SPECIFIC CHROMOSOMAL CHANGES IN ALBUMIN SIMIAN-VIRUS-40 T-ANTIGEN TRANSGENIC RAT-LIVER NEOPLASMS

Hepatocytes isolated from 3-month-old female rats bearing the albumin promoter/enhancer SV40 T antigen construct as a transgene demonstrated a 20% aneuploidy rate and a significant duplication of chromosome 1. Other chromosome changes were observed but were not statistically sign ificant. At this time in the development of hepatic lesions, only a re latively small number of microscopic altered hepatic foci could be not ed. By contrast, hepatocytes isolated from the age-matched nontransgen ic controls demonstrated only 1% aneuploidy. One hundred % of the meta phase spreads isolated from hepatocellular neoplasms in transgenic rat s were aneuploid. Although there were many random changes, 70% of the neoplastic cells demonstrated an amplification of all or portions of c hromosome 1q. Only 2% of the neoplastic cells had both a trisomy and a duplication. The smallest region of chromosome 1 that was duplicated was that between bands q3.7 and q4.3. A loss of chromosome 3 was detec ted in 50% of the neoplasms, as well as a loss of chromosome 6 in 72% of the neoplastic cells. The carcinomas with the highest proliferation rate had also lost at least one copy of chromosome 15 in 70% of the c ells. The loss of chromosomes 3, 6, and 15 indicates that these region s may harbor one or more tumor suppressor genes. The amplification of a specific region of chromosome 1 is thus the first karyotypic alterat ion that can be identified in hepatocytes from livers from which hepat ic neoplasms will arise. This indicates that expression or repression of one or more genes in this region may confer a growth advantage to p reneoplastic hepatocytes, facilitating their transit to the neoplastic state in the stage of progression. Changes in chromosomes 3, 6, and 1 5 that occur subsequent to duplication of the q3.7-q4.3 region of chro mosome 1 are changes possibly reflecting alteration of tumor suppresso r genes with further enhancement of neoplastic growth.