FREQUENT AND CHARACTERISTIC K-RAS ACTIVATION IN ABERRANT CRYPT FOCI OF COLON - IS THERE PREFERENCE AMONG K-RAS MUTANTS FOR MALIGNANT PROGRESSION

Background. To investigate very early lesion of colorectal cancer, K-r as activation and nuclear p53 accumulation were studied in aberrant cr ypt focus (ACF).Methods. ACF were microscopically identified in grossl y normal mucosa of patients with colorectal cancer who underwent surge ry. Each ACF was microdissected from the surgical specimen and divided into two pieces, one for histologic and immunohistochemical examinati ons and the other for K-ras activation. K-ras mutations in codons 12 a nd 13 were sequenced after being screened by polymerase chain reaction amplification followed by restriction fragment length polymorphism an alysis. Intranuclear accumulation of p53 protein was immunostained wit h the avidin-biotin complex method. Results. ACF was predominantly dis tributed in the sigmoid colon and rectum, and its incidence was increa sed with age. Unexpectedly, ACF was very rare in colons of three patie nts with hereditary nonpolyposis colorectal carcinoma. K-ras mutations were detected in 58% (33 of 57) of ACF cases and in 44% (11 of 25) of adenocarcinoma cases. Although GTT mutation in codon 12 was predomina ntly observed in adenocarcinoma (10 of 11), GAT mutation (12 of 33) wa s as frequent as GTT mutation (11 of 33) in ACF together with mutation at codon 13 (7 of 33). No accumulation of p53 protein was found in an y ACF. Conclusion. ACF were not diagnosed as neoplasms histologically, but they were considered to be neoplastic lesions, and K-ras activati on is one of the key events to form ACF. The G-T substitution in K-ras codon 12 may undergo malignant growth easily compared with G-A substi tution in colorectal carcinogenesis.