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Cancer Epidemiology, Biomarkers & Prevention
Cancer Epidemiology, Biomarkers & Prevention
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Research Article

Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial

Sadaf Oliai Araghi, Jessica C. Kiefte-de Jong, Suzanne C. van Dijk, Karin M.A. Swart, Hanneke W. van Laarhoven, Natasja M. van Schoor, Lisette C.P.G.M. de Groot, Valery Lemmens, Bruno H. Stricker, André G. Uitterlinden and Nathalie van der Velde
Sadaf Oliai Araghi
1Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
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Jessica C. Kiefte-de Jong
2Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
3Leiden University College, The Hague, the Netherlands.
4Department of Public Health and Primary Care, Leiden University Medical Center/LUMC Campus, The Hague, the Netherlands.
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  • ORCID record for Jessica C. Kiefte-de Jong
  • For correspondence: j.c.kiefte-dejong@erasmusmc.nl
Suzanne C. van Dijk
1Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
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Karin M.A. Swart
5Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
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Hanneke W. van Laarhoven
6Department of Medical Oncology, Academic Medical Center, Amsterdam, the Netherlands.
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Natasja M. van Schoor
5Department of Epidemiology and Biostatistics, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
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Lisette C.P.G.M. de Groot
7Division of Human Nutrition and Health, Wageningen University, Wageningen, the Netherlands.
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  • ORCID record for Lisette C.P.G.M. de Groot
Valery Lemmens
1Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
8Department of Research, Netherlands Comprehensive Cancer Organisation, Utrecht, the Netherlands.
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Bruno H. Stricker
2Department of Epidemiology, Erasmus University Medical Center, Rotterdam, the Netherlands.
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André G. Uitterlinden
1Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
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  • ORCID record for André G. Uitterlinden
Nathalie van der Velde
1Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, the Netherlands.
9Department of Internal Medicine, Amsterdam UMC, University of Amsterdam, Section of Geriatric Medicine, Amsterdam Public Health Research Institute, Amsterdam, the Netherlands.
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DOI: 10.1158/1055-9965.EPI-17-1198
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Abstract

Background: Folic acid and vitamin B12 play key roles in one-carbon metabolism. Disruption of one-carbon metabolism may be involved in the risk of cancer. Our aim was to assess the long-term effect of supplementation with both folic acid and vitamin B12 on the incidence of overall cancer and on colorectal cancer in the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) trial.

Methods: Long-term follow-up of B-PROOF trial participants (N = 2,524), a multicenter, double-blind randomized placebo-controlled trial designed to assess the effect of 2 to 3 years daily supplementation with folic acid (400 μg) and vitamin B12 (500 μg) versus placebo on fracture incidence. Information on cancer incidence was obtained from the Netherlands cancer registry (Integraal Kankercentrum Nederland), using the International Statistical Classification of Disease (ICD-10) codes C00–C97 for all cancers (except C44 for skin cancer), and C18–C20 for colorectal cancer.

Results: Allocation to B vitamins was associated with a higher risk of overall cancer [171 (13.6%) vs. 143 (11.3%); HR 1.25; 95% confidence interval (CI), 1.00–1.53, P = 0.05]. B vitamins were significantly associated with a higher risk of colorectal cancer [43(3.4%) vs. 25(2.0%); HR 1.77; 95% CI, 1.08–2.90, P = 0.02].

Conclusions: Folic acid and vitamin B12 supplementation was associated with an increased risk of colorectal cancer.

Impact: Our findings suggest that folic acid and vitamin B12 supplementation may increase the risk of colorectal cancer. Further confirmation in larger studies and in meta-analyses combining both folic acid and vitamin B12 are needed to evaluate whether folic acid and vitamin B12 supplementation should be limited to patients with a known indication, such as a proven deficiency.

Footnotes

  • Trial registration: The B-PROOF study is registered with the Netherlands Trial Register (NTR NTR1333) and with ClinicalTrials.gov (NCT00696514).

  • Received January 5, 2018.
  • Revision received March 21, 2018.
  • Accepted October 4, 2018.
  • Published first October 19, 2018.
  • ©2018 American Association for Cancer Research.
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This OnlineFirst version was published on January 15, 2019
doi: 10.1158/1055-9965.EPI-17-1198

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Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial
Sadaf Oliai Araghi, Jessica C. Kiefte-de Jong, Suzanne C. van Dijk, Karin M.A. Swart, Hanneke W. van Laarhoven, Natasja M. van Schoor, Lisette C.P.G.M. de Groot, Valery Lemmens, Bruno H. Stricker, André G. Uitterlinden and Nathalie van der Velde
Cancer Epidemiol Biomarkers Prev January 15 2019 DOI: 10.1158/1055-9965.EPI-17-1198

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Folic Acid and Vitamin B12 Supplementation and the Risk of Cancer: Long-term Follow-up of the B Vitamins for the Prevention of Osteoporotic Fractures (B-PROOF) Trial
Sadaf Oliai Araghi, Jessica C. Kiefte-de Jong, Suzanne C. van Dijk, Karin M.A. Swart, Hanneke W. van Laarhoven, Natasja M. van Schoor, Lisette C.P.G.M. de Groot, Valery Lemmens, Bruno H. Stricker, André G. Uitterlinden and Nathalie van der Velde
Cancer Epidemiol Biomarkers Prev January 15 2019 DOI: 10.1158/1055-9965.EPI-17-1198
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