血清外泌体CEA、CA15-3和CA125水平在非小细胞肺癌和肺部良性病变鉴别诊断中的价值

doi:10.3969/j.issn.1673-8640.2024.11.002

摘要/Abstract

摘要：

目的初步探讨血清外泌体中癌胚抗原（CEA）、糖类抗原（CA）15-3和CA125水平在非小细胞肺癌（NSCLC）和肺部良性病变鉴别诊断中的价值。方法选取2019年1月—2023年12月深圳市龙华区人民医院NSCLC患者152例[NSCLC组，包括NSCLC早期28例（NSCLC早期组）、NSCLC进展期124例（NSCLC进展期组）]和肺部良性病变患者86例（良性疾病组）。提取所有患者血清外泌体，并分别检测外泌体和血清中的CEA、CA15-3和CA125水平。采用受试者工作特征（ROC）曲线评价各项指标鉴别诊断NSCLC和肺部良性病变的效能。采用Logistic回归分析评估发生NSCLC的影响因素。基于外泌体3项肿瘤标志物构建鉴别诊断NSCLC和肺部良性病变的联合检测模型。采用校准曲线和决策曲线评估联合检测模型的临床价值。结果与良性疾病组比较，NSCLC组血清和外泌体CEA、CA15-3、CA125水平均显著增高（P<0.000 1）。CEA、CA15-3、CA125的血清水平高于外泌体水平（P<0.05）。NSCLC组同一肿瘤标志物的血清水平与外泌体水平呈正相关（P<0.000 1）。NSCLC早期组血清CEA、CA15-3、CA125水平均显著高于良性疾病组（P<0.05）。与NSCLC早期组比较，NSCLC进展期组血清CEA水平显著升高（P<0.05），血清CA15-3、CA125和外泌体CEA、CA15-3、CA125水平稍升高，但差异均无统计学意义（P>0.05）。血清CEA、CA15-3、CA125鉴别诊断NSCLC与肺部良性病变的曲线下面积（AUC）分别为0.788 3、0.789 6、0.678 6，外泌体CEA、CA15-3、CA125的AUC分别为0.852、0.918、0.891。联合检测模型的区分度均较好（AUC为0.970），准确性较高（χ2=5.280 7，P=0.503），在高风险阈值（0.00~1.00）范围内的净获益率>0，净获益率最大值为0.703。结论血清外泌体CEA、CA15-3和CA125联合检测可用于NSCLC与肺部良性病变的鉴别诊断，具有较高的临床应用价值。

关键词: 癌胚抗原, 糖类抗原15-3, 糖类抗原125, 外泌体, 非小细胞肺癌

Abstract:

Objective To investigate the roles of serum exosomal carcinoembryonic antigen（CEA），carbohydrate antigen（CA）15-3 and CA125 determinations in the differential diagnosis of non-small cell lung cancer（NSCLC）and benign lung diseases. Methods A total of 152 patients with NSCLC （28 cases of early-stage NSCLC and 124 cases of advanced NSCLC）and 86 patients with benign lung diseases were enrolled from Shenzhen Longhua District People's Hospital from January 2019 to December 2023. The exosomes in serum were extracted，serum and exosomal levels of CEA，CA15-3 and CA125 were determined. The diagnostic performance was assessed by receiver operating characteristic（ROC）curve. Logistic regression analysis was used to evaluate the risk factors of NSCLC. A combined determination model for differentiating NSCLC from benign lung diseases was constructed based on the 3 tumor markers in exosomes. Calibration curve and decision curve were used to evaluate the role of combined determination model. Results Compared with benign group，serum and exosomal levels of CEA，CA15-3 and CA125 in NSCLC group were increased （P<0.000 1）. The serum levels of CEA，CA15-3 and CA125 were higher than exosomal levels （P<0.05）. The serum levels and exosomal levels in NSCLC group showed a positive correlation （P<0.000 1）. The serum levels of CEA，CA15-3 and CA125 in early-stage NSCLC group were higher than those in benign group （P<0.05）. Compared with early-stage NSCLC group，serum CEA level in advanced NSCLC group was increased （P<0.05），while serum CA15-3，serum CA125，exosomal CEA，exosomal CA15-3 and exosomal CA125 levels were slightly increased（P>0.05）. The areas under curves （AUC） for serum CEA，CA15-3 and CA125 in differentiating NSCLC from benign lung diseases were 0.788 3，0.789 6 and 0.678 6，respectively，while the AUC for exosomal CEA，CA15-3 and CA125 were 0.852，0.918 and 0.891，respectively. The combined determination model had good discrimination （AUC=0.970）. The accuracy of the combined determination model was high （χ2=5.280 7，P=0.503），and the net benefit rate was >0 within the high-risk threshold range（0.00-1.00），with the maximum net benefit rate being 0.703. Conclusions The combined determination of exosomal CEA，CA15-3 and CA125 in serum samples has a high clinical value for the differential diagnosis of NSCLC and benign lung diseases.

Key words: Carcinoembryonic antigen, Carbohydrate antigen 15-3, Carbohydrate antigen 125, Exosome, Non-small cell lung cancer

中图分类号:

R446.1

崔晓阳, 刘国栋, 郭慧娟, 廖志宏, 刘运洪, 张伟芬, 陈子尧, 魏晓珠. 血清外泌体CEA、CA15-3和CA125水平在非小细胞肺癌和肺部良性病变鉴别诊断中的价值[J]. 检验医学, 2024, 39(11): 1035-1041.

CUI Xiaoyang, LIU Guodong, GUO Huijuan, LIAO Zhihong, LIU Yunhong, ZHANG Weifen, CHEN Zirao, WEI Xiaozhu. Roles of serum exosomal CEA，CA15-3 and CA125 in the differential diagnosis of non-small cell lung cancer and benign lung diseases[J]. Laboratory Medicine, 2024, 39(11): 1035-1041.

图/表 7

参考文献 18

[1]	LIU Y, XIA Y, SMOLLAR J, et al. The roles of small extracellular vesicles in lung cancer:molecular pathology,mechanisms,diagnostics,and therapeutics[J]. Biochim Biophys Acta Rev Cancer, 2021, 1876(1):188539.
[2]	WU S, LUO M, TO K K W, et al. Intercellular transfer of exosomal wild type EGFR triggers osimertinib resistance in non-small cell lung cancer[J]. Mol Cancer, 2021, 20(1):17. DOI PMID
[3]	MULLEN S, MOVIA D. The role of extracellular vesicles in non-small-cell lung cancer,the unknowns,and how new approach methodologies can support new knowledge generation in the field[J]. Eur J Pharm Sci, 2023,188:106516.
[4]	ASLAN C, MARALBASHI S, SALARI F, et al. Tumor-derived exosomes:implication in angiogenesis and antiangiogenesis cancer therapy[J]. J Cell Physiol, 2019, 234(10): 16885-16903.
[5]	ZHANG Y, LIU Y, LIU H, et al. Exosomes:biogenesis,biologic function and clinical potential[J]. Cell Biosci, 2019,9:19.
[6]	NIU L, SONG X, WANG N, et al. Tumor-derived exosomal proteins as diagnostic biomarkers in non-small cell lung cancer[J]. Cancer Sci, 2019, 110(1):433-442.
[7]	吕丽华, 朱丽娜, 王皓, 等. 血浆外泌体提取方法的比较[J]. 检验医学, 2020, 35(12):1224-1228. DOI
[8]	SMOLARZ M, PIETROWSKA M, MATYSIAK N, et al. Proteome profiling of exosomes purified from a small amount of human serum:the problem of co-purified serum components[J]. Pro-teomes, 2019, 7(2):18.
[9]	LOGOZZI M, OREFICE N S, DI RAIMO R, et al. The importance of detecting,quantifying,and characterizing exosomes as a new diagnostic/prognostic approach for tumor patients[J]. Cancers(Basel), 2023, 15(11):2878.
[10]	YOKOYAMA S, TAKEUCHI A, YAMAGUCHI S, et al. Clinical implications of carcinoembryonic antigen distribution in serum exosomal fraction-measurement by ELISA[J]. PLoS One, 2017, 12(8):e0183337.
[11]	PAN D, CHEN J, FENG C, et al. Preferential localization of MUC1 glycoprotein in exosomes secreted by non-small cell lung carcinoma cells[J]. Int J Mol Sci, 2019, 20(2):323.
[12]	CHEN Z, LIANG Q, ZENG H, et al. Exosomal CA125 as a promising biomarker for ovarian cancer diagnosis[J]. J Cancer, 2020, 11(21):6445-6453. DOI PMID
[13]	LI P, BAI Y, SHAN B, et al. Exploration of potential diagnostic value of protein content in serum small extracellular vesicles for early-stage epithelial ovarian carcinoma[J]. Front Oncol, 2021,11:707658.
[14]	SHI H, LIU L, DENG X, et al. Exosomal biomarkers in the differential diagnosis of ovarian tumors:the emerging roles of CA125,HE4,and C5a[J]. J Ovarian Res, 2024, 17(1):4.
[15]	国家药品监督管理局医疗器械技术审评中心. 体外诊断试剂产品注册技术审评报告人外泌体 CA125、HE4、C5a 检测试剂盒(化学发光法)[EB/OL]. (2024-01-16)[2024-08-30]. https://www.cmde.org.cn/directory/web/cmde/images/1706593096206046026.pdf.
[16]	中国康复医学会医学检验与康复专业委员会, 上海市医学会分子诊断专科分会, 上海市免疫学会肿瘤免疫分会, 等. 肝癌三项(AFP、AFP-L3%、DCP)与GALAD、类GALAD模型临床应用专家共识[J]. 检验医学, 2023, 38(7):607-623. DOI
[17]	KASHIWABARA K, NAKAMURA H, YOKOI T. Chronological change of serum carcinoem-bryonic antigen(CEA)concentrations and pulmonary function data after cessation of smoking in subjects with smoking-associated CEA abnormality[J]. Clin Chim Acta, 2001, 303(1-2):25-32.
[18]	BENEDIKTER B J, VOLGERS C, VAN EIJCK P H, et al. Cigarette smoke extract induced exosome release is mediated by depletion of exofacial thiols and can be inhibited by thiol-antioxidants[J]. Free Radic Biol Med, 2017,108:334-344.

组别	例数	CEA		CA15-3		CA125
组别	例数	血清/（ng·mL-1）	外泌体/（ng·mL-1）	血清/ （U·mL-1）	外泌体/ （U·mL-1）	血清/ （U·mL-1）	外泌体/ （U·mL-1）
腺癌组	87	7.73（5.38~14.48）	4.53（2.91~9.26）	45.56（35.07~89.90）	15.00（11.13~32.75）	76.74（47.94~122.03）	25.05（16.94~62.11）
鳞癌组	65	4.01（2.64~6.48）	2.09（1.25~6.44）	17.83（12.80~33.99）	3.82（2.76~9.53）	8.38（4.02~20.67）	3.95（1.80~10.66）
t值		0.596 6	0.259 5	6.291 0	6.756 0	7.003 0	4.657 0
P值		0.551 7	0.795 6	<0.000 1	<0.000 1	<0.000 1	<0.000 1

组别	例数	CEA		CA15-3		CA125
组别	例数	血清/（ng·mL-1）	外泌体/（ng·mL-1）	血清/ （U·mL-1）	外泌体/ （U·mL-1）	血清/ （U·mL-1）	外泌体/ （U·mL-1）
腺癌组	87	7.73（5.38~14.48）	4.53（2.91~9.26）	45.56（35.07~89.90）	15.00（11.13~32.75）	76.74（47.94~122.03）	25.05（16.94~62.11）
鳞癌组	65	4.01（2.64~6.48）	2.09（1.25~6.44）	17.83（12.80~33.99）	3.82（2.76~9.53）	8.38（4.02~20.67）	3.95（1.80~10.66）
t值		0.596 6	0.259 5	6.291 0	6.756 0	7.003 0	4.657 0
P值		0.551 7	0.795 6	<0.000 1	<0.000 1	<0.000 1	<0.000 1

项目	单因素分析		多因素分析
项目	OR值（95%CI）	P值	OR值（95%CI）	P值
血清CEA	1.46（1.27~1.69）	<0.05	1.25 （1.09~1.44）	<0.05
血清CA15-3	1.09（1.06~1.13）	<0.05	1.07 （1.04~1.11）	<0.05
血清CA125	1.03（1.02~10.5）	<0.05	1.01 （1.00~1.03）	0.108
外泌体CEA	3.81（2.37~6.13）	<0.05	2.72（1.59~4.64）	<0.001
外泌体CA15-3	2.91（2.03~4.17）	<0.05	2.96（1.81~4.83）	<0.001
外泌体CA125	2.07（1.54~2.77）	<0.05	2.29（1.47~3.58）	<0.001

项目	单因素分析		多因素分析
项目	OR值（95%CI）	P值	OR值（95%CI）	P值
血清CEA	1.46（1.27~1.69）	<0.05	1.25 （1.09~1.44）	<0.05
血清CA15-3	1.09（1.06~1.13）	<0.05	1.07 （1.04~1.11）	<0.05
血清CA125	1.03（1.02~10.5）	<0.05	1.01 （1.00~1.03）	0.108
外泌体CEA	3.81（2.37~6.13）	<0.05	2.72（1.59~4.64）	<0.001
外泌体CA15-3	2.91（2.03~4.17）	<0.05	2.96（1.81~4.83）	<0.001
外泌体CA125	2.07（1.54~2.77）	<0.05	2.29（1.47~3.58）	<0.001

项目	AUC（95% CI）	最佳临界值	敏感性/%	特异性/%	Youden指数
血清CEA	0.788（0.734~0.843）	3.67 ng·mL-1	64.86	86.05	0.5091
外泌体CEA	0.852（0.804~0.899）	1.17 ng·mL-1	84.86	87.21	0.7207
血清CA15-3	0.790（0.737~0.842）	26.46 U·mL-1	64.86	93.02	0.5788
外泌体CA15-3	0.918（0.887~0.949）	3.77 U·mL-1	77.30	100.00	0.7730
血清CA125	0.679（0.617~0.740）	35.31 U·mL-1	53.51	91.86	0.4537
外泌体CA125	0.891（0.854~0.928）	2.97 U·mL-1	76.76	97.67	0.7443
联合检测模型	0.970（0.953~0.987）	0.603	96.51	90.81	0.8732