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Folate and cancer

Folate plays a central role both in DNA synthesis and DNA methylation and can therefore influence the risk of cancer. Folate is currently discussed in relation to cancer prevention and cancer induction. On the one hand, folate deficiency can cause misincorporation of uracil into the DNA (instead of thymidine). This may lead to strand breakage during DNA excision repair. The erroneous incorporation of uracil is reversible by means of folate or FA supplementation.


On the other hand, in the past years suspicion arose about potential adverse effects of consumption of high doses of FA. The target group for FA fortification are women of childbearing age, therefore question emerged if it is justifiable to expose the entire population to mandatorily fortified foods with uncertain risk. Oral doses of FA from supplements or fortified foods (above 400 µg/d) result in the presence of unmetabolized FA in serum (1). Unmetabolized FA is discussed for its role in masking vitamin B12 deficiency especially in elderly people with B12 malabsorption. FA might reduce the efficiency of antifolates (chemotherapeutics) that act by limiting the folate supply to tumor cells (2). Moreover, in some studies high plasma folate levels were associated with premenopausal (3) and postmenopausal (4) breast cancer, and colorectal cancer.

 

 

Breast cancer

Evidence from one meta-analysis indicates significant inverse associations between dietary folate intake and risk of breast cancer suggesting a protective effect of the vitamin (5). In the meta-analysis Lewis et al. combined 13 case-control studies and 9 cohort studies that measured the folate intake (5). A summarized odds ratio (OR) of 0.91 (95% CI = 0.87 – 0.96) for breast cancer was reported by case-control studies and a summarized risk ratio (RR) of 0.99 (95% CI = 0.98 – 1.01) for cohort studies for a 100-µg/d increase in the folate intake (5). In the same report the summary OR for premenopausal breast cancer was 0.87 (95% CI = 0.78 – 0.97) for case-control studies and the summarized RR for cohort studies was 1.01 (95% CI = 0.98 – 1.04) (5). A follow-up study over 9 years in > 11,000 postmenopausal women showed a hazard ratio (HR) of 0.56 for a total daily folate intake of > 456 µg compared to 160 µg, which indicates a protective effect of the vitamin (6). In a recent study including 718 Chinese breast cancer cases and > 70,000 non-cases from the prospective cohort Shanghai Women’s Health Study, only in premenopausal women, a higher intake of folate was associated with a decreased breast cancer risk [HR of 0.58 (95% CI = 0.34 – 0.99) for the highest (n = 40 cases; 404 µg/d folate) vs. the lowest (n = 55 cases; 194 µg/d folate) quintile of intake] (7). Despite some reports on positive association between the folate intake and the breast cancer risk, the results are not consistent and do not support a causal role for FA or dietary folate in the range below the upper tolerable limit of 1 mg/d.

Colon cancer

After the introduction of FA fortification programs in the US and Canada in 1998, for the following 3 years a rise in colorectal cancer was observed (8). However, this finding does not prove a causal role for FA and the cancer risk, because over the same time period the diagnostic possibilities for colorectal cancers were notably improved. As the study by Mason et al. did not investigate the mortality due to colorectal cancer, it is not clear whether FA fortification or supplementation is associated is associated with a higher mortality (8).


According to a meta-analysis including 5 cross-sectional and 7 case-control studies, the risk of colorectal tumors was reduced by about 25% with high dietary folate intake (9). Another case-control study reported that high serum folate concentrations (≥ 31.0 nmol/L) were associated with a 50% lower risk [OR = 0.52 (95% CI = 0.27 – 0.97)] for colorectal cancer than low serum folate concentrations (≤ 12.2 nmol/L) (10). A recent meta-analysis of 27 studies (18 case-control studies and 9 cohort studies; FA intake ranging from 150 – 2,430 µg/d) conducted by Kennedy et al. reported an inverse correlation between folate intake and colorectal cancer incidence (11). The summarized risk estimate of high vs. low folate intake was 0.85 (95% CI = 0.74 – 0.99) for case-control studies and was 0.92 (95% CI = 0.81 – 1.05) for cohort studies (11). However, the intake of 1 mg/d FA for 6 to 8 years led to an increased risk for advanced or multiple lesions, whereas the recurrence of colorectal adenomas was not increased (12). In addition, high doses of FA supplementation (2.5 mg/d – 20 mg/d for two to five years with a subsequent follow-up for five to seven years) showed in populations without increased risk for colon cancer no significant effect on the colon cancer risk (13). Van Guelpen et al. observed in a study on 226 cases and 437 matched controls a bell-shaped association between plasma folate concentrations and the colorectal cancer risk (14).


Taken together, FA has a dual role regarding the risk for cancer. While folate deficiency is a risk factor for different tumors via misincorporation of uracil than thymidine into the DNA, excess FA supplementation (far more than 1 mg/d) is being discussed in relation to an increased cancer risk (genetic and epigenetic regulation) (15). High folate status is discussed to promote the progression of already existing preneoplasms (12). As 37.5% of individuals > 50 years have colorectal adenomas, high doses of FA over a longer time might pose a cancer risk. To date no proof exists regarding a causal role of FA intake via fortification or supplements (< 1 mg/d) for an increased cancer incidence or cancer related mortality.

References

1.     Kelly P, McPartlin J, Goggins M, Weir DG, Scott JM. Unmetabolized folic acid in serum: acute studies in subjects consuming fortified food and supplements. Am J Clin Nutr 1997;65:1790-5.
2.     Smith AD, Kim YI, Refsum H. Is folic acid good for everyone? Am J Clin Nutr 2008;87:517-33.
3.     Lin J, Lee IM, Cook NR, Selhub J, Manson JE, Buring JE, Zhang SM. Plasma folate, vitamin B-6, vitamin B-12, and risk of breast cancer in women. Am J Clin Nutr 2008;87:734-43.
4.     Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS et al. Folate intake, alcohol use, and postmenopausal breast cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Am J Clin Nutr 2006;83:895-904.
5.     Lewis SJ, Harbord RM, Harris R, Smith GD. Meta-analyses of observational and genetic association studies of folate intakes or levels and breast cancer risk. J Natl Cancer Inst 2006;98:1607-22.
6.     Ericson U, Sonestedt E, Gullberg B, Olsson H, Wirfalt E. High folate intake is associated with lower breast cancer incidence in postmenopausal women in the Malmo Diet and Cancer cohort. Am J Clin Nutr 2007;86:434-43.
7.     Shrubsole MJ, Shu XO, Li HL, Cai H, Yang G, Gao YT et al. Dietary B vitamin and methionine intakes and breast cancer risk among Chinese women. Am J Epidemiol 2011;173:1171-82.
8.     Mason JB, Dickstein A, Jacques PF, Haggarty P, Selhub J, Dallal G, Rosenberg IH. A temporal association between folic acid fortification and an increase in colorectal cancer rates may be illuminating important biological principles: a hypothesis. Cancer Epidemiol Biomarkers Prev 2007;16:1325-9.
9.     Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer 2005;113:825-8.
10.     Kato I, Dnistrian AM, Schwartz M, Toniolo P, Koenig K, Shore RE et al. Serum folate, homocysteine and colorectal cancer risk in women: a nested case-control study. Br J Cancer 1999;79:1917-22.
11.     Kennedy DA, Stern SJ, Moretti M, Matok I, Sarkar M, Nickel C, Koren G. Folate intake and the risk of colorectal cancer: a systematic review and meta-analysis. Cancer Epidemiol 2011;35:2-10.
12.     Cole BF, Baron JA, Sandler RS, Haile RW, Ahnen DJ, Bresalier RS et al. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007;297:2351-9.
13.     Cooper K, Squires H, Carroll C, Papaioannou D, Booth A, Logan RF et al. Chemoprevention of colorectal cancer: systematic review and economic evaluation. Health Technol Assess 2010;14:1-206.
14.     Van Guelpen B, Hultdin J, Johansson I, Hallmans G, Stenling R, Riboli E et al. Low folate levels may protect against colorectal cancer. Gut 2006;55:1461-6.
15.     Herrmann W, Obeid R. The mandatory fortification of staple foods with folic acid: a current controversy in Germany. Dtsch Arztebl Int 2011;108:249-54.