A proportion of breast cancers acquire genetic alterations at 17q11.2-q12 (HER-2/neu), 20q13.2 (ZNF217 gene) and 17p13.1 (p53). We describe a unique technique (Comet-FISH) in which we documented relative genetic instability at p53 and HER-2/neu gene loci within a panel of malignant breast cancer cell lines (MCF-7; MDA-MB-468 and CRL-2336). Furthermore, Comet-FISH data were consistent with preferential repair of the p53 locus following gentoxic insult and suggest that this assay may be quite useful for the study of genetic instability.