Aberrant Crypt Foci in Colon Cancer Epidemiology

Colonic carcinogenesis is characterized by progressive accumulations of genetic and epigenetic derangements. These molecular events are accompanied by histological changes that progress from mild cryptal architectural abnormalities in small adenomas to eventual invasive cancers. The transition steps from normal colonic epithelium to small adenomas are little understood. In experimental models of colonic carcinogenesis aberrant crypt foci (ACF), collections of abnormal appearing colonic crypts, are the earliest detectable abnormality and precede adenomas. Whether in fact ACF are precursors of colon cancer, however, remains controversial. Recent advances in magnification chromoendoscopy now allow these lesions to be identified in vivo and their natural history ascertained. While increasing lines of evidence suggest that dysplastic ACF harbor a malignant potential, there are few prospective studies to confirm causal relationships and supporting epidemiological studies are scarce. It would be very useful, for example, to clarify the relationship of ACF incidence to established risks for colon cancer, including age, smoking, sedentary lifestyle, and Western diets. In experimental animal models, carcinogens dose-dependently increase ACF, whereas most chemopreventive agents reduce ACF incidence or growth. In humans, however, few agents have been validated to be chemopreventive of colon cancer. It remains unproven, therefore, whether human ACF could be used as reliable surrogate markers of efficacy of chemopreventive agents. If these lesions could be used as reliable biomarkers of colon cancer risk and their reductions as predictors of effective chemopreventive agents, metrics to quantify ACF could greatly facilitate the study of colonic carcinogenesis and chemoprevention.