Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study
Serum DKK1 as a protein biomarker for the diagnosis of hepatocellular carcinoma: a large-scale, multicentre study
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血清 DKK1 作为诊断肝细胞癌的蛋白质生物标志物：一项大规模、多中心研究。
DOI：
10.1016/s1470-2045(12)70233-4
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发表时间：
2012-08-01
期刊：
影响因子：
51.1
通讯作者：
Qin, Wenxin
中科院分区：
文献类型：
--
作者：
Shen, Qiujin;Fan, Jia;Qin, Wenxin
背景肝细胞癌在世界范围内普遍存在，需要提高及时有效的诊断水平。我们评估了血清中Dickkopf-1(Dkk1)的测定是否可以提高对肝癌的诊断准确性。方法我们分析了2008年12月至2009年7月从两个中国中心收集的肝细胞癌患者、慢性乙肝病毒感染患者、肝硬变患者和健康对照的数据。2010年7月至2011年6月，从中国的另一个中心招募了年龄和性别匹配的验证队列。Dkk1是由无法获得患者临床信息的独立研究人员通过酶联免疫吸附试验检测血清中的Dkk1。我们使用受试者操作特征(ROC)来计算诊断的准确性。结果我们评估了831名参与者的血清Dkk1：424名肝细胞癌患者，98名慢性乙肝患者，96名肝硬变患者和213名健康对照。验证队列包括453名参与者：209名肝细胞癌患者、73名慢性乙肝感染患者、72名肝硬变患者和99名健康对照。肝细胞癌患者血清Dkk1水平明显高于正常对照组。ROC曲线显示最佳诊断界值为2.153 ng/mL(曲线下面积[AuC]0.848[95%CI 0.820~0.875]，敏感性69.1%，特异性90.6%；验证队列0.862[0.825~0.899]，71.3%，87.2%)。早期肝癌也有类似的结果(测试队列中0.865[0.835-0.895]，70.9%和90.5%；验证队列中0.896[0.846-0.947]，73.8%和87.2%)。此外，对于甲胎蛋白阴性的肝癌患者，DKK1保持了诊断的准确性(测试队列中0.841[0.801-0.882]，70.4%和90.0%；验证队列中0.869[0.815-0.923]，66.7%和87.2%)，包括早期肝癌患者(0.870[0.829-0.911]，73.1%和90.0%；0.893[0.804-0.983]，验证队列中的72.2%和87.2%)，与所有对照相比。血清中DKK1浓度升高可区分肝细胞癌与慢性乙肝病毒感染和肝硬变(0.834[0.798-0.871]，69.1%，84.7%；0.873[0.832-0.913]，71.3%，90.6%)。此外，联合检测Dkk1和甲胎蛋白可提高肝癌的诊断准确率(分别为0.889[0.866-0.913]，73.3%，93.4%；0.888[0.856-0.920]，78.5%，87.2%)。解释Dkk1可以补充甲胎蛋白检测在肝癌诊断中的作用，提高对甲胎蛋白阴性肝癌患者的辨别能力，并将肝癌与非恶性慢性肝病区分开来。
Background Hepatocellular carcinoma (HCC) is prevalent worldwide and improvements in timely and effective diagnosis are needed. We assessed whether measurement of Dickkopf-1 (DKK1) in serum could improve diagnostic accuracy for HCC.Methods We analysed data for patients with HCC, chronic hepatitis B virus (HBV) infection, liver cirrhosis, and healthy controls, recruited from two Chinese centres between December, 2008, and July, 2009. A validation cohort matched for age and sex was recruited from another centre in China between July, 2010, and June, 2011. DKK1 was measured in serum by ELISA by independent researchers who had no access to patients' clinical information. We used receiver operating characteristics (ROC) to calculate diagnostic accuracy.Findings We assessed serum DKK1 in 831 participants: 424 with HCC, 98 with chronic HBV infection, 96 with cirrhosis, and 213 healthy controls. The validation cohort comprised 453 participants: 209 with HCC, 73 with chronic HBV infection, 72 with cirrhosis, and 99 healthy controls. Levels of DKK1 in serum were significantly higher in patients with HCC than in all controls. ROC curves showed the optimum diagnostic cutoff was 2.153 ng/mL (area under curve [AUC] 0.848 [95% CI 0.820-0.875], sensitivity 69.1%, and specificity 90.6% in the test cohort; 0.862 [0.825-0.899], 71.3%, and 87.2% in the validation cohort). Similar results were noted for early-stage HCC (0.865 [0.835-0.895], 70.9%, and 90.5% in the test cohort; 0.896 [0.846-0.947], 73.8%, and 87.2% in the validation cohort). Furthermore, DKK1 maintained diagnostic accuracy for patients with HCC who were a-fetoprotein (AFP) negative (0.841 [0.801-0.882], 70.4%, and 90.0% in the test cohort; 0.869 [0.815-0.923], 66.7%, and 87.2% in the validation cohort), including for patients with early-stage HCC (0.870 [0.829-0.911], 73.1%, and 90.0% in the test cohort; 0.893 [0.804-0.983], 72.2%, and 87.2% in the validation cohort), compared with all controls. Raised concentrations of DKK1 in serum could differentiate HCC from chronic HBV infection and cirrhosis (0.834 [0.798-0.871], 69.1%, and 84.7% in the test cohort; 0.873 [0.832-0.913], 71.3%, and 90.6% in the validation cohort). Moreover, measurement of DKK1 and AFP together improved diagnostic accuracy for HCC versus all controls compared with either test alone (0.889 [0.866-0.913], 73.3%, and 93.4% in the test cohort; 0.888 [0.856-0.920], 78.5%, and 87.2% in the validation cohort).Interpretation DKK1 could complement measurement of AFP in the diagnosis of HCC and improve identification of patients with AFP-negative HCC and distinguish HCC from non-malignant chronic liver diseases.