Circulating Folate and Vitamin B(12) and Risk of Prostate Cancer: A Collaborative Analysis of Individual Participant Data from Six Cohorts Including 6875 Cases and 8104 Controls

BACKGROUND: Folate and vitamin B(12) 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. OBJECTIVE: To investigate the associations between circulating folate and vitamin B(12) 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 B(12) 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 B(12) 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], p(trend) = 0.018, for folate and 1.12 [95% CI, 1.01–1.25], p(trend) = 0.017, for vitamin B(12)), with no evidence of heterogeneity between studies. The association with folate varied by tumour grade (p(heterogeneity) < 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]; p(trend) = 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 B(12) with risk by stage or grade of disease (p(heterogeneity) > 0.05). Use of single blood-sample measurements of folate and B(12) concentrations is a limitation. CONCLUSIONS: 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.