A variety of chromosomal gains and losses has been detected with comparative genomic hybridization during tumorigenesis in the colon mucosa. The aim of this investigation was to corroborate increasing genomic instability and to elucidate those lesions in which the record from comparative genomic hybridization has remained unexpectedly negative. Replicate paraffin-embedded samples were investigated in detail using image microphotometry. Crucial to the recent approach was the fact that the histological compartments were exactly matched and that the single-cell measurements were highly accurate (CV at 0.05). Feulgen DNA was quantified in interphase nuclei and chromosome division figures, which were found in all cases of high-grade dysplasia and, with increased frequency, of colon carcinoma. The genomic imbalance in chromosome division figures was quantified by the sensitive 4.5 c exceeding rate (where c is the haploid genome equivalent), which was also positive in cases with a negative record from comparative genomic hybridization. The DNA content of chromosome division figures was measured with a mean 4.5 c exceeding rate of 25.8 +/- 4.4% standard error in 12 cases of high-grade dysplasia and of 62.1 +/- 7.1% in colon carcinoma (16 cases). The chromosome division figures were considered to be the first morphological manifestation of genomic instability attending precancerous conditions in the colon. Telophase-like chromosome division figures with unequal amounts of DNA in their hemispheres revealed gross somatic mutations before clonal selection.