Background/aims: In long-term extensive ulcerative colitis, aneuploidy occurs earlier and loss of heterozygosity for p53 (p53 LOH) later during histological progression towards carcinoma. This study determined the time of onset of p53 mutation in this progression.
Methods: We developed a rapid, sensitive screening assay for p53 mutations at codon 248. The geographic distribution of this p53 mutation was mapped in two fresh colectomy specimens with mutations of codon 248 (1 cancer, 1 dysplasia) and correlated with patterns of clonal expansion, histological progression, and allelic loss. Numerous samples from throughout both colons were analyzed (216 for histology, 142 for DNA content, 104 for mutation, and 41 for p53 LOH).
Results: p53 mutation correlated highly with histological grade and was distributed more extensively than p53 LOH. Mutation, but not LOH, was also found in diploid, nondysplastic colonic mucosa adjacent to dysplastic areas.
Conclusions: These findings suggest that p53 mutation appears to be an early genetic event that precedes p53 LOH. The very close correlation of p53 mutation with aneuploidy (P > 0.0001) emphasizes the role of normal p53 at the G1 checkpoint to help prevent entry of genetically damaged cells into the cell cycle.