FREQUENT AND CHARACTERISTIC K-RAS ACTIVATION AND ABSENCE OF P53 PROTEIN ACCUMULATION IN ABERRANT CRYPT FOCI OF THE COLON

Background/Aims: The relationship of aberrant crypt foci (ACF) to colorectal carcinogenesis is still controversial. Histological examination and analyses of K-ras mutations and p53 gene expression were performed to characterize ACF. Methods: ACF were identified microscopically in grossly normal colorectal mucosa. The ACF were separated into two pieces, one for histological and immunohistochemical examinations and the other for molecular analysis. K-ras mutations in codons 12 and 13 were analyzed by polymerase chain reaction amplification, followed by restriction fragment length polymorphism and sequencing analyses. Intranuclear p53 protein was immunostained by the avidin-biotin complex method. Results: Histologically, elongation and apical branching of the crypts in ACF were striking. K-ras mutations were detected in 58% of ACF (33 of 57; 46% [26 of 57] in codon 12, and 12% [7 of 57] in codon 13) and in 44% of adenocarcinomas (11 of 25; all in codon 12). In ACF, GAT mutations (12 of 26) were as frequent as GTT mutations (11 of 26) in codon 12, although GTT mutations in codon 12 were predominant in adenocarcinomas (10 of 11). No accumulation of p53 protein was detected in any ACF, although it was detected in 52% (13 of 25) of the colorectal carcinomas. Conclusions: ACF do not seem histologically to be neoplasms, although genetically they are monoclonal lesions. K-ras mutation is critical in the formation of ACF, but p53 alteration could play a causal role in tumor progression.