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Chromosomal Instability and Its Relationship to Other End Points of Genomic Instability¹

Department of Radiation Oncology [C. L. L., M. I. K., J. C., W. F. M.] and Graduate Group in Biophysics [M. I. K.], University of California, San Francisco, California 94143-0750; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, California 94720 [W. F. M.]; and Department of Human Oncology, University of Wisconsin Medical School and Comprehensive Cancer Center, Madison, Wisconsin 53792 [M. M., D. A. B.]

Chromosomal destabilization is one end point of the more general phenomenon of genomic instability. We previously established that chromosomal instability can manifest in clones derived from single progenitor cells several generations after X-irradiation. To understand the potential relationship between chromosomal destabilization and the other end points of genomic instability, we generated a series of chromosomally stable and unstable clones by exposure to X-rays. All clones were derived from the human-hamster hybrid line GM10115, which contains a single copy of human chromosome 4 in a background of 20–24 hamster chromosomes. These clones were then subjected to a series of assays to determine whether chromosomal instability is associated with a general "mutator phenotype" and whether it modulates other end points of genomic instability. Thus, we analyzed clones for sister chromatid exchange, delayed reproductive cell death, delayed mutation, mismatch repair, and delayed gene amplification. Statistical analyses performed on each group of chromosomally stable and unstable clones indicated that, although individual clones within each group were significantly different from unirradiated clones for many of the end points, there was no significant correlation between chromosomal instability and sister chromatid exchange, delayed mutation, and mismatch repair. Delayed gene amplification was found to be marginally correlated to chromosomal instability (P < 0.1), and delayed reproductive cell death (the persistent reduction in plating efficiency after irradiation) was found to be significantly correlated (P < 0.05). These correlations may be explained by chromosomal destabilization, which can mediate gene amplification and can result in cellular lethality. These data implicate multiple molecular and genetic pathways leading to different manifestations of genomic instability in GM10115 cells surviving exposure to DNA-damaging agents.

¹ This work was supported by the Office of Health and Environmental Research, United States Department of Energy, Contract 4459-011542, and NIH Grant GM 54189 (to W. F. M.), by the NIH National Research Service Award 5-T32-ES07016 from the National Institute of Environmental Health Sciences (to C. L. L.), and by Contract DE-FG02-93ER61707-05 (to D. A. B.).

² To whom requests for reprints should be addressed, at Department of Radiation Oncology, Box 0750, University of California, San Francisco, CA 94143-0750. Phone: (415) 476-2793; Fax: (415) 476-1544; E-mail: Limoli@radlab.ucsf.edu.

Received 6/30/97. Accepted 10/15/97.

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