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Specific Chromosomal Changes in Albumin Simian Virus 40 T Antigen Transgenic Rat Liver Neoplasms¹

McArdle Laboratory for Cancer Research, The Medical School, University of Wisconsin, Madison, Wisconsin 53706-1599 [Y. P. D., G. S., Y-H. X., H. C. P.]; Laboratory of Carcinogenesis, National Cancer Institute, Bethesda, Maryland 20284 [L. M. S.]; and East Carolina University, Greenville, North Carolina [J. W.]

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 significant. At this time in the development of hepatic lesions, only a relatively small number of microscopic altered hepatic foci could be noted. By contrast, hepatocytes isolated from the age-matched nontransgenic controls demonstrated only 1% aneuploidy. One hundred % of the metaphase spreads isolated from hepatocellular neoplasms in transgenic rats were aneuploid. Although there were many random changes, 70% of the neoplastic cells demonstrated an amplification of all or portions of chromosome 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 detected 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 cells. The loss of chromosomes 3, 6, and 15 indicates that these regions may harbor one or more tumor suppressor genes. The amplification of a specific region of chromosome 1 is thus the first karyotypic alteration that can be identified in hepatocytes from livers from which hepatic neoplasms will arise. This indicates that expression or repression of one or more genes in this region may confer a growth advantage to preneoplastic hepatocytes, facilitating their transit to the neoplastic state in the stage of progression. Changes in chromosomes 3, 6, and 15 that occur subsequent to duplication of the q3.7–q4.3 region of chromosome 1 are changes possibly reflecting alteration of tumor suppressor genes with further enhancement of neoplastic growth.

¹ This work was supported in part by National Cancer Institute Research Grants CA-07175, CA-22484, and CA-45700.

² To whom requests for reprints should be addressed, at the McArdle Laboratory, University of Wisconsin-Madison, Medical School, 1400 University Avenue, Madison, WI 53706-1599. Phone: (608) 262-1209; Fax: (608) 262-2824.

Received 2/21/97. Accepted 6/16/97.

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