title: Genome-wide methylation profiling of the different stages of hepatitis B virus-related hepatocellular carcinoma development in plasma cell-free DNA reveals potential biomarkers for early detection and high-risk monitoring of hepatocellular carcinoma.
abstract: BACKGROUND
  An important model of hepatocellular carcinoma (HCC) that has been described in southeast Asia includes the transition from chronic hepatitis B infection (CHB) to liver cirrhosis (LC) and, finally, to HCC. The genome-wide methylation profiling of plasma cell-free DNA (cfDNA) has not previously been used to assess HCC development. Using MethylCap-seq, we analyzed the genome-wide cfDNA methylation profiles by separately pooling healthy control (HC), CHB, LC and HCC samples and independently validating the library data for the tissue DNA and cfDNA by MSP, qMSP and Multiplex-BSP-seq.
  
  
  RESULTS
  The dynamic features of cfDNA methylation coincided with the natural course of HCC development. Data mining revealed the presence of 240, 272 and 286 differentially methylated genes (DMGs) corresponding to the early, middle and late stages of HCC progression, respectively. The validation of the DNA and cfDNA results in independent tissues identified three DMGs, including ZNF300, SLC22A20 and SHISA7, with the potential for distinguishing between CHB and LC as well as between LC and HCC. The area under the curve (AUC) ranged from 0.65 to 0.80, and the odds ratio (OR) values ranged from 5.18 to 14.2.
  
  
  CONCLUSIONS
  Our data revealed highly dynamic cfDNA methylation profiles in support of HBV-related HCC development. We have identified a panel of DMGs that are predictive for the early, middle and late stages of HCC development, and these are potential markers for the early detection of HCC as well as the screening of high-risk populations.
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Yangxing
authors: Y
authors: Zhao
authors: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.
authors: Feng
authors: F
authors: Xue
authors: Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, 200032 China.
authors: Jinfeng
authors: J
authors: Sun
authors: Ministry of Education Key Laboratory of Contemporary Anthropology School of Life Sciences, Fudan University, 220 Handan Road, Shanghai, 200433 China.
authors: Shicheng
authors: S
authors: Guo
authors: Shanghai Cancer Institute,Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Hongyu
authors: H
authors: Zhang
authors: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.
authors: Bijun
authors: B
authors: Qiu
authors: Department of General Thoracic Surgery, Shanghai Chest Hospital, Shanghai Jiao Tong University, 241 West Huaihai Road, Shanghai, 200030 China.
authors: Junfeng
authors: J
authors: Geng
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Jun
authors: J
authors: Gu
authors: Key Laboratory of Contraceptive Drugs and Devices of NPFPC, Shanghai Institute of Planned Parenthood Research, 2140 Xietu Road, Shanghai, 200032 China.
authors: Xiaoyu
authors: X
authors: Zhou
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Wei
authors: W
authors: Wang
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Zhenfeng
authors: Z
authors: Zhang
authors: Shanghai Cancer Institute,Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Ning
authors: N
authors: Tang
authors: Shanghai Cancer Institute,Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Yinghua
authors: Y
authors: He
authors: State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, LN 2200/25,Xietu Road, Shanghai, 200032 China.
authors: Jian
authors: J
authors: Yu
authors: Department of Liver Surgery, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai, 200127 China.
authors: Qiang
authors: Q
authors: Xia
keywords: Cell-free DNA; DNA methylation; Genome-wide; HBV; HCC development; Plasma