Differentially expressed genes between early and advanced hepatocellular carcinoma (HCC) as a potential tool for selecting liver transplant recipients

Abstract

Hepatocellular carcinoma (HCC) is the fifth most common cancer in the world. Liver transplantation (LT) represents a curative treatment for "small" HCC. Preoperative staging is critical in selecting optimal candidates for LT to optimize the use of this scarce resource. From December 1997 to February 2004, 148 patients diagnosed with cirrhosis and HCC were evaluated at our center. After staging, the patients were listed for LT according to United Network for Organ Sharing (UNOS) criteria. When pretransplant liver MRIs were compared with the findings of the explanted livers, 8 of 35 patients (22.8%) were understaged. Three of the 8 patients (37.5%) had recurrence post-LT. A retrospective gene expression profiling study was done using microarray technology for tumor samples in the pretransplant hepatitis C virus (HCV)-HCC understaged patients and in a contemporaneous group of HCV-HCC patients that were accurately staged. Two sample t tests comparing the early versus advanced HCV-HCCs with respect to gene expression showed an important set of genes differentially expressed among the samples. Hierarchical clustering analysis of the gene expression profiling classified 93.8% of the total tumor samples and 85.7% of the understaged samples in concordance with the explanted pathological staging. We found a distinctive pattern of gene expression between early and advanced HCV-HCCs. These results suggest that gene expression profiling could improve the pre-LT HCC staging to more closely mimic the explant pathology. Whether gene expression profiling of HCC will be refined to the point of predicting potential metastatic biologic behavior to predict post-LT recurrence will require longitudinal prospective study of this gene array technology.

Figure 1

Quality control (QC) of the reaction products for microarray analysis. 1. Evaluation of RNA integrity for an individual RNA HCV-HCC sample (sample 5). 2. Capillary electrophoresis of cDNA synthesis product from sample 5. 3. Capillary electrophoresis of IVT product from the same sample.

Figure 2

Cluster analysis. Cluster results for RMA expression summaries using RF proximities when the data set included the 16 individual samples and the 424 probe sets significant comparing the early versus advanced HCV-HCC pools. Black box indicates the advanced HCV-HCC samples (T3N0M0 and T4N0M0) and the gray box the early HCV-HCC samples (T1N0M0 and T2N0M0). *19TS1: pretransplant liver tumor sample 1 from patient 19; 19TS2: pretransplant liver tumor sample 2 from patient 19; 19TS3: recurrent tumor sample from patient 19 (posttransplantation).