GENETIC ALTERATIONS IN ADENOMATOUS POLYPS--DIETARY FIBER, FAT, AND BILE ACIDS

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The molecular genetics of colorectal carcinoma are among the best understood of all common human cancers. The genes involved in progression through the adenoma-carcinoma sequence include oncogenes such as K-ras and suppressor genes such as Deleted In Colorectal Carcinoma (DCC) and p53. Epidemiologic and biochemical risk factors for colorectal cancer have been identified. Dietary factors, particularly high fat and low fiber intake, play a key role and appear to be mediated through the effects of fecal bile acids on colorectal epithelium. The link between the molecular genetic events and the epidemiologic and biochemical risk factors has not been characterized. The hypotheses to be tested are: (1) There is a positive association between high dietary fat and low dietary fiber intake, high fecal and blood secondary bile acid levels, and the frequency of alterations in K-ras,DCC and p53 genes in adenomas obtained from a cancer-free population. (2) Interventions directed at increasing fiber intake and lowering fecal and blood bile acid levels will reduce the frequency of these genetic alterations in recurrent polyps as compared to placebo- treated control patients. The primary specific aims are: (1) To conduct a cross-sectional study of colorectal adenomas examining the frequency of alterations in the genes involved in the adenoma- carcinoma sequence (K-ras mutations, DCC deletion, p53 gene product overexpression as a marker for mutation) and to determine the association between the prevalence of these genetic alterations in the index polyp and dietary fat and fiber intake, as well as fecal and plasma bile acid concentrations. (2) To determine the effect of a dietary intervention (high wheat bran fiber) or chemopreventive agent (ursodeoxycholate) on genetic alterations in recurrent polyps as compared to placebo-treated controls. The secondary specific aim is: (3) To estimate the associations between the occurrence of single or multiple genetic alterations and the intake patterns of those dietary components which are related to bile acid production.