血浆HOXA7基因甲基化在非小细胞肺癌诊断中的应用

Detection of plasma HOXA7 methylation in the diagnosis of non-small cell lung cancer

目的:检测非小细胞肺癌(non-small cell lungcancer,NSCLC)血浆中同源盒基因(homeobox,HOX)家族成员HOXA7基因启动子甲基化水平,并评估HOXA7甲基化与肿瘤标志物血清癌胚抗原(carcinoembryonic antigen,CEA)、糖类抗原(carbohydrate antigen199,CA199)和细胞角蛋白19片段抗原21-1(cytokeratin 19 fragment antigen 21-1,Cyfra21-1)水平辅助诊断NSCLC的价值。方法:选取河南省肿瘤医院2012年1月至2016年12月住院的经病理组织学确诊为NSCLC患者80例为试验组,50例健康人为对照组。采用定量甲基化特异性PCR(quantitativemethylation-specificPCR,q MSP)检测血浆HOXA7甲基化水平,电化学发光检测血浆CEA、CA199和Cyfra21-1水平。构建受试者工作特征曲线(ROC)分析各指标鉴别NSCLC的临床价值,并分析HOXA7甲基化与临床病例参数、肿瘤标志物之间的关系。结果:与健康对照组相比,NSCLC患者血浆中HOXA7基因甲基化水平异常增高(χ^2=36.972,P<0.0001),HOXA7甲基化诊断NSCLC的敏感度为68.8%(55/80),特异度为86.0%(43/50)。血浆HOXA7甲基化与性别、年龄、有无吸烟史和病理类型无关(均P>0.05),但与TNM分期有关(P<0.05),其中Ⅳ期患者血浆HOXA7甲基化水平最高。肿瘤标志物中Cyfra21-1诊断NSCLC的价值最高,敏感度为70.00%,特异度为90.00%。HOXA7甲基化联合三指标诊断NSCLC的效能最高(AUC=0.893,敏感度73.75%,特异度94%)。HOXA7甲基化与Cyfra21-1的相关系数最高(r=0.564,P<0.05)。结论:HOXA7基因甲基化水平对NSCLC的诊断有一定价值,与NSCLC的恶性程度相关,联合肿瘤标志物检测可以提高NSCLC的诊断效能。

Objective: To detect the methylation levels of homeobox protein Hox A7(HOXA7) gene promoter in the plasma of non-small cell lung cancer(NSCLC) and to study the value of HOXA7 methylation and serum levels of the tumor markers carcinoembryonic antigen(CEA), carbohydrate antigen 199(CA199), and cytokeratin 19 fragment(Cyfra21-1) in the auxiliary diagnosis of NSCLC. Methods: Plasma samples were collected from 80 patients with NSCLC and 50 healthy controls, which were enrolled in Henan Cancer Hospital from January2012 to December 2016. The plasma HOXA7 methylation levels were detected by real-time quantitative methylation-specific PCR, and the plasma levels of CEA, CA199, and Cyfra21-1 were detected by electrochemical luminescence. The ROC curve was constructed to analyze the clinical value of each index in the differential diagnosis of NSCLC, and the relationship between HOXA7 methylation, clinical parameters,and tumor markers was analyzed. Results: The serum levels of HOXA7 methylation in NSCLC patients were significantly higher(χ^2=36.972,P<0.000 1) than the healthy control group. The sensitivity and specificity of HOXA7 methylation in the diagnosis of NSCLC were 68.8%(55/80) and 86.0%(43/50), respectively. Plasma HOXA7 methylation was not related to gender, age, smoking history, or pathological type(all P>0.05), but was related to TNM stage(P<0.05). The plasma HOXA7 methylation level of stage Ⅳpatients(81.8%, 18/22) was the highest.Cyfra21-1 had the highest value in the diagnosis of NSCLC among tumor markers with a sensitivity of 70.00% and a specificity of 90.00%.The combination of HOXA7 methylation with all three tumor markers had the highest efficiency(AUC=0.893, sensitivity 73.75%, specificity94%) in the diagnosis of NSCLC. The correlation coefficient between HOXA7 methylation and Cyfra21-1 was the highest(r=0.564, P<0.05).Conclusions: HOXA7 gene methylation is related to the degree of metastasis of NSCLC and proves as an efficient diagnostic marker for NSCLC when combined with tumor marker detection.