Abstract: Objective　To evaluate the value of SHOX2 gene methylation level for differential diagnosis in patients with lung cancer and benign lung diseases.Methods　Patients with lung cancer and benign lung diseases hospitalized in the Department of Thoracic Surgery and Department of Eespiration of the Central Hospital of Wuhan from March 2014 to June 2016 were enrolled.Among them，173 patients with lung cancer were defined as lung cancer group，and 194 patients with benign lung diseases as benign lung disease group.Routine serological examination and tumor markers were detected in all patients.The SHOX2 gene methylation was detected by Sanger sequencing，and the SHOX2 gene methylation level was calculated by △△CT method.The value of each index in differential diagnosis of lung cancer was analyzed by receiver operating characteristic（ROC） curve.The relationship between each index and lung cancer pathological type and TNM staging was analyzed.Results　The white blood cell count（WBC） and △△CT value of lung cancer group were lower than those of benign lung disease group，while the serum gastrin releasing peptide precursor（ProGRP），squamous cell carcinoma antigen（SCC-Ag），cytokeratin 21 fragment antigen（Cyfra21-1） and carcinoembryonic antigen（CEA） were higher than those in benign lung disease group（P<0.05）. The result of multivariate Logistic regression analysis showed that serum ProGRP，serum Cyfra21-1，and △△CT values were factors influencing lung cancer（P<0.05）. The area under ROC curve（AUC） of △△CT value for the diagnosis of lung cancer was 0.843.The sensitivity was 58.2%，and the specificity was 93.1% when the optimal threshold was 2.69.The AUC of serum ProGRP was 0.711，with optimal threshold of 32 ng/L，sensitivity of 63.5% and specificity of 77.4%.The AUC of serum Cyfra21-1 was 0.677，the best cut-off value 2.92 μg/L，sensitivity 56.1%，and specificity 72.3%.The AUC of serum ProGRP for the diagnosis of lung cancer was greater than that of serum Cyfra21-1（Z=3.569，P=0.038）. The AUC of the △△CT value combined with serum ProGRP was 0.860.The AUC of △△CT value combined with serum ProGRP in the diagnosis of lung cancer were greater than that of △△CT value，serum ProGRP，and serum Cyfra21-1（Z=4.046，Z=5.607，Z=8.215，P<0.05）. The △△CT value of patients with squamous cell carcinoma，small cell carcinoma was lower than that of patients with adenocarcinoma，large cell carcinoma and other unknown pathological types（P<0.05）. The △△CT value of patients in stage Ⅲ lung cancer was lower than that of those in stage Ⅰ and stage Ⅱ（P<0.05），and the △△CT value of patients in stage Ⅳ lung cancer was lower than that of those in stage Ⅰ，stage Ⅱ and stage Ⅲ（P<0.05）. Conclusion　SHOX2 gene methylation has its value in the differentiation of lung cancer and benign lung disease.It is correlated with lung cancer pathological type and TNM staging，which can be used as an auxiliary index for diagnosis of lung cancer.

Key words: Lung neoplasms, Lung diseases, Methylation, SHOX2 gene, Serum tumor marker, Diagnosis, Sensitivity, Specificity

摘要： 目的　探究SHOX2基因甲基化水平在肺癌和良性肺部疾病患者中的鉴别诊断价值。方法　选取2014年3月—2016年6月武汉市中心医院胸外科、呼吸科住院的肺癌患者和良性肺部疾病患者，其中肺癌患者173例作为肺癌组，良性肺部疾病患者194例作为良性肺病组，进行常规血清学检查，并检测肿瘤标志物，采用Sanger测序法检测SHOX2基因甲基化，采用??CT法计算SHOX2基因甲基化水平。采用受试者工作特征（ROC）曲线分析各指标鉴别肺癌的临床价值，并分析??CT值与肺癌病理类型、TNM分期的关系。结果　肺癌组患者白细胞计数（WBC）、^△△CT值均低于良性肺病组，血清胃泌素释放肽前体（ProGRP）、鳞状上皮细胞癌抗原（SCC-Ag）、细胞角蛋白21片段抗原（Cyfra21-1）、癌胚抗原（CEA）均高于良性肺病组（P<0.05）。多因素Logistic回归结果显示，血清ProGRP、血清Cyfra21-1、^△△CT值是肺癌的影响因素（P<0.05）。^△△CT值诊断肺癌的ROC曲线下面积（AUC）为0.843，最佳临界值为2.69时，灵敏度为58.2%，特异度为93.1%；血清ProGRP诊断肺癌的AUC为0.711，最佳临界值为32 ng/L时，灵敏度为63.5%，特异度为77.4%；血清Cyfra21-1诊断肺癌的AUC为0.677，最佳临界值为2.92 μg/L时，灵敏度为56.1%，特异度为72.3%。血清ProGRP诊断肺癌的AUC大于血清Cyfra21-1（Z=3.569，P=0.038）。??CT值联合血清ProGRP诊断肺癌的AUC为0.860，均大于^△△CT值、血清ProGRP、血清Cyfra21-1诊断肺癌的AUC（Z=4.046、5.607、8.215，P<0.05）。鳞状细胞癌、小细胞癌患者^△△CT值均低于腺癌、大细胞癌、其他未知病理类型（P<0.05）。Ⅲ期患者??CT值低于Ⅰ期、Ⅱ期（P<0.05）；Ⅳ期患者^△△CT值低于Ⅰ期、Ⅱ期、Ⅲ期（P<0.05）。结论　SHOX2基因甲基化水平对肺癌和良性肺部疾病的鉴别诊断有一定价值，且与肺癌病理类型及TNM分期存在相关性，可作为诊断肺癌的辅助指标。

关键词: 肺肿瘤, 肺疾病, 甲基化, SHOX2基因, 血清肿瘤标志物, 诊断, 灵敏度, 特异度