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Somatic APC and K-ras Codon 12 Mutations in Aberrant Crypt Foci from Human Colons¹

Departments of Surgery [A. J. S., H. S. S., K. H., B. V. B., S. G.] and Pathology [A. M., B. V. B.], and the Samuel Lunenfeld Research Institute [H. S. S., M. P., S. G.], Mount Sinai Hospital, University of Toronto, Toronto M5G 1X5, Canada

Aberrant crypt foci (ACF) are microscopic lesions which have been postulated to precede the development of adenomatous polyps, the precursors to colorectal cancer. APC and ras gene mutations have been shown to be important early molecular events in the development of colorectal neoplasms. The objective of this study was to establish the nature and frequency of these two genetic alterations in ACF harvested from human colorectal resection specimens. One hundred and fifty-four ACF comprised of between 1 and 56 crypts were harvested from the grossly normal mucosa of colorectal resection specimens of 28 patients with varying pathological diagnoses. One hundred and twenty-five ACF from 20 colons were screened for the presence of K-ras codon 12 mutations with a polymerase chain reaction/restriction enzyme-based method. The APC gene mutation cluster region was screened in 65 ACF from 20 colons using a polymerase chain reaction/single strand conformation polymorphism technique. Putative mutations were confirmed by direct sequencing. K-ras codon 12 mutations were identified in 13% (16 of 125) of ACF. We also identified APC mutations in 4.6% (3 of 65) of ACF. The results of this study demonstrate that both APC and K-ras mutations occur in ACF. These observations support the role of the ACF as a colorectal cancer precursor and provide further insight into the early genetic changes which occur during colorectal tumorigenesis.

¹ Supported by the Leon Hirsch Traveling Fellowship and the S. Lederman Fellowship Foundation [A.J.S.], the National Cancer Institute of Canada [B.V.B., S.G.], and the Hospital for Sick Children Foundation [H.S.S., B.V.B.].

² These authors contributed equally to the project.

³ To whom requests for reprints should be addressed, at Department of Surgery, University of Ottawa, Suite 105, 1053 Carling Ave., Ottawa, Ontario K1Y 4E9, Canada.

Received 8/ 1/94. Accepted 9/20/94.

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