Hepatocellular carcinoma (HCC) is one of the ten leading causes of cancer death in the United States and a major cause of cancer death worldwide. Despite the high worldwide incidence of HCC, information is scant regarding the molecular mechanisms leading to the development of this malignancy. The overall goal of this study is to elucidate the complex molecular genetic mechanisms involved in the initiation and progression of hepatocellular cancer. Cells exposed to conditions that inhibit DNA replication form nonrandom gaps or breaks at chromosomal loci known as fragile sites. Deletions in fragile site regions frequently occur in cancer, therefore it has been hypothesized that fragile sites contain genes that are either sensors of genomic damage or tumor suppressors. Mutations close to the FRA16D fragile site on chromosome 16 occur in a variety of human cancers, including hepatocellular cancer. Our hypothesis is that the FRA16D chromosomal fragile site region plays a critical role in initiation and progression of HCC. Our first specific aim will test the hypothesis that deletions and translocations at chromosomal fragile site FRA16D have a role in the development of HCC. We will construct a 1-megabase bacterial artificial chromosome (BAC) contig spanning the FRA16D fragile site and prepare a high-resolution map of the region. Using a combination of fluorescence in-situ hybridization of BAC DNA to metaphase chromosome spreads and microsatellite analysis of tumor genomic DNA and BAC clones, we will co-localize the known region of loss of heterozygosity in HCC at chromosome 16q with the FRA16D fragile site. Our second specific aim will identify genes located in the region of fragile site FRA16D. Genes at or adjacent to the FRA16D fragile site region will be identified, examined for changes in expression in HCC, and analyzed to determine the mechanisms by which loss of genetic material in the FRA16D region leads to changes in gene expression and carcinogenesis. Finally, in the third specific aim, we will perform clinical correlative studies to determine the etiologic and prognostic significance of detectable alterations in the FRA16D fragile site, as well as mutations or altered expression of genes in the FRA16D fragile site region. Our findings will potentially have implications for diagnosis, prognostic prediction, prevention, and treatment of hepatocellular cancer. My long-term goal is to understand of the mechanisms of liver carcinogenesis and develop strategies for early diagnosis, prognostic prediction, prevention, and therapy of hepatocellular cancer. The Clinical Investigator Award will provide essential training and ensure that a major proportion of my time is protected for research. This will enable me to obtain the training and preliminary data I need to launch an independent, productive research career.
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