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LETTERS: Gordon Stirrat Taking folate in pregnancy and risk of maternal breast cancer: Authors and publishers must not disclaim ethical responsibility BMJ 2005; 330: 600 [Full text]

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The folate debate: two sides to every story

Johan Hultdin, Bethany Van Guelpen, Pär Stattin   (18 March 2005)

The folate debate: two sides to every story 18 March 2005
Johan Hultdin, MD and Consultant Medical Biosciences, Clinical Chemistry, Umeå University Hospital, SE-901 85 Umeå, Sweden, Bethany Van Guelpen, Pär Stattin Send response to journal: Re: The folate debate: two sides to every story	The recent report by Charles et al. (1) of an increased risk of death from breast cancer after folate supplementation during pregnancy has been criticised for its small size, lack of biological plausibility, and for causing unfounded alarm in the general population (2). However, in a recent prospective case-control study of 254 prostate cancer cases and 514 matched controls, we made a similar observation. A statistically significant positive association was found between plasma folate and vitamin B12 levels and risk of prostate cancer (odds ratio 1.60 for folate and 2.63 for vitamin B12 for highest vs. lowest quartile) (3). In a multivariate model including folate, vitamin B12, homocysteine, BMI, and smoking, the OR for vitamin B12 increased slightly whereas the OR for folate was attenuated to 1.30 (p>0.05). The relatively low plasma vitamin levels of the study subjects, however, suggest that supplementation as an explanation for our results is unlikely. Potential mechanisms for a stimulatory effect of folate and vitamin B12 on carcinogenesis exist. Folate metabolism provides one-carbon groups for DNA synthesis and repair and for methylation reactions. Yet while uracil misincorporation and global DNA hypomethylation are characteristics of many tumours, so is promoter-specific hypermethylation and consequent silencing of tumour suppressor genes (4). Studies in mice suggest that increased availability of one-carbon groups may enhance susceptibility to such site-specific hypermethylation (5). Furthermore, very high doses of folate have been shown to promote colorectal cancer in rodent models (6). In the Charles study, increased risk was seen at 5 mg of folic acid daily, a high dosage recommended only in secondary prevention of neural tube defects. Efforts to elucidate the putatively adverse effects of folate on cancer risk should be encouraged, not condemned, even if the benefits of increasing intake are shown in the end to outweigh any detrimental effects. 1. Charles D, Ness AR, Campbell D, Davey Smith G, Hall MH. Taking folate in pregnancy and risk of maternal breast cancer. BMJ. 2004;329:1375 -1376. 2. Stirrat G. Taking folate in pregnancy and risk of maternal breast cancer: Authors and publishers must not disclaim ethical responsibility. BMJ. 2005;330:600; author reply 600-601. 3. Hultdin J, Van Guelpen B, Bergh A, Hallmans G, Stattin P. Plasma folate, vitamin B12, and homocysteine and prostate cancer risk: A prospective study. Int J Cancer. 2005;113:819-24. 4. Jones PA, Baylin SB. The fundamental role of epigenetic events in cancer. Nat Rev Genet. 2002;3:415-428. 5. Waterland RA, Jirtle RL. Transposable elements: Targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293-5300. 6. Kim YI. Will mandatory folic acid fortification prevent or promote cancer? Am J Clin Nutr. 2004;80:1123-1128. Competing interests: None declared