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.

Agency
National Institute of Health (NIH)
Institute
Division of Clinical Sciences - NCI (NCI)
Type
Intramural Research (Z01)
Project #
1Z01SC010385-05
Application #
7070848
Study Section
(LEC)
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2004
Total Cost
Indirect Cost
Name
Clinical Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code
Kremer-Tal, Sigal; Narla, Goutham; Chen, Yingbei et al. (2007) Downregulation of KLF6 is an early event in hepatocarcinogenesis, and stimulates proliferation while reducing differentiation. J Hepatol 46:645-54
Kaposi-Novak, Pal; Lee, Ju-Seog; Gomez-Quiroz, Luis et al. (2006) Met-regulated expression signature defines a subset of human hepatocellular carcinomas with poor prognosis and aggressive phenotype. J Clin Invest 116:1582-95
Thorgeirsson, Snorri S; Lee, Ju-Seog; Grisham, Joe W (2006) Molecular prognostication of liver cancer: end of the beginning. J Hepatol 44:798-805
Lee, Ju-Seog; Heo, Jeonghoon; Libbrecht, Louis et al. (2006) A novel prognostic subtype of human hepatocellular carcinoma derived from hepatic progenitor cells. Nat Med 12:410-6
Thorgeirsson, Snorri S; Lee, Ju-Seog; Grisham, Joe W (2006) Functional genomics of hepatocellular carcinoma. Hepatology 43:S145-50
Martin, Juliette; Magnino, Fabrice; Schmidt, Karin et al. (2006) Hint2, a mitochondrial apoptotic sensitizer down-regulated in hepatocellular carcinoma. Gastroenterology 130:2179-88
Lee, J-S; Thorgeirsson, S S (2006) Comparative and integrative functional genomics of HCC. Oncogene 25:3801-9
Calvisi, Diego F; Ladu, Sara; Gorden, Alexis et al. (2006) Ubiquitous activation of Ras and Jak/Stat pathways in human HCC. Gastroenterology 130:1117-28
Calvisi, Diego F; Conner, Elizabeth A; Ladu, Sara et al. (2005) Activation of the canonical Wnt/beta-catenin pathway confers growth advantages in c-Myc/E2F1 transgenic mouse model of liver cancer. J Hepatol 42:842-9
Pascale, Rosa M; Simile, Maria M; Calvisi, Diego F et al. (2005) Role of HSP90, CDC37, and CRM1 as modulators of P16(INK4A) activity in rat liver carcinogenesis and human liver cancer. Hepatology 42:1310-9

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