Identification of a liver cirrhosis signature in plasma for predicting hepatocellular carcinoma risk in a population-based cohort of hepatitis B carriers

Authors

  • Chia-Chi Liu,

    1. Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Ya-Hui Wang,

    1. Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Eric Y Chuang,

    1. Graduate Institute of Biomedical Electronics and Bioinformatics, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Mong-Hsun Tsai,

    1. Institute of Biotechnology, Center for Systems Biology and Bioinformatics, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Ya-Hui Chuang,

    1. Department of Clinical Laboratory Sciences and Medical Biotechnology, College of Medicine, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Chih-Lin Lin,

    1. Department of Gastroenterology, Ren-Ai Branch, Taipei City Hospital, Taipei, Taiwan
    Search for more papers by this author
  • Chun-Jen Liu,

    1. Department of Internal Medicine, Division of Gastroenterology, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
    Search for more papers by this author
  • Bo-Yu Hsiao,

    1. Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Shi-Ming Lin,

    1. Liver Research Unit, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taipei, Taiwan
    Search for more papers by this author
  • Li-Yu Liu,

    1. Department of Agronomy, Biometry Division, National Taiwan University, Taipei, Taiwan
    Search for more papers by this author
  • Ming-Whei Yu

    Corresponding author
    1. Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan
    • Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Room 522 No.17, Xuzhou Road Zhongzheng District, Taipei 10055, Taiwan.

    Search for more papers by this author

Abstract

Liver cirrhosis is a critical state in the natural course of hepatocellular carcinoma (HCC). We sought to investigate the potential of in-depth proteomics to reveal plasma protein signatures that reflect common networks/pathways of liver cirrhosis, and to determine whether the cirrhosis-related signature in plasma is linked to the development of HCC among hepatitis B virus (HBV) carriers. We first compared plasma protein profiles using a 174-antibody microarray system between three groups of HBV carriers with different Child's grades of cirrhosis, which revealed a panel of 45 differentially expressed proteins with a high accuracy for discriminating Child's B/C. Ingenuity Pathway Analysis identified two main up-regulated networks connecting the 45 proteins that were most enriched for genes in the pathway of hepatic stellate cell activation. A parsimonious subset of 11 pathway-based proteins was then selected for quantification to correlate with HCC risk among 49 HCC cases and 50 controls in a nested case–control study within a 16-yr follow-up cohort of HBV carriers. A high risk score derived from a principal component analysis, which was used to extract the cluster structure of the 11 proteins, was associated with HCC (odds ratio = 4.83, 95% confidence interval: 1.26–18.56) even after adjustment for viral and clinical variables, implying the involvement of a pattern of coordinated proteins. Stepwise logistic regression on the 11 proteins revealed ICAM-2 as an independent predictor for HCC. These findings may give further insight into the pathobiology of hepatocarcinogenesis, allow testing of the cirrhosis-related plasma protein signature as a potential predictive biomarker for HCC. Copyright © 2012 Wiley Periodicals, Inc. © 2013 Wiley Periodicals, Inc.

Ancillary