Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling

Ju-Seog Lee 1, In-Sun Chu 1, Jeonghoon Heo 1, Diego F. Calvisi 1, Zongtang Sun 2, Tania Roskams 3, Anne Durnez 3, Anthony J. Demetris 4, Snorri S. Thorgeirsson 1 *

¹Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
²National Laboratory of Molecular Oncology, Cancer Institute, Chinese Academy of Medical Sciences, Beijing, China
³Departments of Morphology and Molecular Pathology and Hepatology, University of Leuven, Leuven, Belgium
⁴Thomas E. Starzl Transplant Institute, University of Pittsburgh Medical Center, Pittsburgh, PA
^*Correspondence to Snorri S. Thorgeirsson, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4255
fax: (301) 496-0734

Abstract
We analyzed global gene expression patterns of 91 human hepatocellular carcinomas (HCCs) to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. Unsupervised classification methods revealed two distinctive subclasses of HCC that are highly associated with patient survival. This association was validated via 5 independent supervised learning methods. We also identified the genes most strongly associated with survival by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provides new molecular insight into the pathogenesis of HCC. Tumors from the low survival subclass have strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and histone modification, suggesting an etiological involvement of these processes in accelerating the progression of HCC. In conclusion, the biological differences identified in the HCC subclasses should provide an attractive source for the development of therapeutic targets (e.g., HIF1a) for selective treatment of HCC patients. Supplementary material for this article can be found on the HEPATOLOGY Web site (http://interscience.wiley.com/jpages/0270-9139/suppmat/index.html) (HEPATOLOGY 2004;40:667-676.)

Received: 8 April 2004; Accepted: 5 May 2004

Digital Object Identifier (DOI)

10.1002/hep.20375 About DOI

Additional Material
This article includes Supplementary Notes, Tables, and Figures available at http://www.interscience.wiley.com/jpages/0270-9139/suppmat

저자코멘트
The link below directs to the editorial comment on my published work in the same issue of Hepatology. It provides different view of my works that will also be very useful to oncologists/clinicians or someone who is very much interested in microarray studies of human cancer in regard of its clinical implication.
Editorials, "A new way to look at liver cancer" :
http://www3.interscience.wiley.com/cgi-bin/abstract/109606306/ABSTRACT