KARYOTYPE OF MALIGNANT SKIN TUMORS OF TG.AC (ZETA-GLOBIN PROMOTED V-HA-RAS) MICE

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Initial karyotypic analysis of malignant fibrosarcoma tumor cells from explants in early passage secondary culture suggested non-random aneuploidy in the gain of a chromosome 6 and 9 and loss of chromosome 13. These tumor cell lines induced tumors in 7 to 10 days in 100% of syngeneic hosts (10e5 cells/host, subdermal). Re-evaluation of these cell lines using improved procedures to increase banding resolution resulted in the elimination of trisomy 9 and monosomy 13 under stringent evaluation conditions, but indicated that non-random aneuploidy in the gain of a chromosome 6, 10, or 15 (10/14 fibrosarcomas and 3/5 squamous cell carcinomas). Approximately 50% of the tumor cell lines of both types were observed with a significant increase in trisomy 15. No significant chromosomal abnormalities were observed in the remainder of the mitotic cells from malignant tumors observed under these culture conditions. These observations are consistent regardless of whether the malignancy resulted from chemical promotion (TPA or benzene), DMBA/TPA treatment of non-transgenic FVB, or rare malignancies arising in aging acetone treated controls and whether the tumors were diagnosed as fibrosarcomas or squamous cell carcinomas. The aneuploidy observed in early passage culture of malignant cells from TG.AC mice may represent clonal selection pressure and growth conditions independent of the critical genetic events involved in tumor initiation and promotion. However, these data are in distinct contrast to the paradigm of DMBA/TPA induction of squamous cell carcinomas in Sencar mice where mutated c-Ha-ras, trisomy 6 and 7, and allelic imbalance of c-Ha-ras, loss of heterozygosity on chromosome 7 and 11 have been described. Additional karyologic and molecular genetic studies will be required to corroborate these findings and determine whether this transgenic mouse model is unique and whether alternate pathways of tumorigenesis are involved in the development of sarcomas of the subcutis or squamous cell carcinomas.