Carcinogenesis, Vol. 20, No. 12, 2345-2350,
December 1999
© 1999 Oxford University Press
Short Communications |
The effect of dietary folate on Apc and p53 mutations in the dimethylhydrazine rat model of colorectal cancer *
1 Division of Gastroenterology, Department of Medicine, St Michael's Hospital and University of Toronto, Room 7258, Medical Sciences Building, 1 King's College Circle, Toronto, Ontario, Canada M5S 1A8,
2 Vitamin Metabolism Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University,
3 Department of Pathology, New England Medical Center, Tufts University School of Medicine,
4 Department of Pathology, Massachusetts General Hospital, Harvard Medical School and
5 Divisions of Gastroenterology and Clinical Nutrition, Department of Internal Medicine, New England Medical Center, Tufts University School of Medicine, Boston, MA, USA and
6 Department of Pathology, University of Toronto, Toronto, Ontario, Canada
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 nucleotides, aberrations of which play important roles in mutagenesis. This study investigated whether the mutational hot spots of the Apc and p53 genes for human colorectal cancer are mutated in dimethylhydrazine-induced colorectal neoplasms and whether dietary folate can modulate mutations in these regions. Rats were fed diets containing 0, 2 (basal requirement), 8 or 40 mg folate/kg diet. Five weeks after diet initiation, dimethylhydrazine was injected weekly for 15 weeks. Mutations were determined by direct sequencing in 11 low and seven high grade dysplasias and 13 invasive adenocarcinomas. A total of six Apc 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 cluster region. Dietary folate had no effect on the frequency and type of Apc mutations. No mutations were detected in exons 5–9 of the p53 gene in neoplastic lesions. These data suggest that in the dimethylhydrazine rat model of colorectal cancer, the Apc gene is mutated in early stages, albeit to a lesser degree than observed in human colorectal cancer, whereas the mutational hot spot of the p53 gene for human colorectal cancer is not commonly mutated. Although the low frequency of Apc 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 significant effect on Apc and p53 mutations.
Abbreviations: CA, invasive adenocarcinoma; CpG, cytosine–guanine doublet; CRC, colorectal cancer; DMH, dimethylhydrazine; H&E, hematoxylin and eosin; HGD, high grade dysplasia; LGD, low grade dysplasia; MCR, mutation cluster region; dNTP, deoxynucleotide precursors.
7 To whom correspondence should be addressed Email: youngin.kim{at}utoronto.ca
* Presented in part at the 1998 Digestive Disease Week, May 17–20, 1998, New Orleans, LA, USA, and published in abstract form in Gastroenterology, 1998, 114, G2571.
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