = .002). In the verification phase, lncRNA-GC1 retained its diagnostic efficiency in discriminating patients with GC from those with gastric precancerous lesions as well from HDs. Moreover, lncRNA-GC1 exhibited a higher AUC compared with those of CEA, CA72-4, and CA19-9 for early detection of GC with sufficient specificity and sensitivity, especially for patients with GC with negative standard biomarkers. Moreover, the levels of circulating exosomal lncRNA-GC1 were significantly associated with GC from early to advanced stages (HD vs stage I,<i>t</i> = 20.98;<i>P</i> &lt; .001; stage I vs stage II,<i>t</i> = 2.787;<i>P</i> = .006; stage II vs stage III,<i>t</i> = 4.471;<i>P</i> &lt; .001; stage III vs stage IV,<i>t</i> = 1.023;<i>P</i> = .30), independent of pathological grading and Lauren classification (pathological grading: HD vs G1,<i>t</i> = 21.09;<i>P</i> &lt; .001; G1 vs G2,<i>t</i> = 0.3718;<i>P</i> = .71; G2 vs G3,<i>t</i> = 0.3598;<i>P</i> = .72; Lauren classification:<i>t</i> = 24.81;<i>P</i> &lt;.001). In the supplemental phase, the levels of circulating exosomal lncRNA-GC1 were consistent with those in GC tissues and cells and were higher compared with those in normal tissues and cells. Furthermore, the levels of circulating lncRNA-GC1 were unchanged after exosomes were treated with RNase and remained constant after prolonged exposure to room temperature or after repeated freezing and thawing (<i>t</i> = 1.443;<i>P</i> = .39). Total circulating lncRNA-GC1 was nearly all packaged within exosomes rather than a free form in plasma. <h3>Conclusions and Relevence</h3> Circulating exosomal lncRNA-GC1 may serve as a noninvasive biomarker for detecting early-stage GC and for monitoring disease progression. Combining circulating exosomal lncRNA-GC1 detection with endoscopy could improve the early diagnostic rate of GC.