|Hazra, Aditi -|
|Selhub, Jacob -|
|Chao, Wei-Hsun -|
|Ueland, Per Magne -|
|Hunter, David -|
|Baron, John -|
Submitted to: American Journal of Clinical Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: October 12, 2009
Publication Date: January 20, 2010
Citation: Hazra, A., Selhub, J., Chao, W., Ueland, P., Hunter, D., Baron, J. 2010. Uracil misincorporation into DNA and folic acid supplementation. American Journal of Clinical Nutrition. 91(1):160-165. Interpretive Summary: Folate, a water-soluble B vitamin, is an important cofactor for DNA methylation reactions and nucleotide synthesis (1). In observational studies, there is an inverse association between folate intake (2–13) or circulating folate concentrations (3, 14, 15) and the risk of colorectal cancer and adenomas. However, in the Aspirin/Folate Polyp Prevention Study, supplementation with 1 mg folic acid/d did not reduce colorectal adenoma risk (16). In secondary analyses, there was evidence of increased risk, with higher rates of advanced adenomas and multiple adenomas. Folate plays a dual role in animal carcinogenesis (17, 18). Thus, folate deficiency may promote carcinogenesis, whereas high folate status may stimulate the growth of existing preneoplastic and malignant lesions(9, 19). Deficient cellular folate decreases thymidylate synthesis, producing deoxyribonucleotide pool imbalances. This results in uracil misincorporation (UrMis) into DNA during replication and repair (20–22). In addition, UrMis can also occur from spontaneous hydrolytic deamination of cytosine. Repair of uracil residues produces double-strand breaks, deletions, chromosomal breaks, micronucleus formation, and loss of heterozygosity (20–23). The resultant DNA damage may contribute to the increased risk of cancer (24) associated with folate inadequacy (25). It is not known to what extent folate supplementation in a population with folic acid fortification of the food supply affects UrMis or whether there are differences between white blood cells (WBCs) and rectal mucosa tissue in the extent of UrMis or in the response to folate supplementation. To clarify these issues, we evaluated the relation between UrMis and the risk of colorectal adenomas among 98 individuals in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to receive folate treatment or placebo and then evaluated for adenoma recurrence.
Technical Abstract: BACKGROUND: Folate deficiency decreases thymidylate synthesis from deoxyuridylate, which results in an imbalance of deoxyribonucleotide that may lead to excessive uracil misincorporation (UrMis) into DNA during replication and repair. OBJECTIVE: We evaluated the relation between UrMis in different tissues and the effect of folate supplementation on UrMis. DESIGN: We analyzed UrMis concentrations in rectal mucosa (n = 92) and white blood cells (WBCs; n = 60) among individuals randomly assigned to receive supplementation with 1 mg folate/d or placebo, who were then evaluated for colorectal adenoma recurrence. RESULTS: As expected, total homocysteine was significantly lower among the study participants who received active folate treatment (Wilcoxon's P = 0.003) than among those in the placebo group. The median UrMis concentration in rectal mucosa and WBCs among individuals treated with folate was not significantly lower than that in those who received placebo (Wilcoxon's P = 0.17). UrMis concentrations in both rectal mucosa and WBCs did not correlate significantly with folate measured in plasma and red blood cells. UrMis in rectal mucosa was marginally associated with an increased risk of adenoma recurrence (odds ratio per SD: 1.43; 95% CI: 0.91, 2.25). CONCLUSIONS: UrMis measurements in WBCs are not a robust surrogate for UrMis measurements in the rectal mucosa (Spearman correlation coefficient = 0.23, P = 0.08). Furthermore, folate supplementation in an already replete population (half treated with folic acid supplements and all exposed to folic acid fortification of the food supply) was not significantly associated with reduced UrMis in rectal mucosa cells or WBCs. Large-scale studies are needed to evaluate whether excessive UrMis concentrations are an important risk factor for colorectal neoplasia.