Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Folate intake and the risk of prostate cancer: a systematic review and meta-analysis

Abstract

There is conflicting evidence regarding the role of folate on the risk of developing prostate cancer. We performed a systematic review and quantitative meta-analysis of folate blood levels and folate intake, and the risk of prostate cancer. Four electronic databases (Medline, PubMed, Embase and Current Contents Connect) were searched to 11 October 2013, with no language restrictions for observational studies that measured folate intake or blood levels and the risk of prostate cancer. Pooled odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using a random effects model. The dietary folate meta-analysis comprising 11 studies with 15 336 cases and a total sample size of 146 782 found no statistically significant association with prostate cancer, with an OR of 0.97 (95% CI 0.89–1.06). The total folate meta-analysis comprising of 5 studies with 7114 cases and a total sample size of 93 781 also found no statistically significant association with prostate cancer, with an OR of 0.99 (95% CI 0.82–1.19). The blood folate meta-analysis comprising of seven studies with 6122 cases and a total sample size of 10 232 found an increased risk of prostate cancer with high blood folate levels, with an OR of 1.43 (95% CI 1.06–1.93). There was significant heterogeneity (I2=79.5%, P<0.01). Removal of an outlier study removed the heterogeneity (I2=0.0%, P=0.54) and the association remained significant with an OR of 1.14 (95% CI 1.02–1.28). Dietary and total folate intake do not appear to be significantly associated with the risk of prostate cancer. High blood folate levels are associated with an increased risk of prostate cancer. These conclusions are limited by the predominance of included studies originating from developed countries with mostly Caucasian populations. Further research in populations with a high prevalence of non-Caucasian backgrounds is needed.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D . Global cancer statistics. Cancer J Clin 2011; 61: 69–90.

    Article  Google Scholar 

  2. Blount BC, Mack MM, Wehr CM, MacGregor JT, Hiatt RA, Wang G et al. Folate deficiency causes uracil misincorporation into human DNA and chromosomal breakage; implications for cancer and neuronal damage. Proc Natl Acad Sci USA 1997; 94: 3290–3295.

    Article  CAS  PubMed  Google Scholar 

  3. Stempak JM, Sohn KY, Chiang EP, Shane B, Kim YI . Cell and stage of transformation-specific effects of folate deficiency on methionine cycle intermediates and DNA methylation in an in vitro model. Carcinogenesis 2005; 26: 981–990.

    Article  CAS  PubMed  Google Scholar 

  4. Bistulfi G, Vandette E, Matsui S, Smiraglia DJ . Mild folate deficiency induces genetic and epigenetic instability and phenotype changes in prostate cancer cells. BMC Biol 2010; 8: 6.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Bistulfi G, Foster BA, Karasik E, Gillard B, Miecznikowski J, Dhiman VK et al. Dietary folate deficiency blocks prostate cancer progression in the TRAMP model. Cancer Prev Res 2011; 4: 1825–1834.

    Article  CAS  Google Scholar 

  6. Shabbeer S, Williams SA, Simons BW, Herman JG, Carducci MA . Progression of prostate carcinogenesis and dietary methyl donors: temporal dependence. Cancer Prev Res 2012; 5: 229–239.

    Article  CAS  Google Scholar 

  7. 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: 819–824.

    Article  CAS  PubMed  Google Scholar 

  8. Pelucchi C, Galeone C, Talamini R, Negri E, Parpinel M, Franceschi S et al. Dietary folate and risk of prostate cancer in Italy. Cancer Epidemiol Biomarkers Prev 2005; 14: 944–948.

    Article  CAS  PubMed  Google Scholar 

  9. Stevens VL, Rodriguez C, Pavluck Al, McCullough ML, Thun MJ, Calle EE . Folate nutrition and prostate cancer incidence in a large cohort of US men. Am J Epidemiol 2006; 163: 989–996.

    Article  PubMed  Google Scholar 

  10. Weinstein SJ, Hartman TJ, Stolzenberg-Solomon R, Pietinen P, Barrett MJ, Taylor PR et al. Null association between prostate cancer and serum folate, vitamin B6, vitamin B12, and homocysteine. Cancer Epidemiol Biomarkers Prev 2003; 12: 1271–1272.

    CAS  PubMed  Google Scholar 

  11. Wien TN, Pike E, Wisloff T, Staff A, Smeland S, Klemp M . Cancer risk with folic acid supplements: a systematic review and meta-analysis. BMJ Open 2012; 12: e000653.

    Article  Google Scholar 

  12. Quin X, Cui Y, Shen L, Sun N, Zhang Y, Li J et al. Folic acid supplementation and cancer risk: a meta-analysis of randomized controlled trials. Int J Cancer 2013; 133: 1033–1041.

    Article  Google Scholar 

  13. Vollset SE, Clarke R, Lewington S, Ebbing M, Halsey J, Lonn E et al. Effects of folic acid supplementation on overall and site-specific cancer incidence during the randomised trials: meta-analyses of data on 50 000 individuals. Lancet 2013; 381: 1029–1036.

    Article  CAS  PubMed  Google Scholar 

  14. Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D et al. Metaanalysis of Observational Studies in Epidemiology (MOOSE) Group. Meta-analysis of observational studies in epidemiology: a proposal for reporting. JAMA 2000; 283: 2008–2012.

    Article  CAS  PubMed  Google Scholar 

  15. DerSimonian R, Laird N . Meta-analysis in clinical trials. Control Clin Trials 1986; 7: 177–188.

    Article  CAS  PubMed  Google Scholar 

  16. Higgins JP, Thompson SG, Deeks JJ, Altman DG . Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Egger M, Davey Smith G, Schneider M, Minder C . Bias in meta-analysis detected by a simple, graphical test. BMJ 1997; 315: 629–634.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Aune D, Deneo-Pellegrini H, Ronco AL, Boffetta P, Acosta G, Mendilaharsu M et al. Dietary folate intake and the risk of 11 types of cancer: a case control study in Uruguay. Ann Oncol 2011; 22: 444–451.

    Article  CAS  PubMed  Google Scholar 

  19. Bassett JK, Severi G, Hodge AM, Baglietto L, Hopper JL, English DR et al. Dietary intake of B vitamins and methionine and prostate cancer incidence and mortality. Cancer Causes Control 2012; 23: 855–863.

    Article  PubMed  Google Scholar 

  20. Beilby J, Ambrosini GL, Rossi E, de Klerk NH, Musk AW . Serum levels of folate, lycopene, beta-carotene, retinol and vitamin E and prostate cancer risk. Eur J Clin Nutr 2010; 64: 1235–1238.

    Article  CAS  PubMed  Google Scholar 

  21. Collin SM, Metcalfe C, Refsum H, Lewis SJ, Zuccolo L, Smith GD et al. Circulating folate, vitamin B12, homocysteine, vitamin B12 transport proteins, and risk of prostate cancer: a case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 2010; 19: 1632–1642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jackson MD, Tulloch-Reid MK, McFarlane-Anderson N, Watson A, Seers V, Bennett FI et al. Complex interaction between serum folate levels and genetic polymorphisms in folate pathway genes: biomarkers of prostate cancer aggressiveness. Genes Nutr 2013; 8: 199–207.

    Article  CAS  PubMed  Google Scholar 

  23. Johansson M, Appleby PN, Allen NE, Travis RC, Roddam AW, Egevad L et al. Circulating concentrations of folate and vitamin B12 in relation to prostate cancer risk: results from the European Prospective Investigation into Cancer and Nutrition study. Cancer Epidemiol Biomarkers Prev 2008; 17: 279–285.

    Article  CAS  PubMed  Google Scholar 

  24. Kobayashi LC, Limburg H, Miao Q, Woolcott C, Bedard LL, Massey TE et al. Folate intake, alcohol consumption, and the methylenetetrahydrofolate reductase (MTHFR) C677T gene polymorphism: influence on prostate cancer risk and interactions. Front Oncol 2012; 2: 100.

    PubMed  PubMed Central  Google Scholar 

  25. Lewis JE, Soler-Vila H, Clark PE, Kresty LA, Allen GO, Hu JJ . Intake of plant foods and associated nutrients in prostate cancer risk. Nutr Cancer 2009; 61: 216–224.

    Article  CAS  PubMed  Google Scholar 

  26. Shannon J, Phoutrides E, Palma A, Farris P, Peters L, Forester A et al. Folate intake and prostate cancer risk: a case-control study. Nutr Cancer 2009; 61: 617–628.

    Article  CAS  PubMed  Google Scholar 

  27. Verhage BA, Cremers P, Schouten LJ, Goldbohm RA, van den Brandt PA . Dietary folate and folate vitamers and the risk of prostate cancer in The Netherlands Cohort Study. Cancer Causes Control 2012; 23: 2003–2011.

    Article  PubMed  Google Scholar 

  28. Vidal AC, Grant DJ, Williams CD, Masko E, Allott EH, Shuler K et al. Associations between Intake of Folate, Methionine, and Vitamins B12,B6, and Prostate Cancer Risk in American Veterans. J Cancer Epidemiol 2012; 2012: 957467.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Vlajinac HD, Marinkovic JM, Ilic MD, Kocev NI . Diet and prostate cancer: a case-control study. Eur J Cancer 1997; 33: 101–107.

    Article  CAS  PubMed  Google Scholar 

  30. Weinstein SJ, Stolzenberg-Solomon R, Pietinen P, Taylor PR, Virtamo J, Albanes D . Dietary factors of one-carbon metabolism and prostate cancer risk. Am J Clin Nutr 2006; 84: 929–935.

    Article  CAS  PubMed  Google Scholar 

  31. Roswall N, Larsen SB, Friis S, Outzen M, Olsen A, Christensen J et al. Micronutrient intake and risk of prostate cancer in a cohort of middle-aged, Danish men. Cancer Causes Control 2013; 24: 1129–1135.

    Article  PubMed  Google Scholar 

  32. de Vogel S, Meyer K, Fredriksen A, Ulvik A, Ueland PM, Nygard O et al. Serum folate and vitamin B12 concentrations in relation to prostate cancer risk–a Norwegian population-based nested case-control study of 3000 cases and 3000 controls within the JANUS cohort. Int J Epidemiol 2013; 42: 201–210.

    Article  PubMed  Google Scholar 

  33. Cai D, Ning L, Pan C, Liu X, Bu R, Chen X et al. Association of polymorphisms in folate metabolic genes and prostate cancer risk: a case-control study in a Chinese population. J Genet 2010; 89: 263–267.

    Article  PubMed  Google Scholar 

  34. Collin SM, Metcalf C, Zuccolo L, Lewis SJ, Chen L, Cox A et al. Association of folate-pathway gene polymorphisms with the risk of prostate cancer: a population-based nested case-control study, systematic review, and meta-analysis. Cancer Epidemiol Biomarkers Prev 2009; 18: 2528–2539.

    Article  CAS  PubMed  Google Scholar 

  35. Ebbing M, Bonaa KH, Nygard O, Arnesen E, Ueland PM, Nordrehaug JE et al. Cancer incidence and mortality after treatment with folic acid and vitamin B12. JAMA 2009; 302: 2119–2126.

    Article  CAS  PubMed  Google Scholar 

  36. Figueiredo JC, Grau MV, Haile RW, Sandler RS, Summers RW, Bresalier RS et al. Folic acid and risk of prostate cancer: results from a randomized trial. J Natl Cancer Inst 2009; 101: 432–435.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Hankey GJ, Eikelboom JW, Yi Q, Lees KR, Chen C, Xavier D et al. Treatment with B vitamins and incidence of cancer in patients with previous stroke or transient ischemic attack: results of a randomized placebo-controlled trial. Stroke 2012; 43: 1572–1577.

    Article  CAS  PubMed  Google Scholar 

  38. Kasperzyk JL, Fall K, Mucci LA, Hakansson N, Wolk A, Johansson JE et al. One-carbon metabolism-related nutrients and prostate cancer survival. Am J Clin Nutr 2009; 90: 561–569.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Neuhouser ML, Kristal AR, Patterson RE, Goodman PJ, Thompson IM . Dietary supplement use in the Prostate Cancer Prevention Trial: implications for prevention trials. Nutr Cancer 2001; 39: 12–18.

    Article  CAS  PubMed  Google Scholar 

  40. Rossi E, Hung J, Beilby JP, Knuiman MW, Divitni ML, Bartholomew H . Folate levels and cancer morbidity and mortality: prospective cohort study from Busselton, Western Australia. Ann Epidemiol 2006; 16: 206–212.

    Article  PubMed  Google Scholar 

  41. Tavani A, Malerba S, Pelucchi C, Dal Maso L, Zuchetto A, Serraino D et al. Dietary folates and cancer risk in a network of case-control studies. Ann Oncol 2012; 23: 2737–2742.

    Article  CAS  PubMed  Google Scholar 

  42. Van Guelphen BR, Wiren SM, Bergh AR, Hallmans G, Stattin PE, Hultdin J . Polymorphisms of methylenetetrahydrofolate reductase and the risk of prostate cancer: a nested case-control study. Eur J Cancer Prev 2006; 15: 46–50.

    Article  Google Scholar 

  43. Zhang Y, Coogan P, Palmer JR, Strom BL, Rosenberg L . Vitamin and mineral use and risk of prostate cancer: the case-control surveillance study. Cancer Causes Control 2009; 20: 691–698.

    Article  CAS  PubMed  Google Scholar 

  44. Bailey RL, Gahche JJ, Lentino CV, Dwyer JT, Engel JS, Thomas PR et al. Dietary supplement use in the United States, 2003–2006. J Nutr 2011; 141: 261–266.

    Article  CAS  PubMed  Google Scholar 

  45. Skeie G, Braaten T, Hjartaker A, Lentjes M, Amiano P, Jakszyn P et al. Use of dietary supplements in the European Prospective Investigation into Cancer and Nutrition calibration study. Eu J Clin Nutr 2009; 63: S226–S238.

    Article  CAS  Google Scholar 

  46. Powell IJ . Epidemiology and pathophysiology of prostate cancer in African-American med. J Urol 2007; 177: 444–449.

    Article  PubMed  Google Scholar 

  47. Baade PD, Youlden DR, Krnjacki LJ . International epidemiology of prostate cancer: geographical distribution and secular trends. Mol Nutr Food Res 2009; 53: 171–184.

    Article  CAS  PubMed  Google Scholar 

  48. Mordukhovich I, Reiter PL, Backes DM, Family L, McCullough LE, O.Brien KM et al. A review of African American-white differences in risk factors for cancer: prostate cancer. Cancer Causes Control 2011; 22: 341–357.

    Article  PubMed  Google Scholar 

  49. Appel LJ, Miller ER 3rd, Jee SH, Stolzenberg-Solomon R, Lin PH, Erlinger T et al. Effect of dietary patterns on serum homocysteine: results of a randomized, controlled feeding study. Circulation 2000; 102: 852–857.

    Article  CAS  PubMed  Google Scholar 

  50. Venn BJ, Mann JI, Williams SM, Riddell LJ, Chisholm A, Harper MJ et al. Dietary counseling to increase natural folate intake: a randomized, placebo-controlled trial in free-living subjects to assess effects on serum folate and plasma total homocysteine. Am J Clin Nutr 2002; 76: 758–765.

    Article  CAS  PubMed  Google Scholar 

  51. Park YJ, Vollset SE, Melse-Boonstra A, Chajes V, Ueland PM, Slimani N . Dietary intake and biological measurement of folate: a qualitative review of validation studies. Mol Nutr Food Res 2013; 57: 562–581.

    Article  CAS  PubMed  Google Scholar 

  52. Green R . Indicators for assessing folate and vitamin B-12 status and for monitoring the efficacy of intervention strategies. Am J Clin Nutr 2011; 94: 666S–672SS.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to G D Eslick.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tio, M., Andrici, J., Cox, M. et al. Folate intake and the risk of prostate cancer: a systematic review and meta-analysis. Prostate Cancer Prostatic Dis 17, 213–219 (2014). https://doi.org/10.1038/pcan.2014.16

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/pcan.2014.16

This article is cited by

Search

Quick links