Genome-scale profiling of gene expression in hepatocellular carcinoma: classification, survival prediction, and identification of therapeutic targets.

The heterogeneous nature of human hepatocellular carcinoma (HCC) has hampered both treatment and prognostic predictions. Gene expression profiles of human HCC were analyzed to define the molecular characteristics of the tumors and to test the prognostic value of the expression profiles. By applying global gene expression analyses, including unsupervised and supervised methods, 2 distinctive subclasses of HCC that were highly homogeneous for both the underlying biology and the clinical outcome were discovered. Tumors from the low survival subclass had strong cell proliferation and antiapoptosis gene expression signatures. In addition, the low survival subclass displayed higher expression of genes involved in ubiquitination and sumoylation, suggesting an etiologic involvement of these processes in accelerating the progression of HCC. Genes most strongly associated with survival were identified by using the Cox proportional hazards survival analysis. This approach identified a limited number of genes that accurately predicted the length of survival and provided new molecular insights into the pathogenesis of HCC. Future studies will evaluate potential diagnostic markers and therapeutic targets identified during the global gene expression studies. Furthermore, cross-species similarity of gene expression patterns will also allow prioritization of a long list of genes obtained from human gene expression profiling studies and focus on genes whose expression is altered during tumorigenesis in both species.

[1]  Michele Pagano,et al.  When protein destruction runs amok, malignancy is on the loose. , 2003, Cancer cell.

[2]  J. Bruix,et al.  Prognostic factors of hepatocellular carcinoma in the west: A multivariate analysis in 206 patients , 1990, Hepatology.

[3]  Ash A. Alizadeh,et al.  Distinct types of diffuse large B-cell lymphoma identified by gene expression profiling , 2000, Nature.

[4]  John Wong,et al.  Natural History of Untreated Nonsurgical Hepatocellular Carcinoma , 2005, The American Journal of Gastroenterology.

[5]  T. Tsunoda,et al.  Genome-wide analysis of gene expression in human hepatocellular carcinomas using cDNA microarray: identification of genes involved in viral carcinogenesis and tumor progression. , 2001, Cancer research.

[6]  F. Izzo,et al.  A new prognostic system for hepatocellular carcinoma: A retrospective study of 435 patients , 1998, Hepatology.

[7]  S. Terai,et al.  Ubiquitin is a possible new predictive marker for the recurrence of human hepatocellular carcinoma. , 2002, Liver.

[8]  J. Bruix,et al.  Prognosis of hepatocellular carcinoma. , 2002, Hepato-gastroenterology.

[9]  S. Thorgeirsson,et al.  Molecular pathogenesis of human hepatocellular carcinoma , 2002, Nature Genetics.

[10]  D. Machin,et al.  Simple clinical prognostic model for hepatocellular carcinoma in developing countries and its validation. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[11]  J. Bruix,et al.  HCC surveillance: Who is the target population? , 2003, Hepatology.

[12]  H. Hasegawa,et al.  Natural history of hepatocellular carcinoma and prognosis in relation to treatment study of 850 patients , 1985, Cancer.

[13]  J. Bruix,et al.  Prognosis of Hepatocellular Carcinoma: The BCLC Staging Classification , 1999, Seminars in liver disease.

[14]  X. Wang,et al.  Predicting hepatitis B virus–positive metastatic hepatocellular carcinomas using gene expression profiling and supervised machine learning , 2003, Nature Medicine.

[15]  D. Botstein,et al.  Gene expression patterns in human liver cancers. , 2002, Molecular biology of the cell.

[16]  R. Pugh,et al.  Transection of the oesophagus for bleeding oesophageal varices , 1973, The British journal of surgery.

[17]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[18]  N. Iizuka,et al.  MECHANISMS OF DISEASE Mechanisms of disease , 2022 .

[19]  Katsuhiko Itoh,et al.  Reduced stability of retinoblastoma protein by gankyrin, an oncogenic ankyrin-repeat protein overexpressed in hepatomas , 2000, Nature Medicine.

[20]  Ubiquitin and hepatocellular carcinoma , 2002 .

[21]  Yudong D. He,et al.  Gene expression profiling predicts clinical outcome of breast cancer , 2002, Nature.

[22]  S. Thorgeirsson,et al.  Functional and genomic implications of global gene expression profiles in cell lines from human hepatocellular cancer , 2002, Hepatology.

[23]  S. Chevret,et al.  A new prognostic classification for predicting survival in patients with hepatocellular carcinoma. Groupe d'Etude et de Traitement du Carcinome Hépatocellulaire. , 1999, Journal of hepatology.

[24]  J. Bruix,et al.  Natural history of untreated nonsurgical hepatocellular carcinoma: Rationale for the design and evaluation of therapeutic trials , 1999, Hepatology.

[25]  L. Staudt,et al.  The proliferation gene expression signature is a quantitative integrator of oncogenic events that predicts survival in mantle cell lymphoma. , 2003, Cancer cell.

[26]  L. Staudt,et al.  The use of molecular profiling to predict survival after chemotherapy for diffuse large-B-cell lymphoma. , 2002, The New England journal of medicine.