Circulating Exosomal Gastric Cancer-Associated Long Noncoding RNA1 as a Bioniarker for Early Detection and Monitoring Progression of Gastric Cancer A Multiphase Study
Circulating Exosomal Gastric Cancer-Associated Long Noncoding RNA1 as a Bioniarker for Early Detection and Monitoring Progression of Gastric Cancer A Multiphase Study
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循环外泌体胃癌相关长非编码 RNA1 作为早期检测和监测胃癌进展的生物标志物一项多阶段研究
DOI：
10.1001/jamasurg.2020.1133
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发表时间：
2020-07-01
期刊：
影响因子：
16.9
通讯作者：
Chen, Lin
中科院分区：
文献类型：
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作者：
Guo, Xin;Lv, Xiaohui;Chen, Lin
重要性：胃癌（GC）相关长链非编码RNA1（lncRNA - GC1）在胃癌发生中起重要作用。然而，外泌体lncRNA - GC1及其在胃癌中的潜在作用知之甚少。
目的：评估循环外泌体lncRNA - GC1对胃癌早期检测和病情进展监测的诊断价值。
设计、地点和参与者：我们对循环外泌体lncRNA - GC1进行了多阶段研究，以早期检测胃癌，研究对象包括2016年12月至2019年2月在中国人民解放军总医院连续就诊的胃癌患者（n = 522）、胃癌前病变患者（n = 85）和健康供体个体（HDs；n = 219）。lncRNA - GC1由无法获取患者信息的独立研究人员通过逆转录 - 聚合酶链反应进行检测。采用受试者工作特征曲线计算lncRNA - GC1与3种传统生物标志物（癌胚抗原[CEA]、癌抗原72 - 4[CA72 - 4]和CA19 - 9）相比的诊断效率。
主要结果和测量指标：根据曲线下面积（AUC）、特异性和敏感性评估诊断效率。
结果：研究纳入的826例患者中，508例为男性（61.5%），所有患者的中位年龄为60岁（范围28 - 82岁）。在测试阶段，lncRNA - GC1在区分胃癌患者和健康供体方面比标准生物标志物CEA、CA72 - 4和CA19 - 9具有更好的诊断性能（AUC = 0.9033）。此外，胃癌细胞培养基中的外泌体lncRNA - GC1水平明显高于正常胃上皮细胞（t = 5.310；P = 0.002）。在验证阶段，lncRNA - GC1在区分胃癌患者与胃癌前病变患者以及健康供体方面仍保持其诊断效率。而且，lncRNA - GC1与CEA、CA72 - 4和CA19 - 9相比，在早期检测胃癌时具有更高的AUC，且具有足够的特异性和敏感性，特别是对于标准生物标志物阴性的胃癌患者。此外，从早期到晚期，循环外泌体lncRNA - GC1水平与胃癌显著相关（健康供体与I期相比，t = 20.98；P < 0.001；I期与II期相比，t = 2.787；P = 0.006；II期与III期相比，t = 4.471；P < 0.001；III期与IV期相比，t = 1.023；P = 0.30），且与病理分级和Lauren分型无关（病理分级：健康供体与G1相比，t = 21.09；P < 0.001；G1与G2相比，t = 0.3718；P = 0.71；G2与G3相比，t = 0.3598；P = 0.72；Lauren分型：t = 24.81；P < 0.001）。在补充阶段，循环外泌体lncRNA - GC1水平与胃癌组织和细胞中的水平一致，且高于正常组织和细胞中的水平。此外，外泌体经核糖核酸酶处理后循环lncRNA - GC1水平不变，长时间暴露于室温或反复冻融后也保持恒定（t = 1.443；P = 0.39）。循环中的总lncRNA - GC1几乎全部包裹在外泌体中，而非以游离形式存在于血浆中。
结论和相关性：循环外泌体lncRNA - GC1可作为一种非侵入性生物标志物用于检测早期胃癌和监测疾病进展。将循环外泌体lncRNA - GC1检测与内镜检查相结合可提高胃癌的早期诊断率。
IMPORTANCE The gastric cancer (GC)-associated long noncoding RNA1 (IncRNA-GC1) plays an important role in gastric carcinogenesis. However, exosomal IncRNA-GC1 and its potential role in GC are poorly understood.OBJECTIVE To evaluate the diagnostic value of circulating exosomal IncRNA-GC1 for early detection and monitoring progression of GC.DESIGN, SETTING, AND PARTICIPANTS We performed a multiphase investigation of circulating exosomal IncRNA-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 a 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 IncRNA-GC1 and 3 traditional biomarkers (carcinoembryonic antigen [[EA], cancer antigen 72-4 [[A72-4], and CA19-9).MAIN OUTCOMES AND MEASURES Assessment of diagnostic efficiency on the basis of area under curve (AUC), specificity, and sensitivity. RESULTS Of the 826 patients included in the study, 508 were men (615%), and the median age of all patients was 60 years (range, 28-82 years). In the test phase, IncRNA-GClachieved 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 IncRNA-GC1 levels were significantly higher in culture media from GC cells compared with those of normal gastric epithelial cells (t = 5.310; P = .002). In the verification phase, IncRNA-GC1 retained its diagnostic efficiency in discriminating patients with GC from those with gastric precancerous lesions as well from HDs. Moreover, IncRNA-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 IncRNA-GC1 were significantly associated with GC from early to advanced stages (HD vs stage I, t = 20.98; P < .001; stage I vs stage II, t = 2.787; P = .006; stage II vs stage III, t = 4.471; P < .001; stage III vs stage IV, t 1.023; P =.30), independent of pathological grading and Lauren classification (pathological grading: HD vs G1, t = 21.09; P < .001: G1 vs G2, t 0.3718; P.71; G2 vs G3, t 0.3598; P=.72: Lauren classification: t 24.81; P < .001). In the supplemental phase, the levels of circulating exosomal IncRNA-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 IncRNA-GClwere unchanged after exosomes were treated with RNase and remained constant after prolonged exposure to room temperature or after repeated freezing and thawing (t = 1.443; P = .39). Total circulating IncRNA-GC1 was nearly all packaged within exosomes rather than a free form in plasma.CONCLUSIONS AND RELEVENCE Circulating exosomal IncRNA-GC1 may serve as a noninvasive biomarker for detecting early-stage GC and for monitoring disease progression. Combining circulating exosomal IncRNA-GC1 detection with endoscopy could improve the early diagnostic rate of GC.