SOMATIC APC AND K-RAS CODON-12 MUTATIONS IN ABERRANT CRYPT FOCI FROM HUMAN COLONS

Aberrant crypt foci (ACF) are microscopic lesions which have been post ulated to precede the development of adenomatous polyps, the pre curso rs 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 aci d frequency of these two genetic alterations in ACF harvested from hum an colorectal resection specimens. One hundred and fifty-four ACF comp rised of between 1 and 56 crypts were harvested from the grossly norma l mucosa of colorectal resection specimens of 28 patients with varying pathological diagnoses. One hundred and twenty-five ACF from 20 colon s were screened for the presence of K-ras codon 12 mutations with a po lymerase chain reaction/restriction enzyme-based method, The APC gene mutation duster region was screened in 65 ACF from 20 colons using a p olymerase chain reaction/single strand conformation polymorphism techn ique. Putative mutations were confirmed by direct sequencing. K-ras co don 12 mutations were identified in 13% (16 of 125) of ACF. We also id entified APC mutations in 4.6% (3 of 65) of ACF. The results of this s tudy demonstrate that both APC and K-ras mutations occur in ACF. These observations support the role of the ACF as a colorectal cancer precu rsor and provide further insight into the early genetic changes which occur during colorectal tumorigenesis.