The steps which lead to development of primary hepatocellular carcinoma (PHC) remain enigmatic, although several possible etiologic agents have been identified. The major goal of this proposal is to identify the common changes that lead to hepatocarcinogenesis of different etiologies, and to determine whether or not specific mechanisms underlie the induction of these changes. We will characterized these changes on a chromosomal and molecular level by direct investigation of tumor and normal cells from the same patient and by preparing hepatoma-derived cell lines and normal cells from the same patient and by preparing hepatoma- derived cell lines and normal fibroblasts from the same patient to provide unlimited quantities of material for assay. Our previous chromosome analyses pointed to consistent translocation and deletions of chromosome analyses pointed to consistent translocation and deletions of chromosome 1 in hepatoma-derived cells. Comparison of DNA obtained form tumor cells and normal cells from the same patient using probes form 1p revealed loss of heterozygosity in this area of the genome in the tumor cells. On the basis of these preliminary data, we hypothesized that the loss of a tumor suppressor gene is a likely initiating step in PHC development. Our proposal is aimed at establishing evidence for a chromosome 1 encoded change common to PHCs of multiple origins. We will then define how such a change may be initiated. To accomplish this, we will extend our study of loss of heterozygosity of 1p-encoded genes to more patients with PHC of different etiologies and expand our panel of 1p-derived probes. We will also attempt to detect genetic instability and the mutagenic role of hepatitis B virus (HBV) in PHC development.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Metabolic Pathology Study Section (MEP)
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Wistar Institute
United States
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Livezey, Kristin W; Negorev, Dmitri; Simon, Daniela (2002) Increased chromosomal alterations and micronuclei formation in human hepatoma HepG2 cells transfected with the hepatitis B virus HBX gene. Mutat Res 505:63-74
Livezey, K W; Negorev, D; Simon, D (2000) Investigation of the expression of Bin1, a putative suppressor, in human hepatoma cells. Cancer Genet Cytogenet 116:35-9
Fang, W; Piao, Z; Simon, D et al. (2000) Mapping of a minimal deleted region in human hepatocellular carcinoma to 1p36.13-p36.23 and mutational analysis of the RIZ (PRDM2) gene localized to the region. Genes Chromosomes Cancer 28:269-75
Livezey, K W; Negorev, D; Simon, D (2000) Hepatitis B virus-transfected Hep G2 cells demonstrate genetic alterations and de novo viral integration in cells replicating HBV. Mutat Res 452:163-78
Hammond, C; Jeffers, L; Carr, B I et al. (1999) Multiple genetic alterations, 4q28, a new suppressor region, and potential gender differences in human hepatocellular carcinoma. Hepatology 29:1479-85
Livezey, K W; Simon, D (1997) Accumulation of genetic alterations in a human hepatoma cell line transfected with hepatitis B virus. Mutat Res 377:187-98
Negorev, D; Riethman, H; Wechsler-Reya, R et al. (1996) The Bin1 gene localizes to human chromosome 2q14 by PCR analysis of somatic cell hybrids and fluorescence in situ hybridization. Genomics 33:329-31
Simon, D; Carr, B I (1995) Integration of hepatitis B virus and alteration of the 1p36 region found in cancerous tissue of primary hepatocellular carcinoma with viral replication evidenced only in noncancerous, cirrhotic tissue. Hepatology 22:1393-8