Journal of the National Cancer Institute Advance Access originally published online on August 8, 2007
JNCI Journal of the National Cancer Institute 2007 99(16):1214-1215; doi:10.1093/jnci/djm105
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Published by Oxford University Press 2007.
EDITORIAL |
One-Carbon Metabolism, Colorectal Carcinogenesis, Chemoprevention—with Caution
Correspondence to: Regina G. Ziegler, PhD, MPH, Epidemiology and Biostatistics Program, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Executive Plaza South 8098, Bethesda, MD 20892-7246 (e-mail: zieglerr{at}mail.nih.gov).
One-carbon metabolism comprises a network of integrated biochemical pathways that donate, and regenerate, the one-carbon moieties needed for physiologic processes. Efficient one-carbon metabolism is required for the biosynthesis of the purines, adenine and guanine, and the conversion of uridylate to thymidylate, which prevents the misincorporation of uracil into DNA (1). By donating a methyl group to homocysteine to create methionine, one-carbon metabolism also generates S-adenosylmethionine, the universal methyl donor, which is required for DNA methylation (1). Disruption of one-carbon metabolism can, therefore, interfere with DNA replication, DNA repair, and regulation of gene expression through methylation, each of which could promote carcinogenesis. One-carbon metabolism requires optimal activity of 25 or more enzymes, some of which depend on not only folate, a B vitamin, but also vitamins B-12, B-6, and B-2 (riboflavin) as coenzymes. Over the past 15 years, one-carbon metabolism has received increasing attention as a process whereby diet and genetic variation could modulate cancer risk. Based on the biochemistry, hypotheses were generated about the influence on cancer risk of folate and B-vitamin intake; folate and B-vitamin status; alcohol use, which interferes with folate bioavailability (2); and altered enzyme activity related to common genetic polymorphisms—hypotheses that could be tested in animal experiments, epidemiologic studies, and randomized clinical trials.
In epidemiologic studies, low folate intake has been linked to increased risks of several cancers, including cancers of the breast, ovary, cervix, esophagus, stomach, pancreas, and lymphoid tissues, but the evidence is most extensive for colorectal cancer and its precursor, colorectal adenoma. In both men and women, low folate intake is associated with increased risk of colorectal adenoma and cancer in the majority of the epidemiologic studies (3,4). Serum and red blood cell folate have generally, although not always, been inversely associated with risk (3). Limited data suggest that intake of methionine, an essential source of one-carbon groups, may also be protective (3). High alcohol consumption, which interferes with folate utilization and other aspects of one-carbon metabolism (2), was associated with increased risk, especially when folate intake was low (3). In rodent models, usually folate depletion enhanced and folate supplementation protected against the early stages of intestinal carcinogenesis (5).
Although folate and methionine have received more attention as one-carbon donors in studies of chronic disease, choline and its metabolite betaine merit comparable consideration. Like 5-methyl tetrahydrofolate, choline, once oxidized to betaine, can transfer a one-carbon moiety to homocysteine to produce methionine and then generate the universal methyl donor, S-adenosylmethionine. In animals and humans, dietary choline can compensate for folate deprivation and dietary folate can compensate for choline deprivation (6). It has been estimated that humans ingest approximately 50 mmol of methyl groups per day; approximately 60% are derived from choline, 20% from methionine, and 10%–20% from folate (7). Epidemiologic studies of choline and betaine intake have been sparse because of the absence of food composition data. However, a database of concentrations of free choline, choline-containing phospholipids, and betaine in common US foods has recently been developed (8). In the Framingham Offspring Study, intake of dietary choline and betaine assessed with this database was found to have a statistically significant inverse relationship to circulating homocysteine concentrations, particularly among participants with low folate intake or who consumed alchohol, thus confirming the role of choline and betaine as one-carbon donors in the general population (9). In a case–control study in California, higher maternal choline intake around the time of conception, also estimated with this database, was associated with a 50% reduction in neural tube defects, a birth defect previously linked to low perinatal folate intake (10). Both studies suggest that the normal variation in dietary intake of choline and betaine is physiologically important and can be measured with some degree of validity.
In this issue of the Journal, in the first epidemiologic study of choline and betaine intake and subsequent cancer risk, Cho et al. (11) use the new database to examine whether these one-carbon donors are, like folate, associated with reduced risk of colorectal adenoma. Their analysis was conducted among the approximately 39000 women in the Nurses’ Health Study who completed a 130-item food-frequency questionnaire in 1984 and also reported having a sigmoidoscopy or colonoscopy during the subsequent 18 years of follow-up (
50% of women completing the 1984 questionnaire). Approximately 2400 women with histologically confirmed adenoma of the distal colon or rectum were identified. Repeat food-frequency questionnaires were given every 2–4 years; to estimate long-term intake, cumulative average intake from all questionnaires before the date of endoscopy was calculated. Mean energy-adjusted total choline intake (331 ± 80 mg/day), primarily from red meat, eggs, poultry, and milk, was less than the current recommended daily intake of 425 mg/d for women (7) and approximately twice as high as mean energy-adjusted betaine intake (189 ± 97 mg/day), primarily from spinach, white bread, cold cereal, pasta, and dark bread.
Although it was hypothesized that choline and betaine intake would be associated with a reduced risk of colorectal adenoma, the risk of colorectal adenoma increased to a statistically significant extent with increasing choline intake; women in the highest quintile of choline intake, compared with women in the lowest quintile, had a multivariable-adjusted relative risk of 1.45 (95% confidence interval [CI] = 1.27 to 1.67; Ptrend<.001). The weak inverse association of betaine intake was not statistically significant (multivariable-adjusted relative risk between extreme quintiles = 0.90). The combined effect of choline and betaine was not estimated, nor was folate or methionine intake integrated. However, the positive association between choline intake and adenoma risk was strongest among those with low folate intake and those with higher alcohol intake, which suggests that one-carbon metabolism may be involved. The authors conjecture that choline might stimulate the growth of already initiated colorectal adenomas but also recognize that other dietary factors concentrated in the same foods as choline might be responsible for the elevated risk. Nevertheless, they cannot explain why intake of choline and betaine, important sources of one-carbon units capable of remethylating homocysteine, was, unlike intake of dietary folate, not inversely associated with risk of colorectal adenoma.
Other reasonable hypotheses about one-carbon metabolism and colorectal carcinogenesis, based on our current understanding of the biochemistry and underlying mechanisms, have also not been proven correct. In a recently published placebo-controlled randomized clinical trial among 1021 men and women with a recent history of colorectal adenoma, supplemental folic acid at 1 mg/d for up to 6 years did not reduce the incidence of subsequent colorectal adenomas and might have increased it (12). At the first colonoscopic follow-up, 3 years later, the relative risk for folic acid of at least one new colorectal adenoma was 1.04 (95% CI = 0.90 to 1.20); at the second follow-up, an additional 3–5 years later, risk for folic acid increased to 1.13 (95% CI = 0.93 to 1.37). Furthermore, there was a suggestion of increased risk of advanced lesions and of multiple adenomas among participants randomly assigned to folic acid. The clinical trial investigators pointed out that animal experiments on folate have been inconsistent, with several suggesting that folate deficiency can protect against, and folate supplementation can enhance, colorectal carcinogenesis (5,12). A reasonable explanation for the unexpected trial results is that supplemental folic acid promoted growth of undetected very early lesions in the colorectal mucosa (12,13).
Still another plausible hypothesis about one-carbon metabolism is that the folic acid used in vitamin supplements and food fortification will function in the same manner as naturally occurring food folate in ensuring efficient one-carbon metabolism. However, several recent epidemiologic studies have suggested that supplemental folic acid, possibly because of its structure, bioavailability, or dose, or because it enters one-carbon metabolism at a different point than food folate, may not provide comparable physiologic benefits (4,14,15,16).
Clearly, one-carbon metabolism and its role in carcinogenesis is more complicated than originally anticipated, and our understanding of the underlying mechanisms is probably incomplete. More research, and caution in developing public health policy and guidance, is warranted. We should remember the surprises and complexities that emerged for 
-carotene, vitamin E, vitamin C, and selenium, other initially promising chemopreventive agents.
NOTES
This research was supported by the Intramural Research Program of the National Cancer Institute, National Institutes of Health.
REFERENCES
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(3) Giovannucci E. Epidemiologic studies of folate and colorectal neoplasia: a review. J Nutr (2002) 132:2350S–2355S.
(4) Sanjoaquin MA, Allen N, Couto E, Roddam AW, Key TJ. Folate intake and colorectal cancer risk: a meta-analytical approach. Int J Cancer (2005) 113:825–828.[CrossRef][Web of Science][Medline]
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(6) Niculescu MD, Zeisel SH. Diet, methyl donors and DNA methylation: interactions between dietary folate, methionine and choline. J Nutr (2002) 132:2333S–2335S.
(7) Institute of Medicine and National Academy of Sciences USA. Dietary Reference Intakes for Folate, Thiamin, Riboflavin, Niacin, Vitamin B12, Pantothenic Acid, Biotin, and Choline, vol. 1. (1998) Washington, D.C: National Academy Press.
(8) Zeisel SH, Mar MH, Howe JC, Holden JM. Concentrations of choline-containing compounds and betaine in common foods. J Nutr (2003) 133:1302–1307. (Published erratum appears in J Nutr 2003;133:2918-2919.)
(9) Cho E, Zeisel SH, Jacques P, Selhub J, Dougherty L, Colditz GA, Willett WC. Dietary choline and betaine assessed by food-frequency questionnaire in relation to plasma total homocysteine concentration in the Framingham Offspring Study. Am J Clin Nutr (2006) 83:905–911.
(10) Shaw GM, Carmichael SL, Yang W, Selvin S, Schaffer DM. Periconceptional dietary intake of choline and betaine and neural tube defects in offspring. Am J Epidemiol (2004) 160:102–109.
(11) Cho E, Willett WC, Colditz GA, Fuchs CS, Wu K, Chan AT, et al. Dietary choline and betaine and the risk of distal colorectal adenoma in women. J Natl Cancer Inst (2007) 99:1224–31.
(12) Cole BF, Baron JA, Sandler RS, et al. for the Polyp Prevention Study Group. Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA (2007) 297:2351–2359.
(13) Ulrich CM, Potter JD. Folate and cancer—timing is everything. JAMA (2007) 297:2408–2409.
(14) Zhang SM, Moore SC, Lin J, Cook NR, Mason JE, Lee IM, Buring JE. Folate, vitamin B6, multivitamin supplements, and colorectal cancer risk in women. Am J Epidemiol (2006) 163:108–115.
(15) Martinez ME, Giovannucci E, Jiang R, Henning SM, Jacobs ET, Thompson P, Smith-Warner SA, Alberts DS. Folate fortification, plasma folate, homocysteine and colorectal adenoma recurrence. Int J Cancer (2006) 119:1440–1446.[CrossRef][Web of Science][Medline]
(16) Stolzenberg-Solomon RZ, Chang SC, Leitzmann MF, Johnson KA, Johnson C, Buys SS, Hoover RN, Ziegler RG. 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.
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