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Latent Expression of p53 Mutations and Radiation-induced Mammary Cancer¹

Departments of Radiation Therapy [C. S. S., C. M. D., M. N. C., R. L. U.] and Human Biological Chemistry and Genetics [M. N. C., R. L. U.], University of Texas Medical Branch, Galveston, Texas 77555-0656

EF42 is a clonally derived preneoplastic cell lineage from irradiated mouse mammary tissue, which becomes neoplastic with time in vitro or in vivo. We now report that multiple mutations in p53 occur before the acquisition of the neoplastic phenotype. The selective expansion of mutant cells is accompanied by loss of heterozygosity at the p53 locus and c-myc amplification. Although p53 mutations represent critical early events, our data argue these mutations were not directly induced by radiation but arose in the progeny of irradiated cells several cell generations later. The data are consistent with a multistep model of carcinogenesis that identifies genomic instability as the earliest step.

¹ This work was supported by NIH Grant R01 CA 43322 and Department of Energy Grant ER61234.

² To whom requests for reprints should be addressed, at University of Texas, Medical Branch at Galveston, Department of Radiation Therapy, 301 University Boulevard, Galveston, TX 77555-0656.

Received 3/13/95. Accepted 5/31/95.

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