The genetic changes 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 investigate the genetic changes common to PHC of different etiologies in an effort to understand development of this disease. Our previous investigations pointed to consistent translocations and deletions of chromosome 1 in hepatoma-derived cells. Comparison of genomic DNA obtained from tumor cells and normal cells from the same patient using "RFLP probes" which map to distal 1p revealed loss of genetic heterozygosity in the tumor cell. On the basis of these preliminary data, we hypothesize that the loss of a tumor suppressor gene is a likely and possibly initiating step in PHC. Our proposal is geared to substantiating this chromosome 1-encoded genetic change in PHCs of multiple origins and to defining how this and the genetic changes described by others may lead to PHC. To accomplish this, we will look for genetic instability and chromosome loss in premalignant livers and will transfer individual normal human chromosomes into different hepatoma-derived cell lines to determine if they suppress tumor cell growth or tumorigenicity. To verify our hypothesis of the importance of 1p loss of heterozygosity, we will extend our study to tissue from more patients and to other probes in order to pinpoint the region containing the putative suppressor gene, a prerequisite for its cloning.