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 colo rectal carcinogenesis is still controversial. Histological examination and analyses of K-ras mutations and p53 gene expression were performe d to characterize ACF. Methods: ACF were identified microscopically in grossly normal colorectal mucosa. The ACF were separated into two pie ces, one for histological and immunohistochemical examinations and the other for molecular analysis. K-ras mutations in codons 12 and 13 wer e analyzed by polymerase chain reaction amplification, followed by res triction fragment length polymorphism and sequencing analyses. Intranu clear p53 protein was immunostained by the avidin-biotin complex metho d. Results: Histologically, elongation and apical branching of the cry pts 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 adeno carcinomas (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 neoplasm s, although genetically they are monoclonal lesions. K-ras mutation is critical in the formation of ACF, but p53 alteration could play a cau sal role in tumor progression.