多天线N-糖链对双表型肝细胞癌的辅助诊断价值

冯惠娟; 张宇; 卓传尚; 黄晨军; 房萌; 柳丽娟

doi:10.3969/j.issn.1001-5256.2022.06.019

多天线N-糖链对双表型肝细胞癌的辅助诊断价值

DOI: 10.3969/j.issn.1001-5256.2022.06.019

冯惠娟¹,
张宇¹,
卓传尚¹,
黄晨军²,
房萌²,
柳丽娟^1, , ,

1.
福建医科大学孟超肝胆医院检验科，福州 350025
2.
上海东方肝胆外科医院实验诊断科, 上海 200438

基金项目:

福州市卫生健康中青年科学研究项目 (2019-S-wq19);

福建医科大学启航基金项目 (2019QH1296);

福建省自然科学基金项目(面上) (2020J011169)

伦理学审查：本研究于2020年2月14日经福建医科大学孟超肝胆医院伦理委员会批准，批号：科审2020_008_01。所有对象均签署知情同意书。

利益冲突声明：本研究不存在研究者、伦理委员会成员、受试者监护人以及与公开研究成果有关的利益冲突。

作者贡献声明：冯惠娟、柳丽娟负责设计研究方案；张宇负责样本收集及分析；黄晨军、房萌负责样本检测与数据整理分析；卓传尚负责指导论文的撰写与修改。

详细信息

通信作者:
柳丽娟，ljliu@126.com

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出版历程
- 收稿日期: 2021-09-27
- 录用日期: 2021-12-23
- 出版日期: 2022-06-20

Value of multi-glycan in the auxiliary diagnosis of dual-phenotype hepatocellular carcinoma

1.
Department of Clinical Laboratory, Mengchao Hepatobiliary Hospital of Fujian Medical University, Fuzhou 350025, China
2.
Department of Laboratory Medicine, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai 200438, China

Research funding:

Sponsored by Fuzhou Health Technology Project (2019-S-wq19);

Startup Fund for Scientific Research, Fujian Medical University (2019QH1296);

Fujian Provincial Natural Science Foundation Projects (general) (2020J011169)

More Information

Corresponding author: LIU Lijuan, ljliu@126.com (ORCID:0000-0001-9809-0056)

摘要

摘要: 目的探讨双表型肝细胞癌(DPHCC)患者血清中多天线N-糖链(Multi-glycan)的表达及其临床意义。方法收集2019年6月—2020年12月福建医科大学孟超肝胆医院65例DPHCC、80例原发性肝细胞癌(HCC)及120例肝硬化(LC)血清样本，采用基于DNA测序仪的荧光毛细管电泳(DSA-FACE)技术检测三组血清中N-糖链的表达，正态分布的计量资料两组间比较采用t检验，多组间比较采用方差分析；非正态分布的计量资料两组间比较采用Mann - Whitney U检验，多组间比较采用Kruskal- Wallis H检验。计数资料组间比较采用χ²检验。采用logistic回归方法建立常见指标模型。采用受试者工作特征(ROC)曲线评价AFP、PIVKA-Ⅱ、CEA、CA19-9及Multi-glycan诊断DPHCC的效能，ROC曲线下面积(AUC)比较采用Z检验。结果在DPHCC组及HCC组比较中，仅Multi-glycan差异有统计学意义(P＜0.001)，而AFP、PIVKA-Ⅱ、CEA、CA19-9及SUM差异均无统计学意义(P值均＞0.05)。DPHCC组与HCC组相比，Multi-glycan的曲线下面积(AUC_Multi-glycan)为0.775，显著高于AFP(0.507)、PIVKA-Ⅱ(0.584)、CEA(0.537)、CA19-9(0.505)及SUM(0.561)，Multi-glycan的灵敏度(69.23%)高于其他5项。在DPHCC组与LC组比较中，Multi-glycan、AFP、PIVKA-Ⅱ、CA19-9及SUM差异均有统计学意义(P值均＜0.001)。AUC_Multi-glycan(0.780)也均高于AFP(0.767)、PIVKA-Ⅱ(0.743)、CEA(0.566)、CA19-9(0.689)及SUM(0.713)，Multi-glycan灵敏度(89.23%)高于其他5项。结论 Multi-glycan可作为DPHCC的辅助诊断指标之一。
- 癌, 肝细胞 /
- 多天线N-糖链 /
- 诊断
Abstract: Objective To investigate the expression of multi-glycan in serum of patients with dual-phenotype hepatocellular (DPHCC) and its clinical significance. Methods Serum samples were collected from 65 patients with DPHCC, 80 patients with primary hepatocellular carcinoma (HCC), and 120 patients with liver cirrhosis (LC) who were treated in Mengchao Hepatobiliary Hospital of Fujian Medical University from June 2019 to December 2020. DNA sequencer-aided fluorophore-assisted carbohydrate electrophoresis was used to measure the expression of N-glycan in serum, The measurement data of normal distribution were compared by t-test between the two groups and analysis of variance between multiple groups; The measurement data with non normal distribution were compared by Mann-Whitney U test between the two groups and Kruskal-Wallis H test between multiple groups, the chi-square test was used for comparison of categorical data between groups.The logistic regression method was used to establish the common index model. The efficacy of AFP, PIVKA - Ⅱ, CEA, CA19-9 and multi glycan in the diagnosis of DPHCC was evaluated by receiver operating characteristic (ROC) curve, and the area under ROC curve (AUC) was compared by Z test. Results There was a significant difference in multi-glycan between the DPHCC group and the HCC group (P < 0.001), while there were no significant differences in AFP, PIVKA-Ⅱ, CEA, CA19-9, and SUM between the two groups (P=0.924, 0.084, 0.442, 0.924, and 0.206). Multi-glycan had an area under the ROC curve (AUC) of 0.775, which was significantly higher than that of AFP (0.507), PIVKA-Ⅱ (0.584), CEA (0.537), CA19-9 (0.505), and SUM (0.561), and multi-glycan had a sensitivity of 69.23%, which was increased compared with the other 5 items. There were significant differences in multi-glycan, AFP, PIVKA-Ⅱ, CA19-9, and SUM between the DPHCC group and the LC group (all P < 0.001), but there was no significant difference in CEA between the two groups (P=0.14). Multi-glycan had an AUC of 0.780, which was also higher than that of AFP (0.767), PIVKA-Ⅱ (0.743), CEA (0.566), CA19-9 (0.689), and SUM (0.713), and multi-glycan had a sensitivity of 89.23%, which was increased compared with the other five items. Conclusion Multi-glycan can be used as one of the indicators for the auxiliary diagnosis of DPHCC.
- Carcinoma, Hepatocellular /
- Multi-antenna of N-glycan /
- Diagnosis

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图 1 N-糖链各峰糖型结构

Figure 1. The structure of each peak of N-glycan

下载: 全尺寸图片幻灯片

图 2 三组中血清肿瘤指标及Multi-glycan的表达

Figure 2. The expression of serum tumor indexs and Multi-glycan in three groups

下载: 全尺寸图片幻灯片

图 3 三组中血清肿瘤指标、差异N-糖链及Multi-glycan的ROC曲线

Figure 3. ROC curve of serum tumor indexs, differential N-glycan and Multi-glycan in three groups

下载: 全尺寸图片幻灯片

表 1 三组中各指标的表达水平

Table 1. The expression of various indexes in three groups

指标	DPHCC组(n=65)	HCC组(n=80)	LC组(n=120)	统计值	P值
男性[例(%)]	55 (84.62)	67 (83.75)	98 (83.05)	χ²=0.03	0.975
年龄(岁)	55.00(46.50~63.00)	56.50(49.00~64.75)	55.00(46.25~65.00)	H=0.17	0.727
AFP (ng/mL)	59.84(9.25~906.32)	73.28(5.95~2 000.00)	6.65(3.50~26.90)	H=10.61	＜0.001
PIVKA-Ⅱ (mAU/mL)	154.00(40.00~865.50)	603.00(50.50~5 940.14)	38.50(32.25~48.25)	H=9.90	＜0.001
CEA (ng/mL)	2.70(1.60~4.30)	3.00(1.80~4.60)	2.55(1.50~2.55)	H=4.19	0.044
CA19-9 (U/mL)	16.84(8.96~31.72)	18.88(8.17~31.38)	44.86(13.57~73.84)	H=5.19	＜0.001
TP (g/L)	64.51±9.10	63.56±9.63	68.94±7.63	F=11.02	＜0.001
Alb (g/L)	37.60±5.17	36.78±6.00	40.01±5.23	F=9.50	＜0.001
TBil (μmol/L)	18.20(13.15~23.85)	17.10(12.88~22.78)	16.80(12.00~28.55)	H=2.80	0.06
ALT (U/L)	53.00(33.50~101.00)	69.00(33.25~188.50)	32.00(23.25~64.75)	H=14.38	＜0.001
AST (U/L)	57.00 (32.00~113.00)	79.00(37.25~264.25)	31.00(23.00~49.75)	H=16.30	＜0.001
SUM	398.80(224.40~712.00)	377.50(169.10~622.40)	897.20(271.40~1 457.80)	H=4.74	0.01
肿瘤分期(例)
Ⅰ级	0	0
Ⅱ级	20	25
Ⅲ级	40	48
Ⅳ级	5	7
N-glycan
Peak1	8.78(6.51~10.52)	8.64(6.93~10.20)	8.62(6.52~8.62)	H=0.33	0.652
Peak2	1.27(0.95~1.89)	1.31(1.04~1.69)	1.15(0.79~1.77)	H=1.02	0.216
Peak3	6.69(5.65~8.01)	6.08(5.41~7.12)	7.24(6.27~8.72)	H=12.20	＜0.001
Peak4	5.92±0.90	5.72±0.86	5.27±0.97	F=12.10	＜0.001
Peak5	38.26±5.52	39.40±5.24	34.29±8.39	F=15.07	＜0.001
Peak6	20.37±3.10	18.74±3.39	22.61±5.37	F=19.63	＜0.001
Peak7	6.19±1.38	5.99±1.45	6.58±2.17	F=2.75	0.172
Peak8	6.81±2.22	6.13±2.01	6.17±2.62	F=0.98	0.241
Peak9	4.18(2.92~4.18)	3.24(2.17~5.15)	2.82(2.20~4.31)	H=5.97	0.001
Peak9’	0.98(0.80~1.16)	0.76(0.63~1.00)	0.92(0.70~1.29)	H=5.60	0.001
Peak10	0.16(0.09~0.69)	0.30(0.23~0.37)	0.38(0.26~0.57)	H=5.62	0.001
Peak11	1.99±0.62	1.64±0.64	1.59±0.73	F=7.87	0.001
Peak12	0.86(0.64~1.02)	0.65(0.49~1.11)	0.70(0.58~0.94)	H=3.36	0.073
Multi-glycan	16.87±2.96	13.60±3.30	13.32±3.58	F=25.93	＜0.001
注：Multi-glycan= Peak8+Peak9+Peak9’+Peak10+Peak11+Peak12。

下载: 导出CSV

表 2 三组中各指标的诊断效能

Table 2. The diagnostic efficiency of various indexes in three groups

指标	Cut-off值	灵敏度(%)	特异度(%)	AUC(95%CI)
DPHCC组vs HCC组
AFP	6.67 ng/mL	35.38	73.75	0.507(0.413~0.601)
PIVKA-Ⅱ	554 mAU/mL	27.69	41.25	0.584(0.490~0.677)
CEA	1.65 ng/mL	58.46	22.50	0.537(0.442~0.632)
CA19-9	23.59 U/mL	33.85	53.75	0.505(0.410~0.600)
SUM	690.40	69.23	56.25	0.561(0.467~0.655)
Multi-glycan	16.67	69.23	73.75	0.775(0.699~0.850)
DPHCC组vs LC组
AFP	106.13 ng/mL	30.77	74.17	0.767(0.690~0.844)
PIVKA-Ⅱ	72.50 mAU/mL	64.62	75.80	0.743(0.645~0.841)
CEA	3.85 ng/mL	32.31	65.00	0.566(0.476~0.656)
CA19-9	43.48 U/mL	12.31	46.67	0.689(0.610~0.767)
SUM	865.80	71.88	45.83	0.713(0.642~0.784)
Multi-glycan	13.51	89.23	66.67	0.780(0.713~0.848)

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