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Cellular and Molecular Biology 73: Translational Genomics

Abstract #5692

Identification of novel prognostic subtype of hepatocellular carcinoma derived from hepatic stem cells by comparative functional genomic approach.

NCI, Bethesda, MD, University of Leuven, Leuven, Belgium, Korea Research Institute of Bioscience and Biotechnology, Taejun, Republic of Korea, Mayo Clinic, Rochester, MN, University of Pittsburgh Medical Center, Pittsburgh, PA, Chinese Academy of Medical Sciences, Beijing, China

Patients with HCC have highly variable clinical courses supporting the notion that HCC comprises several biologically distinctive subgroups. The variability likely reflects a molecular heterogeneity that has not been appreciated from methods traditionally used to characterize HCC. These phenotypes may result from different neoplastic pathways and/or from a different cell of origin for the tumor. Improving the classification of HCC into groups with both homogeneous prognosis and the molecular pathogenesis of the tumors would at minimum improve the application of currently available treatment modalities and at best provide new treatment strategies. Here we address if the transcriptional characteristics of the HCC would provide insight into the cellular origin of the tumors. We applied gene expression pattern analysis of HCC to stratify patients into homogeneous subgroups. Gene expression profiles from 139 HCC patients were generated and cross-compared with those from animal models. Using orthologous genes, we integrated gene expression data from 9 rat samples from fetal hepatoblasts and adult hepatocytes, 39 mouse HCC from 5 different mouse HCC models, and 61 human HCC. A subgroup of the human HCC that shared gene expression patterns with fetal hepatoblasts was identified on the basis of unsupervised hierarchical cluster analysis. Using supervised methods, molecular predictors were constructed to stratify patients with genes whose expression are enriched in fetal hepatoblasts, and tested in a validation patient group (78 patients). HCC patients who shared gene expression patterns with fetal hepatoblasts showed extremely poor prognosis with mean length of survival (±SE) of 11.9±4.77 months when compared with those lacking the hepatoblast signature (64.4±8.05). The gene expression program that distinguishes this novel subgroup from the rest of HCC includes well known markers of hepatic oval cells (KRT19, KRT7, and VIM), strongly suggesting that HCC in this subgroup may arise from hepatic stem cells. Two independent gene network analyses (Ingenuity Pathway Analysis and PathwayAssist) of unique gene expression signature for these patients revealed that activation of AP-1 transcription factors (JUN and FOS) might play key roles in tumor development in the newly identified HCC subtype. This finding is highly concordant with previous studies showing that Jun is essential for hepatogenesis in development and critical for initiation of HCC development in mouse. In addition, by applying two independent gene expression signatures, hepatoblast-specific signature and genome-wide global signature, HCC patients were further stratified into three subgroups with significant association of overall survival and recurrence (P < 0.001). In conclusion, the length of survival and recurrence in HCC patients is strongly associated with the origin of tumor cells.