Using oligonucleotide microarray data of 45 hepatocellular carcinoma (HCC) samples, we evaluated gene expression in hepatitis B virus-positive and hepatitis C virus-positive HCCs (HBV-and HCV-HCCs) for an association with liver cirrhosis (LC). In all, 89 genes were expressed differentially between HBV-HCCs associated with LC and those not associated with LC. Among them, tumors from LC patients showed significantly lower expression levels of 72 genes and significantly higher levels of 17 genes than the levels found in tumors from non-LC patients. The former included genes responsible for signal transduction, transcription, metabolism, and cell growth. The latter included a tumor suppressor gene and a cell-growth-related gene. Only eight genes were expressed differentially between HCV-HCCs associated with and without LC. Our findings provide as a framework for clarifying the role of LC in HBV-and HCVrelated hepatocarcinogenesis.

To clarify the genetic aberrations involved in the development and progression of hepatitis C virus-associated hepatocellular carcinoma (HCV-HCC), we investigated DNA copy number aberrations (DCNAs) in 19 surgically resected HCCs by conventional CGH and array CGH. Conventional CGH revealed that increases of DNA copy number were frequent at 1q (79% of the cases), 8q (37%), 6p (32%), and 10p (32%) and that decreases were frequent at 17p (79%), 16q (58%), 4q (53%), 13q (42%), 10q (37%), 1p (32%), and 8p (32%). In general, genes that showed DCNAs by array CGH were usually located in chromosomal regions with DCNAs detected by conventional CGH analysis. Increases in copy numbers of the LAMC2, TGFB2, and AKT3 genes (located on 1q) and decreases in copy numbers of FGR/SRC2 and CYLD (located on 1p and 16q, respectively) were observed in more than 30% of tumors, including small, well-differentiated carcinomas. These findings suggest that these genes are associated with the development of HCV-HCC. Increases of MOS, MYC, EXT1, and PTK2 (located on 8q) were detected exclusively in moderately and poorly differentiated tumors, suggesting that these alterations contribute to tumor progression. In conclusion, chromosomal and array CGH technologies allow identification of genes involved in the development and progression of HCV-HCC.

The outcome of patients with hepatocellular carcinoma (HCC) remains poor because of the high frequency of intrahepatic recurrence (IHR), particularly early IHR within 1 year of hepatectomy. To search for genes involved in early IHR, we performed DNA microarray analysis in a training set of 33 HCCs and selected 46 genes linked to early IHR from approximately 6,000 genes by means of a supervised learning method. Gene selection was validated by a false discovery rate of 0.37%. The 46 genes included many immune response-related genes, which were all downregulated in HCCs with early IHR. Four of these genes (HLA-DRA, HLA-DRB1, HLA-DG and HLA-DQA), encoding MHC class II antigens, were coordinately downregulated in HCCs with early IHR compared to levels in HCCs with nonrecurrence. A cluster analysis reproduced expression patterns of the 4 MHC class II genes in 27 blinded HCC samples. To localize the major site of production of HLA-DR protein in the tumor, we used 50 frozen specimens from 50 HCCs. Immunofluorescence staining showed that HLA-DR protein levels in tumor cells, but not in stromal cells, were associated with the transcription levels of HLA-DRA determined by both DNA microarray analysis and real-time quantitative reverse transcription-PCR. Univariate analysis showed that tumor HLA-DR protein expression, pTNM stage and venous invasion were associated with early IHR. Multivariate analysis showed that tumor HLA-DR protein expression was one of the independent risk factors for early IHR, suggesting HLA-DR protein potential as a biomarker and a molecular target for therapeutic intervention. ' 2005 Wiley-Liss, Inc.

Background: With tumor progression, genomic aberrations accumulate in cancer cells

No abstract