GENETIC MODIFIERS OF MURINE HEPATOCARCINOGENESIS

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The overall goal of our research program is to identify and understand the mechanisms of action of specific genes that modulate risk for cancer development in inbred mice. These studies will provide insights into the signaling pathways critical for hepatocarcinogenesis in mice, as well as models for understanding the action of modifier genes for cancer risk in humans. We have identified the Hcs7 locus as the major determinant of the high susceptibility of C3H/HeJ (C3H) and CBA/J mice to liver tumor induction relative to C57BL/6J (B6) mice and demonstrated that this gene is located on distal Chromosome 1. We also found that one of the susceptibility genes, Hcf2, carried by sensitive C57BR/cdJ (BR) mice mapped to the same region. Comparative studies of hepatocarcinogenesis in C3H, BR, and B6 mice by our group and others demonstrate that the Hcs7 and Hcf2 loci act cell autonomously to control the growth or development of preneoplastic hepatic lesions, but the molecular identities of these genes are still unknown. We have localized the Hcs7gene to a 6.4 Mbp interval on Chromosome 1. We propose to elucidate the mechanisms by which Hcs7 modulates liver cancer risk through the following approaches. First, we will determine the molecular identity of Hcs7 through positional cloning. We will prioritize candidate genes based on mapping to sub-centiMorgan resolution, analysis of shared SIMP haplotypes for relevant strains, hepatic gene expression, and functional criteria. Candidates will then be tested by transgenesis using Bacterial Artificial Chromosome (BAG) clones or gene replacement. Second, we will elucidate the biological basis for Hcs7 modulation of cancer risk by comparing Hcs7 BAG transgenic or allelic replacement strains to control parental or congenic mice for phenotypes related to hepatocarcinogenesis. Finally, we will determine the molecular mechanisms by which Hcs7 acts through analysis of hepatic gene expression in BAG transgenic and congenic mice, and characterization of mice carrying germ-line or liver-specific null mutations in Hcs7.