血清G-17、PGR、HLA-G、ANXA1联合幽门螺杆菌IgG抗体对胃癌和癌前病变的鉴别诊断价值.pdf

海南医学2023年8月第34卷第15期Hainan Med J,Aug.2023,Vol.34,No.15血清G-17、PGR、HLA-G、ANXA1联合幽门螺杆菌IgG抗体对胃癌和癌前病变的鉴别诊断价值杨燕燕，王捷虹，许永攀，穆恒，尤金枝陕西中医药大学附属医院消化一科，陕西咸阳712000【摘要】目的探讨血清胃泌素-17(G-17)、胃蛋白酶原(PG-)/胃蛋白酶原(PG-)比值(PGR)、人类白细胞抗原-G(HLA-G)、膜联蛋白A1(ANXA1)联合幽门螺杆菌(HP)-免疫球蛋白G(IgG)抗体(HP-IgG抗体)对胃癌和癌前病变的鉴别诊断价值。方法选择2021年1月至2022年5月在陕西中医药大学附属医院接受诊治的80例胃癌患者作为胃癌组，70例癌前病变患者作为癌前病变组，另选取在我院体检的健康人群50例作为健康对照组。比较三组受检者HP-IgG抗体阳性率以及血清G-17、PGR、HLA-G、ANXA1水平。根据胃癌组和癌前病变组患者HP-IgG抗体阳性情况，分为HP-IgG抗体阳性组(n=71)、HP-IgG抗体阴性组(n=9)，比较两组血清患者的G-17、PGR、HLA-G、ANXA1水平。采用受试者工作特征曲线(ROC)分析血清G-17、PGR、HLA-G、ANXA1联合HP-IgG抗体检测对胃癌和癌前病变的鉴别诊断价值。结果胃癌组患者的PGR为1.450.74，明显低于癌前病变组的5.021.88和健康对照组的12.362.02，G-17、HLA-G、ANXA1及HP-IgG抗体阳性率分别为(81.0710.70)ng/mL、(90.889.13)U/mL、(6.931.64)g/L 及 88.75%，明显高于癌前病变组的(67.649.88)ng/mL、(68.358.84)U/mL、(4.851.02)g/L、75.71%和健康对照组的(54.328.74)ng/mL、(41.346.76)U/mL、(1.580.70)g/L、46.00%，而癌前病变组患者的上述各项指标明显高于健康对照组，差异均有统计学意义(P0.05)；胃癌HP-IgG抗体阳性组患者的PGR为1.230.55，明显低于胃癌HP-IgG抗体阴性组的 3.151.38，G-17、HLA-G、ANXA1 分别为(81.9611.34)ng/mL、(91.7110.16)U/mL、(7.131.74)g/L，明显高于胃癌HP-IgG抗体阴性组的(74.039.92)ng/mL、(84.359.46)U/mL、(5.351.44)g/L，差异均有统计学意义(P0.05)；癌前病变HP-IgG抗体阳性组患者的PGR为4.541.83，明显低于癌前病变HP-IgG抗体阴性组的6.512.50，G-17、HLA-G、ANXA1 分别为(69.259.35)ng/mL、(69.838.18)U/mL、(5.151.54)g/L，明显高于癌前病变HP-IgG抗体阴性组的(62.659.42)ng/mL、(63.758.16)U/mL、(3.901.20)g/L，差异均具有统计学意义(P0.05)，具有可比性，见表1。本研究经我院医学伦理委员会批准。1.2检测方法抽取所有患者入院后隔天清晨、体检健康人群于体检当日的空腹外周静脉血5 mL。采用酶联免疫吸附试验测定血清G-17、PG-、PG-、HLA-G、ANXA1水平，并计算PGR，试剂盒均购自北京利德曼生化股份有限公司。血清HP-IgG抗体进行定性测试，检测仪器：Varioskan LUX全自动酶标仪(美国Thermo Fisher Scientific 公司)。HP-IgG抗体试剂盒购自上海惠泰医疗科技公司，严格按照说明书进行操作。1.3观察指标(1)比较三组受检者的 G-17、PGR、HLA-G、ANXA1、HP-IgG抗体阳性率；(2)比较胃癌组HP-IgG抗体阳性和阴性者的G-17、PGR、HLA-G、ANXA1；(3)比较癌前病变组HP-IgG抗体阳性和阴性者的G-17、PGR、HLA-G、ANXA1；(4)分析血清G-17、PGR、HLA-G、ANXA1 联合 HP-IgG 抗体检测对胃癌和癌前病变的鉴别诊断效能。1.4统计学方法应用SPSS20.0统计软件分析数据。计数资料比较采用2检验，计量资料以均数标准差(x-s)表示，组间比较采用t检验，多组间比较采用than(67.649.88)ng/mL,(68.358.84)U/mL,(4.851.02)g/L,and 75.71%of the precancerous lesions group and(54.328.74)ng/mL,(41.346.76)U/mL,(1.580.70)g/L,and 46.00%of the healthy control group;the above indica-tors in the precancerous lesions group were significantly higher than those in the healthy control group;the differenceswere statistically significant(P0.05).The PGR of patients in the HP-IgG antibody positive group of gastric cancer was1.230.55,significantly lower than 3.151.38 of the HP-IgG antibody negative group of gastric cancer;the levels ofG-17,HLA-G,and ANXA1 were(81.9611.34)ng/mL,(91.7110.16)U/mL,(7.131.74)g/L,significantly higher than(74.039.92)ng/mL,(84.359.46)U/mL,(5.351.44)g/L of the HP-IgG antibody negative group of gastric cancer;thedifferences were statistically significant(P0.05).The PGR in the HP-IgG antibody positive group of precancerous le-sions was 4.541.83,significantly lower than 6.512.50 in the HP-IgG negative positive group of precancerous lesions;the levels of G-17,HLA-G,and ANXA1 were(69.259.35)ng/mL,(69.838.18)U/mL,(5.151.54)g/L,significantlyhigher than(62.659.42)ng/mL,(63.758.16)U/mL,(3.901.20)g/L in HP-IgG antibody negative group of precancer-ous lesions;the differences were statistically significant(P0.05).The area under ROC curve(AUC)of serum G-17,PGR,HLA-G,ANXA1,and HP-IgG antibody alone and in combination for the differential diagnosis of gastric cancerand precancerous lesions were 0.716,0.717,0.733,0.735,0.709,0.882,respectively.ConclusionThe detection of se-rum G-17,PGR,HLA-G,ANXA1 combined with HP-IgG antibody has good clinical application value in the differen-tial diagnosis of gastric cancer and precancerous lesions.【Key words】Gastric cancer;Precancerous lesions;Annexin A1;Human leukocyte antigen-G;Gastrin-17;Pep-sinogen/pepsinogen;Differential diagnosis表1三组受检者的性别和年龄比较例(%)，x-sTable 1Comparison of gender and age among the three groups ofsubjects n(%),x-s组别健康对照组癌前病变组胃癌组2/F值P值例数507080女性20(40.00)29(41.43)32(40.00)男性30(60.00)41(58.57)48(60.00)年龄(岁)63.639.7562.778.6962.649.430.0980.907性别0.0390.9812199海南医学2023年8月第34卷第15期Hainan Med J,Aug.2023,Vol.34,No.15单因素方差分析，采用受试者工作特征曲线(ROC)分析血清G-17、PGR、HLA-G、ANXA1联合HP-IgG抗体检测对胃癌和癌前病变的鉴别诊断价值。以P0.05为差异具有统计学意义。2结果2.1三组受检者的血清指标比较胃癌组、癌前病变组患者的PGR明显低于健康对照组，且胃癌组明显低于癌前病变组，差异均有统计学意义(P0.05)；胃癌组、癌前病变组患者的G-17、HLA-G、ANXA1水平及HP-IgG抗体阳性率明显高于健康对照组，且胃癌组明显高于癌前病变组，差异均有统计学意义(P0.05)，见表2。2.2胃癌组HP-IgG抗体阳性和阴性者的血清指标比较根据胃癌组患者HP-IgG抗体是否阳性分为胃癌HP-IgG抗体阳性组71例和胃癌HP-IgG抗体阴性组9例。胃癌HP-IgG抗体阳性组PGR明显低于胃癌HP-IgG抗体阴性组，G-17、HLA-G、ANXA1水平明显高于胃癌HP-IgG抗体阴性组，差异均有统计学意义(P0.05)，见表3。2.3癌前病变组HP-IgG抗体阳性和阴性者的血清指标比较根据癌前病变组患者HP-IgG抗体是否阳性分为癌前病变HP-IgG抗体阳性组53例和HP-IgG抗体阴性组17例。癌前病变HP-IgG抗体阳性组患者的PGR明显低于癌前病变HP-IgG抗体阴性组，G-17、HLA-G、ANXA1水平明显高于癌前病变HP-IgG抗体阴性组，差异均有统计学意义(P0.05)，见表4。2.4血清G-17、PGR、HLA-G、ANXA1联合HP-IgG抗体检测对胃癌和癌前病变的鉴别诊断效能(1)构建5个因子回归风险模型：纳入表3、表4中差异有显著意义的指标，建立Logistic回归风险模型(逐步后退法，退=0.10，进=0.05)，见表5。由其知，血清G-17、PGR、HLA-G、ANXA1及HP-IgG抗体均和胃癌的发生有密切关联。遂构建其联合应用的回归诊断评估模型，即以Ln(P/1-P)=0.054G-17-0.360PGR+0.071HLA-G+0.269ANXA1+0.318HP-IgG抗体作为5个指标联合表2三组受检者的血清指标比较x-s，例(%)Table 2Comparison of serum indicators among the three groups of subjects x-s,n(%)组别健康对照组癌前病变组胃癌组F/2值P值例数507080G-17(ng/mL)54.328.7467.649.88a81.0710.70ab113.3500.001PGR12.362.025.021.88a1.450.74ab744.2490.001HLA-G(U/mL)41.346.7668.358.84a90.889.13ab527.0180.001ANXA1(g/L)1.580.704.851.02a6.931.64ab281.4050.001HP-IgG抗体阳性率23(46.00)53(75.71)a71(88.75)ab33.6060.001注：与健康对照组比较：aP0.05；与癌前病变组比较：bP0.05。Note:Compared with that in the healthy control group:aP0.05;Compared with that in precancerous lesions group:bP0.05.表3胃癌组HP-IgG抗体阳性和阴性者的血清指标比较(x-s)Table 3Comparison of serum indicators between HP-IgG antibody positive and negative individuals in gastric cancer group(x-s)组别胃癌HP-IgG抗体阳性组胃癌HP-IgG抗体阴性组t值P值例数719G-17(ng/mL)81.9611.3474.039.922.0010.049PGR1.230.553.151.384.1330.003HLA-G(U/mL)91.7110.1684.359.462.0610.043ANXA1(g/L)7.131.745.351.442.9390.004表4癌前病变组HP-IgG抗体阳性和阴性者的血清指标比较(x-s)Table 4Comparison of serum indicators between HP-IgG antibody positive and negative individuals in the precancerous lesions group(x-s)组别癌前病变HP-IgG抗体阳性组癌前病变HP-IgG抗体阴性组t值P值例数5317G-17(ng/mL)69.259.3562.659.422.5280.014PGR4.541.836.512.503.5200.001HLA-G(U/mL)69.838.1863.758.162.6680.010ANXA1(g/L)5.151.543.901.203.0570.003表5血清G-17、PGR、HLA-G、ANXA1联合HP-IgG抗体检测对胃癌和癌前病变鉴别诊断的风险评估模型Table 5Risk assessment model of serum G-17,PGR,HLA-G,ANXA1 combined with HP-IgG antibody detection for differential diagnosis ofgastric cancer and precancerous lesions指标/因素G-17PGRHLA-GANXA1HP-IgG抗体0.054-0.3600.0710.2690.318Se0.0180.1000.0170.0960.120Wald 2值9.24812.89318.4487.8526.9780.95CI1.0191.0930.5730.8491.0391.1091.0841.5801.0861.740赋值连续数值原型输入连续数值原型输入连续数值原型输入连续数值原型输入阳性=1，阴性=0P值0.0020.0000.0000.0050.008OR1.0550.6981.0741.3091.3752200Hainan Med J,Aug.2023,Vol.34,No.15海南医学2023年8月第34卷第15期指标G-17PGRHLA-GANXA1HP-IgG抗体联合应用AUC(0.95CI)0.716(0.4820.926)0.717(0.4570.975)0.733(0.5580.912)0.735(0.5150.950)0.709(0.4830.937)0.882(0.7870.982)阈值753805.5110.448灵敏度(n/N)0.725(58/80)0.700(56/80)0.750(60/80)0.713(57/80)0.725(58/80)0.875(70/80)特异度(n/N)0.657(46/70)0.729(51/70)0.729(51/70)0.743(52/70)0.686(48/70)0.900(63/70)约登指数0.3820.4290.4790.4560.4110.775准确度(n/N)0.693(104/150)0.713(107/150)0.740(111/150)0.727(109/150)0.707(106/150)0.887(133/150)表6血清G-17、PGR、HLA-G、ANXA1联合HP-IgG抗体检测对胃癌和癌前病变的鉴别诊断效能Table 6Differential diagnostic efficacy of serum G-17,PGR,HLA-G,ANXA1 combined with HP-IgG antibody detection for gastric cancerand precancerous lesions注：联合应用的阈值系根据Ln(P/1-P)模型(无常数项)计算所得。Note:The threshold for joint applications is calculated based on the Ln(P/1-P)model(with no constant terms).3讨论正常黏膜-慢性浅表性胃炎-慢性萎缩性胃炎-肠上皮化生-不典型增生-癌变是目前公认的胃癌的一般演变过程，此过程称之为癌前病变1。超声、内窥镜、影像学检查、血清检查、病理组织活检是目前临床常用的胃癌诊断方法，但X线、电子计算机断层扫描(CT)等影像学检测具有辐射性，内窥镜以及病理组织活检对机体创伤较大，临床应用均具有一定的局限性。血清学指标具有方便、快捷等优势，已成为癌症临床诊断的研究趋势。胃癌前病变主要伴存于慢性萎缩性胃炎中，研究发现，慢性萎缩性胃炎患者确诊后5年内胃癌的年发病率为0.1%9。另外，研究表明，约80%的中至重度慢性萎缩性胃炎患者HP-IgG抗体检测呈阳性10。本研究中结果显示在出现胃癌前病变时，大部分患者均已发生HP感染，易诱发胃细胞发生癌变。推测HP感染可通过促进胃黏膜细胞增生活跃增加脱氧核糖核酸(DNA)突变风险；另外，HP的代谢产物脂酶和氨具有破坏胃黏膜保护屏障的作用，进一步诱发胃细胞发生癌变11。PG包括PG-和PG-两个亚群，当PGR异常时，提示可能发生胃黏膜损伤、胃部病变12。本研究结果发现，癌前病变组PGR水平明显低于健康对照组，且胃癌组低于癌前病变组。提示PG的水平变化与胃癌疾病的发生发展密切相关。本研究结果还发现，随着胃癌病程的进展，HP感染阳性可影响PG-和PG-表达，从而降低PGR水平。推测在此进程中胃黏膜细胞被大量损伤，腺体与主细胞数量减少，引起胃底的黏液颈细胞以及主细胞分泌PG-的能力下降，而PG-还可由近端十二指肠Brunner腺以及胃窦幽门腺分泌，故总体表现为PGR明显降低13。另有研究发现，HP感染可通过增加主细胞内钙离子流、磷酸肌醇以及环磷腺苷浓度刺激PG-分泌，并引起胃蛋白酶基因发生突变降低胃黏膜分泌PG-，导致PGR水平下降逐渐显著14。G-17是一种多肽胃肠激素，研究发现，G-17水平变化与机体免疫反应、炎症反应、胃癌细胞侵袭及转移等病理过程密切相关15。本研究中，癌前病变组G-17水平明显高于健康对照组，胃癌组G-17水平明显高于健康对照组和癌前病变组。提示G-17的水平变化与胃癌疾病的发生发展密切相关。本研究还发现，随着胃癌病程的进展，患者在HP感染阳性情况下，G-17水平显著升高。分析胃黏膜癌前病变和癌变可引起胃窦黏膜萎缩，两者相互促进胃酸的分泌量下降，导致G-17的分泌量增加、水平逐渐上升16。HLA-G是一种非经典的主要组织相容性抗原，具有维持正常机体生长、发育中的免疫耐受和稳态作用17。本研究中，HLA-G的水平变化与胃癌疾病的发生发展密切相关。研究发现，HLA-G在肿瘤的免疫逃逸过程中起着重要的作用，能有效帮助肿瘤细胞逃避宿主的免疫反应，促进胃癌的发生发展18。图1血清G-17、PGR、HLA-G、ANXA1联合HP-IgG抗体检测对胃癌和癌前病变鉴别诊断效能的ROCFigure 1ROC of the differential diagnostic efficacy of serum G-17,PGR,HLA-G,ANXA1 combined with HP-IgG antibodydetection for gastric cancer and precancerous lesions应用的虚拟指标，进行后续的 ROC 分析。(2)血清G-17、PGR、HLA-G、ANXA1、HP-IgG 抗体检测及联合模型的鉴别诊断效能：经ROC分析结果显示，血清G-17、PGR、HLA-G、ANXA1、HP-IgG 抗体等 5 个指标单独及联合应用时，ROC-AUC(0.95CI)分别为0.716(0.4820.926)、0.717(0.4570.975)、0.733(0.5580.912)、0.735(0.5150.950)、0.709(0.4830.937)、0.882(0.7870.982)，其中联合应用诊断效能明显更高，AUC及灵敏度、特异度、准确度均较各单独应用指标有较大的提升，见表6和图1。2201海南医学2023年8月第34卷第15期Hainan Med J,Aug.2023,Vol.34,No.15ANXA1是钙离子依赖的磷脂结合蛋白家族中的一员，参与机体炎症和免疫反应、细胞的分化、增殖和凋亡、细胞内外信号转导等多种生理过程19。研究发现，ANXA1与肿瘤发生、发展以及侵袭转移等密切相关15。本研究中，癌前病变组与胃癌组ANXA1水平分别高于健康对照组与癌前病变组。胃癌HP-IgG抗体阳性组ANXA1水平明显高于胃癌HP-IgG抗体阴性组，癌前病变HP-IgG抗体阳性组ANXA1水平明显高于癌前病变HP-IgG抗体阴性组。提示ANXA1的水平变化与胃癌疾病的发生发展密切相关。ANXA1可与促炎症蛋白如膜受体蛋白(FPR)、S100钙结合蛋白A11(S100A11)、细胞质磷脂酶A2(cPLA2)相互作用，可活化以上炎症因子调节肿瘤的浸润和转移，促进胃癌的发生发展20。同时，本研究结果还发现血清G-17、PGR、HLA-G、ANXA1、HP-IgG抗体单独及联合检测对胃癌和癌前病变鉴别诊断的 AUC 值分别为 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