Genome-wide identification of differential methylation between primary and recurrent hepatocellular carcinomas

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• 作者：Chenghua Cui ; Zheming Lu ; Liu Yang ; Yanhong Gao ; Wei Liu ; Liankun Gu ; Chen Yang ; James Wilson ; Zhiqian Zhang ; Baocai Xing ; Dajun Deng and Zhong Sheng Sun
• 刊名：Molecular Carcinogenesis
• 出版年：2016
• 出版时间：July 2016
• 年：2016
• 卷：55
• 期：7
• 页码：1163-1174
• 全文大小：2287K
• ISSN：1098-2744

文摘

A biomarker capable of clinically predicting hepatocellular carcinoma (HCC) recurrence has not previously been established. Here genome-wide differential methylation between primary and recurrent HCC cell lines (Hep-11 and Hep-12) from the same patient was characterized. The HCC samples from two independent cohorts, complete with follow-up data, were used to validate the feasibility of the selected methylation biomarkers in predicting HCC prognosis. A methylation array assay identified 30 candidate genes or intergenic-fragments with an absolute methylation fold-change >2.0 between these cell lines; 22 candidates were hypomethylated in Hep-12 cells relative to Hep-11 cells. Bisulfite sequencing confirmed these results. Most importantly, classification of tumors by LINE-2 methylation level was significantly associated with HCC recurrence in both cohorts (P < 0.02). Similarly, MAD1L1 and LINC00682 methylation levels also correlated with HCC recurrence. Survival analysis showed that a combined baseline LINE-2, MAD1L1, and LINC00682 methylation signature was significantly associated with short recurrence-free survival in patients from both cohorts. A synergic effect was observed between these markers on both recurrence-free survival (P < 0.010) and overall survival (P < 0.040). In conclusion, low levels of LINE-2, MAD1L1, and LINC00682 methylation were associated with recurrence and decreased overall survival in HCC patients.