Quantitative analysis of multiple methylated genes in plasma for the diagnosis and prognosis of hepatocellular carcinoma |
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Authors: | Huang Zhao-Hui Hu Yu Hua Dong Wu Yu-Yu Song Ming-Xu Cheng Zhi-Hong |
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Affiliation: | aOncology Institute, The Fourth Affiliated Hospital of Suzhou University, Wuxi, 214062 China |
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Abstract: | This study was aimed to evaluate the clinical value of plasma methylation analysis of a panel of four genes (APC, GSTP1, RASSF1A, and SFRP1), which was identified by our previous work, for the noninvasive diagnosis of hepatocellular carcinoma (HCC). The methylation status of these four genes in 150 plasma samples from 72 patients with HCC, 37 benign live diseases and 41 normal controls was detected with methylation-sensitive restriction enzymes-based quantitative PCR (MSRE-qPCR) method. The plasma methylation levels of APC, GSTP1, RASSF1A, and SFRP1 were significantly higher in HCCs than those in normal or benign controls (P < 0.05). Although the area under the receiver-operation characteristic curve (AUC-ROC) for individual gene was moderate (range, from 0.800 to 0.881), the combination analysis of these four genes resulted in an increased AUC of 0.933 with 92.7% sensitivity, 81.9% specificity, 90.5% positive predictive value (PPV), and 87.2% negative predictive value (NPV) in discriminating HCC from normal control. The combination analysis also indicated an increased AUC of 0.877 when compared with individual gene (from 0.666 to 0.850) in discriminating HCC from benign control, and the consultant sensitivity, specificity, PPV, and NPV was 84.7%, 81.1%, 89.7%, and 73.2%, respectively. Patients with elevated plasma methylation levels of APC or RASSF1A showed poorer overall survival than those with low levels (P < 0.05). Cox multivariate analysis demonstrated methylated RASSF1A in plasma to be an independent prognostic factor for overall survival (hazard ratio = 3.262, 95% CI: 1.476–7.209, P = 0.003). These data showed that quantitative analysis of multiple methylated genes in plasma may be a promising tool for noninvasive diagnosis of HCC; and methylated plasma RASSF1A appears to be a prognostic marker of HCC. |
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Keywords: | Abbreviations: HCC, hepatocellular carcinoma MSRE, methylation-sensitive restriction enzymes qPCR, quantitative polymerase chain reaction AFP, α-fetoprotein TSG, tumor suppressor gene ROC, receiver operator characteristic curve AUC, area under the curve MP, methylation percentage PPV, positive predictive value NPV, negative predictive value OS, overall survival HR, hazard ratios CI, confidence intervals |
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