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We have characterized the copy number of various loci on chromosome 3p in a series of breast cancers. To determine the precise region(s) involved, restriction fragment length polymorphism (RFLP) analysis for loss of heterozygosity (LOH) was performed using a panel of RFLP probes at 3p13-14, 3p21-22, and 3p24-26. The incidence of LOH at the three loci was 41, 32, and 45%, respectively. To validate the LOH data and to gain insights into the mechanisms resulting in LOH, chromosome 3 pericentromeric and 3p region-specific DNA probes were used to determine the DNA copy number by fluorescence in situ hybridization (FISH). Among 22 cases examined, 15 showed loss by both LOH and FISH, indicating that the dominant mechanism of LOH at 3p in breast cancer is a physical deletion. Two of the 22 cases showed loss by RFLP analysis but not by FISH, suggesting either mitotic recombination or loss and endoreduplication. In three cases, RFLP analysis indicated allelic imbalance, which was incorrectly interpreted as LOH, since a gain of one allele was suggested by FISH. By constructing a deletion map, we found that 2 separate regions, 3p13-14 and 3p24-26, were independently deleted in some breast cancers. Additionally, four cases had break points within the 3p24-26 region and one case had a homozygous deletion at 3p13, further supporting the hypothesis that there are tumor suppressor genes at both 3p13-14 and 3p24-26. Although high frequency of LOH was observed at the 3p21-22 region, there was no direct evidence supporting the existence of a breast cancer tumor suppressor gene there as opposed to codeletion with either the proximal or distal region.