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CpG Methylation Signature Predicts Recurrence in Early-Stage Hepatocellular Carcinoma: Results From a Multicenter Study

医学 肝细胞癌 阶段(地层学) 肿瘤科 甲基化 内科学 基因 生物 遗传学 古生物学
作者
Jiliang Qiu,Baogang Peng,Yunqiang Tang,Yeben Qian,Pi Guo,Mengfeng Li,Junhang Luo,Bin Chen,Hui Tang,Canliang Lu,Muyan Cai,Zunfu Ke,Wei He,Yun Zheng,Dan Xie,Binkui Li,Yunfei Yuan
出处
期刊:Journal of Clinical Oncology [Lippincott Williams & Wilkins]
卷期号:35 (7): 734-742 被引量:150
标识
DOI:10.1200/jco.2016.68.2153
摘要

Purpose Early-stage hepatocellular carcinoma (E-HCC) is being diagnosed increasingly, and in one half of diagnosed patients, recurrence will develop. Thus, it is urgent to identify recurrence-related markers. We investigated the effectiveness of CpG methylation in predicting recurrence for patients with E-HCCs. Patients and Methods In total, 576 patients with E-HCC from four independent centers were sorted by three phases. In the discovery phase, 66 tumor samples were analyzed using the Illumina Methylation 450k Beadchip. Two algorithms, Least Absolute Shrinkage and Selector Operation and Support Vector Machine-Recursive Feature Elimination, were used to select significant CpGs. In the training phase, penalized Cox regression was used to further narrow CpGs into 140 samples. In the validation phase, candidate CpGs were validated using an internal cohort (n = 141) and two external cohorts (n = 191 and n =104). Results After combining the 46 CpGs selected by the Least Absolute Shrinkage and Selector Operation and the Support Vector Machine-Recursive Feature Elimination algorithms, three CpGs corresponding to SCAN domain containing 3, Src homology 3-domain growth factor receptor-bound 2-like interacting protein 1, and peptidase inhibitor 3 were highlighted as candidate predictors in the training phase. On the basis of the three CpGs, a methylation signature for E-HCC (MSEH) was developed to classify patients into high- and low-risk recurrence groups in the training cohort ( P < .001). The performance of MSEH was validated in the internal cohort ( P < .001) and in the two external cohorts ( P < .001; P = .002). Furthermore, a nomogram comprising MSEH, tumor differentiation, cirrhosis, hepatitis B virus surface antigen, and antivirus therapy was generated to predict the 5-year recurrence-free survival in the training cohort, and it performed well in the three validation cohorts (concordance index: 0.725, 0.697, and 0.693, respectively). Conclusion MSEH, a three-CpG-based signature, is useful in predicting recurrence for patients with E-HCC.
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