| Although the presence of aberrant crypt foci (ACF) in the colon is correlated to the occurrence of colon cancer, there is a need to demonstrate that some subpopulations of ACF progress to colon cancer and are not merely hyperplastic lesions and that, perhaps, different regions of the colon may give rise to distinct ACF types. It is the hypothesis of this proposal that ACF are neoplastic lesions in the colon and are the earliest identifiable precursors of some colorectal cancers (CRC). In order to support this hypothesis, two different projects were undertaken. First, grossly normal human colonic mucosa specimens obtained from surgical resections were evaluated by the methylene blue technique for the presence of ACF, which were then serially sectioned. Sections selected at a fixed interval were then viewed and evaluated for the presence and degree of dysplasia. Dysplasia is characteristic of preneoplastic or neoplastic epithelium; it was thus proposed here that a subpopulation of human ACF will also exhibit some degree of dysplasia if they are precursors of CRC. The results of this study demonstrate that 54% of human ACF exhibit some degree of dysplasia and that 3 ACF were found to be carcinoma in situ, or noninvasive cancer. The second project entailed using serial sections of ACF from female patients which have been evaluated for the presence and degree of dysplasia in the first study to determine the clonality status of these ACF by use of an X-linked chromosomal marker. X chromosomal inactivation, as described by the Lyon hypothesis, has been used to establish the monoclonality of human tumors. The demonstration of ACF as monoclonal populations would further support the hypothesis that ACF are precursors of CRC. It was found that 11 of 11 human ACF which could be analyzed were monoclonal, suggesting that ACF are indeed neoplastic lesions and that ACF may provide insight into the mechanism of clonality. |
