Identification of a liver cirrhosis signature in plasma for predicting hepatocellular carcinoma risk in a population-based cohort of hepatitis B carriers.
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.
Graduate Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan.
Chia-Chi
CC
Liu
Ya-Hui
YH
Wang
Eric Y
EY
Chuang
Mong-Hsun
MH
Tsai
Ya-Hui
YH
Chuang
Chih-Lin
CL
Lin
Chun-Jen
CJ
Liu
Bo-Yu
BY
Hsiao
Shi-Ming
SM
Lin
Li-Yu
LY
Liu
Ming-Whei
MW
Yu
D000328:Adult; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000209:etiology*; D016022:Case-Control Studies; D016000:Cluster Analysis; D006509:Hepatitis B / Q000097:blood / Q000150:complications*; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood* / Q000150:complications*; D008113:Liver Neoplasms / Q000097:blood / Q000209:etiology*; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D025941:Protein Interaction Mapping; D040901:Proteomics / Q000379:methods; D012306:Risk; D015398:Signal Transduction
D015415:Biomarkers; D001798:Blood Proteins