Platinum Priority – Prostate Cancer
Editorial by XXX on pp. x–y of this issue

Circulating Folate and Vitamin B12 and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls

By: Alison J. Pricea b , Ruth C. Travisa, Paul N. Applebya, Demetrius Albanesc, Aurelio Barricarte Gurread e f, Tone Bjørgeg h, H. Bas Bueno-de-Mesquitai j k l, Chu Chenm, Jenny Donovann, Randi Gislefossh ff, Gary Goodmanm, Marc Gunterk, Freddie C. Hamdyo, Mattias Johanssonp q, Irena B. Kingr, Tilman Kühns, Satu Männistöt, Richard M. Martinn u v, Klaus Meyerw, David E. Nealx, Marian L. Neuhouserm, Ottar Nygårdy z, Par Stattinaa, Grethe S. Tellg, Antonia Trichopouloubb cc, Rosario Tuminodd, Per Magne Uelandy, Arve Ulvikw, Stefan de Vogelg, Stein Emil Vollsetg ee, Stephanie J. Weinsteinc, Timothy J. Keya , Naomi E. Allengg on behalf of the Endogenous Hormones, Nutritional Biomarkers, and Prostate Cancer Collaborative Group.

European Urology, Volume 70 Issue 6, December 2016, Pages 941-951

Published online: 01 December 2016

Keywords: Folate, Vitamin B, Prostate cancer, High grade, Prospective cohort, Pooled data meta-analysis

Abstract Full Text Full Text PDF (2,8 MB)



Folate and vitamin B12 are essential for maintaining DNA integrity and may influence prostate cancer (PCa) risk, but the association with clinically relevant, advanced stage, and high-grade disease is unclear.


To investigate the associations between circulating folate and vitamin B12 concentrations and risk of PCa overall and by disease stage and grade.

Design, setting, and participants

A study was performed with a nested case–control design based on individual participant data from six cohort studies including 6875 cases and 8104 controls; blood collection from 1981 to 2008, and an average follow-up of 8.9 yr (standard deviation 7.3). Odds ratios (ORs) of incident PCa by study-specific fifths of circulating folate and vitamin B12 were calculated using multivariable adjusted conditional logistic regression.

Outcome measurements and statistical analysis

Incident PCa and subtype by stage and grade.

Results and limitations

Higher folate and vitamin B12 concentrations were associated with a small increase in risk of PCa (ORs for the top vs bottom fifths were 1.13 [95% confidence interval (CI), 1.02–1.26], ptrend = 0.018, for folate and 1.12 [95% CI, 1.01–1.25], ptrend = 0.017, for vitamin B12), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (pheterogeneity < 0.001); higher folate concentration was associated with an elevated risk of high-grade disease (OR for the top vs bottom fifth: 2.30 [95% CI, 1.28–4.12]; ptrend = 0.001), with no association for low-grade disease. There was no evidence of heterogeneity in the association of folate with risk by stage or of vitamin B12 with risk by stage or grade of disease (pheterogeneity > 0.05). Use of single blood-sample measurements of folate and B12 concentrations is a limitation.


The association between higher folate concentration and risk of high-grade disease, not evident for low-grade disease, suggests a possible role for folate in the progression of clinically relevant PCa and warrants further investigation.

Patient summary

Folate, a vitamin obtained from foods and supplements, is important for maintaining cell health. In this study, however, men with higher blood folate levels were at greater risk of high-grade (more aggressive) prostate cancer compared with men with lower folate levels. Further research is needed to investigate the possible role of folate in the progression of this disease.

Take Home Message

Higher folate concentration was associated with an increased risk of high-grade disease that was not evident for low-grade disease. This finding suggests a possible role for folate in the progression of clinically relevant prostate cancer and warrants further investigation.

Keywords: Folate, Vitamin B12, Prostate cancer, High grade, Prospective cohort, Pooled data meta-analysis.


a Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK

b London School of Hygiene and Tropical Medicine, London, UK

c Nutritional Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda MD, USA

d Navarra Public Health Institute, Pamplona, Spain

e Navarra Institute for Health Research (IdiSNA), Pamplona, Spain

f CIBER Epidemiology and Public Health (CIBERESP), Madrid, Spain

g Department of Global Public Health and Primary Care, University of Bergen, Bergen, Norway

h Cancer Registry of Norway, Oslo, Norway

i Department for Determinants of Chronic Diseases, National Institute for Public Health and the Environment (RIVM), Bilthoven, The Netherlands

j Department of Gastroenterology and Hepatology, University Medical Centre, Utrecht, The Netherlands

k Department of Epidemiology and Biostatistics, The School of Public Health, Imperial College London, London, UK

l Department of Social and Preventive Medicine, Faculty of Medicine, University of Malaya, Kuala Lumpur, Malaysia

m Public Health Sciences Division, Program in Epidemiology, Fred Hutchinson Cancer Research Center, Seattle, WA, USA

n School of Social and Community Medicine, University of Bristol, Bristol, UK

o Nuffield Department of Surgery, University of Oxford, John Radcliffe Hospital, Oxford, UK

p International Agency for Research on Cancer, Lyon, France

q Department of Biobank Research, Umeå University, Umeå, Sweden

r Department of Internal Medicine, University of New Mexico, Albuquerque, NM, USA

s Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany

t Department of Health, National Institute for Health and Welfare, Helsinki, Finland

u Medical Research Council/University of Bristol Integrative Epidemiology Unit, University of Bristol, Bristol, UK

v National Institute for Health Research, Bristol Biomedical Research Unit in Nutrition, Bristol, UK

w Bevital AS, Bergen, Norway

x Department of Oncology, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK

y Department of Clinical Science, University of Bergen, Bergen, Norway

z Department of Heart Disease, Haukeland University Hospital, Bergen, Norway

aa Department of Surgical and Perioperative Sciences, Urology and Andrology, Umeå University, Umeå, Sweden

bb WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Department of Hygiene, Epidemiology and Medical Statistics, University of Athens, Greece

cc Hellenic Health Foundation, Athens, Greece

dd Cancer Registry and Histopathology Unit, “Civic - M.P. Arezzo” Hospital, ASP Ragusa, Ragusa, Italy

ee Norwegian Institute of Public Health, Bergen, Norway

ff Institute of Population-based research, Montebello, Oslo, Norway

gg Clinical trial Service Unit and Epidemiological Studies Unit, Nuffield Department of Clinical Medicine, University of Oxford, UK

Corresponding author. Cancer Epidemiology Unit, Nuffield Department of Population Health, University of Oxford, Oxford, OX3 7LF, UK. Tel. +44 (0) 1865 289600; fax: +44 (0) 1865 289610.

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