The effect of dietary folate on Apc and p53 mutations in the dimethylhydrazine rat model of colorectal cancer

Dietary inadequacy of folate enhances and folate supplementation suppresses colorectal carcinogenesis in the dimethylhydrazine rat model. Folate is an essential factor for DNA methylation and the de novo biosynthesis of nucle otides, aberrations of which play important roles in mutagenesis, This stud y investigated whether the mutational hot spots of the Ape and p53 genes fo r human colorectal cancer are mutated in dimethylhydrazine-induced colorect al neoplasms and whether dietary folate can modulate mutations in these reg ions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg f olate/ kg diet. Five weeks after diet initiation, dimethylhydrazine was inj ected weekly for 15 weeks. Mutations were determined by direct sequencing i n 11 low and seven high grade dysplasias and 13 invasive adenocarcinomas. A total of six Ape mutations were found in four dysplastic and carcinomatous lesions: two in two low grade dysplasias, two in one high grade dysplasia and two in one adenocarcinoma. All mutations were single base substitutions , four of which were A:T-->G:C transitions. Five of the six mutations were located upstream from the region corresponding to the human APC mutation cl uster region. Dietary folate had no effect on the frequency and type of Ape mutations. No mutations were detected in exons 5-9 of the p53 gene in neop lastic lesions. These data suggest that in the dimethylhydrazine rat model of colorectal cancer, the Ape gene is mutated in early stages, albeit to a lesser degree than observed in human colorectal cancer, whereas the mutatio nal hot spot of the p53 gene for human colorectal cancer is not commonly mu tated. Although the low frequency of Ape mutations and the small number of neoplasms studied in this study might have precluded our ability to observe modulatory effects of folate, dietary folate appears to have no significan t effect on Ape and p53 mutations.