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A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells


The variability in the prognosis of individuals with hepatocellular carcinoma (HCC) suggests that HCC may comprise several distinct biological phenotypes. These phenotypes may result from activation of different oncogenic pathways during tumorigenesis and/or from a different cell of origin. Here we address whether the transcriptional characteristics of HCC can provide insight into the cellular origin of the tumor. We integrated gene expression data from rat fetal hepatoblasts and adult hepatocytes with HCC from human and mouse models. Individuals with HCC who shared a gene expression pattern with fetal hepatoblasts had a poor prognosis. The gene expression program that distinguished this subtype from other types of HCC included markers of hepatic oval cells, suggesting that HCC of this subtype may arise from hepatic progenitor cells. Analyses of gene networks showed that activation of AP-1 transcription factors in this newly identified HCC subtype might have key roles in tumor development.

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Figure 1: Hierarchical cluster analysis of integrated gene expression data from rat hepatoblasts and hepatocytes, and from mouse and human HCC.
Figure 2: Construction of prediction models and evaluation of predicted outcome.
Figure 3: Three distinctive subtypes of HCC defined by gene expression patterns.
Figure 4: Cross-comparison of gene lists from two independent statistical tests.
Figure 5: Gene networks of AP-1 transcription factors in the HB subtype of HCC.

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This research was supported by the Intramural Research Program of the US National Institutes of Health, National Cancer Institute, Center for Cancer Research. L. Libbrecht is a “postdoctoraal onderzoeker” of the “F.W.O.-Vlaanderen.” I.-S. Chu is supported by a grant from the Ministry of Science and Technology (21C Frontier Functional Human Genome Project), Korea.

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Correspondence to Snorri S Thorgeirsson.

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Supplementary information

Supplementary Fig. 1

Gene networks from PathwayAssist. (PDF 332 kb)

Supplementary Fig. 2

Expression of hepatic oval cell marker genes in human HCC. (PDF 25 kb)

Supplementary Fig. 3

Comparison of proliferation and apoptosis indices among subtypes of HCC. (PDF 21 kb)

Supplementary Table 1

Top 10 list of gene networks from Ingenuity Pathway Analysis. (PDF 35 kb)

Supplementary Table 2

Clinical and pathological features of HCC patients. (PDF 8 kb)

Supplementary Table 3

Univariate and multivariate Cox proportional hazard regression analyses of HCC. (PDF 8 kb)

Supplementary Note (PDF 12 kb)

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Lee, JS., Heo, J., Libbrecht, L. et al. A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12, 410–416 (2006).

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