Dataset Information

Global analysis of DNA methylation in hepatocellular carcinoma by a liquid hybridization capture-based bisulfite sequencing approach.

ABSTRACT: Epigenetic alterations, such as aberrant DNA methylation of promoter and enhancer regions, which lead to atypical gene expression, have been associated with carcinogenesis. In hepatocellular carcinoma (HCC), genome-wide analysis of methylation has only recently been used. For a better understanding of hepatocarcinogenesis, we applied an even higher resolution analysis of the promoter methylome to identify previously unknown regions and genes differentially methylated in HCC.Optimized liquid hybridization capture-based bisulfite sequencing (LHC-BS) was developed to quantitatively analyze 1.86 million CpG sites in individual samples from eight pairs of HCC and adjacent tissues. By linking the differentially methylated regions (DMRs) in promoters to the differentially expressed genes (DEGs), we identified 12 DMR-associated genes. We further utilized Illumina MiSeq combining the bisulfite sequencing PCR approach to validate the 12 candidate genes. Analysis of an additional 78 HCC pairs on the Illumina MiSeq platform confirmed that 7 genes showed either promoter hyper-methylation (SMAD6, IFITM1, LRRC4, CHST4, and TBX15) or hypo-methylation (CCL20 and NQO1) in HCC.Novel methylome profiling provides a cost-efficient approach to identifying candidate genes in human HCC that may contribute to hepatocarcinogenesis. Our work provides further information critical for understanding the epigenetic processes underlying tumorigenesis and development of HCC.

SUBMITTER: Gao F

PROVIDER: S-EPMC4546208 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Global analysis of DNA methylation in hepatocellular carcinoma by a liquid hybridization capture-based bisulfite sequencing approach.

Gao Fei F Liang Huifang H Lu Hanlin H Wang Junwen J Xia Meng M Yuan Zhimei Z Yao Yu Y Wang Tong T Tan Xiaolong X Laurence Arian A Xu Hua H Yu Jingjing J Xiao Wei W Chen Wei W Zhou Ming M Zhang Xiuqing X Chen Qian Q Chen Xiaoping X

Clinical epigenetics 20150821

<h4>Background</h4>Epigenetic alterations, such as aberrant DNA methylation of promoter and enhancer regions, which lead to atypical gene expression, have been associated with carcinogenesis. In hepatocellular carcinoma (HCC), genome-wide analysis of methylation has only recently been used. For a better understanding of hepatocarcinogenesis, we applied an even higher resolution analysis of the promoter methylome to identify previously unknown regions and genes differentially methylated in HCC.<h ...[more]

PMID: 26300991

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Project description:Background Aberrant methylation of CpG sites served as an epigenetic marker for building diagnostic, prognostic, and recurrence models for hepatocellular carcinoma (HCC). Methods Using Illumina 450K and EPIC Beadchip, we identified 34 CpG sites in peripheral blood mononuclear cell (PBMC) DNA that were differentially methylated in early HCC versus HBV-related liver diseases (HBVLD). We employed multiplex bisulfite sequencing (MBS) based on next-generation sequencing (NGS) to measure methylation of 34 CpG sites in PBMC DNA from 654 patients that were divided into a training set (n = 442) and a test set (n = 212). Using the training set, we selected and built a six-CpG-scorer (namely, cg14171514, cg07721852, cg05166871, cg18087306, cg05213896, and cg18772205), applying least absolute shrinkage and selection operator (LASSO) regression. We performed multivariable analyses of four candidate risk predictors (namely, six-CpG-scorer, age, sex, and AFP level), using 20 times imputation of missing data, non-linearly transformed, and backwards feature selection with logistic regression. The final model’s regression coefficients were calculated according to “Rubin’s Rules”. The diagnostic accuracy of the model was internally validated with a 10,000 bootstrap validation dataset and then applied to the test set for validation. Results The area under the receiver operating characteristic curve (AUROC) of the model was 0.81 (95% CI, 0.77–0.85) and it showed good calibration and decision curve analysis. Using enhanced bootstrap validation, adjusted C-statistics and adjusted Brier score were 0.809 and 0.199, respectively. The model also showed an AUROC value of 0.84 (95% CI 0.79–0.88) of diagnosis for early HCC in the test set. Conclusions Our model based on the six-CpG-scorer was a reliable diagnosis tool for early HCC from HBVLD. The usage of the MBS method can realize large-scale detection of CpG sites in clinical diagnosis of early HCC and benefit the majority of patients.

Dataset Information

Global analysis of DNA methylation in hepatocellular carcinoma by a liquid hybridization capture-based bisulfite sequencing approach.

Publications

Global analysis of DNA methylation in hepatocellular carcinoma by a liquid hybridization capture-based bisulfite sequencing approach.

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