title: Genome-wide identification of differential methylation between primary and recurrent hepatocellular carcinomas.
abstract: 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. © 2015 Wiley Periodicals, Inc.
authors.affiliation: Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Peking University Cancer Hospital Institute, Beijing, China.
authors.forename: Chenghua
authors.initials: C
authors.lastname: Cui
authors.affiliation: Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Peking University Cancer Hospital Institute, Beijing, China.
authors.forename: Zheming
authors.initials: Z
authors.lastname: Lu
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
authors.forename: Liu
authors.initials: L
authors.lastname: Yang
authors.affiliation: Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Peking University Cancer Hospital Institute, Beijing, China.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.affiliation: Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Peking University Cancer Hospital Institute, Beijing, China.
authors.forename: Liankun
authors.initials: L
authors.lastname: Gu
authors.affiliation: Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Peking University Cancer Hospital Institute, Beijing, China.
authors.forename: Chen
authors.initials: C
authors.lastname: Yang
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, Georgia.
authors.forename: James
authors.initials: J
authors.lastname: Wilson
authors.affiliation: GRU Cancer Center, Georgia Regents University, Augusta, Georgia.
authors.forename: Zhiqian
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Department of Surgery, Peking University Cancer Hospital and Institute, Beijing, China.
authors.forename: Baocai
authors.initials: B
authors.lastname: Xing
authors.affiliation: Division of Cancer Etiology, Key Laboratory of Carcinogenesis and Translational Research Ministry of Education, Peking University Cancer Hospital Institute, Beijing, China.
authors.forename: Dajun
authors.initials: D
authors.lastname: Deng
authors.affiliation: Beijing Institutes of Life Science, Chinese Academy of Sciences, Beijing, China.
authors.forename: Zhong Sheng
authors.initials: ZS
authors.lastname: Sun
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000235:genetics*; D018797:Cell Cycle Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D055106:Genome-Wide Association Study; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics*; D020084:Long Interspersed Nucleotide Elements; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016019:Survival Analysis
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C501384:MAD1L1 protein, human; D009687:Nuclear Proteins; D062085:RNA, Long Noncoding
keywords: DNA methylation; LINC00682; LINE-2; MAD1L1; followup recurrence; hepatocellular carcinoma