Abstract
Purpose: Folate is essential to DNA methylation and synthesis and may have a complex dualistic role in prostate cancer. Alcohol use may increase risk and epigenetic factors may interact with lifestyle exposures. We aimed to characterize the independent and joint effects of folate intake, alcohol consumption, and the MTHFR C677T gene polymorphism on prostate cancer risk, while accounting for intakes of vitamins B2, B6, B12, methionine, total energy, and confounders. Methods: A case-control study was conducted at Kingston General Hospital of 80 incident primary prostate cancer cases and 334 urology clinic controls, all with normal age-specific PSA levels (to exclude latent prostate cancers). Participants completed a questionnaire on folate and alcohol intakes and potential confounders prior to knowledge of diagnosis, eliminating recall bias, and blood was drawn for MTHFR genotyping. Joint effects of exposures were assessed using unconditional logistic regression and significance of multiplicative and additive interactions using general linear models. Results: Folate, vitamins B2, B6, B12, methionine, and the CT and TT genotypes were not associated with prostate cancer risk. The highest tertile of lifetime alcohol consumption was associated with increased risk (OR = 2.08; 95% CI: 1.12–3.86). Consumption of >5 alcoholic drinks per week was associated with increased prostate cancer risk among men with low folate intake (OR = 2.38; 95% CI: 1.01–5.57), and higher risk among those with the CC MTHFR genotype (OR = 4.43; 95% CI: 1.15–17.05). Increased risk was also apparent for average weekly alcohol consumption when accounting for the multiplicative interaction between folate intake and MTHFR C677T genotype (OR = 3.22; 95% CI: 1.36–7.59). Conclusion: Alcohol consumption is associated with increased prostate cancer risk, and this association is stronger among men with low folate intake, with the CC MTHFR genotype, and when accounting for the joint effect of folate intake and MTHFR C677T genotype.
Highlights
Prostate cancer is the second most common malignancy among men (Ferlay et al, 2010)
Deficient folate levels have been shown in murine prostate cancer models to result in CpG island hypermethylation and misincorporation of uracil into DNA strands, leading to genetic and epigenetic instability that is characteristic of carcinogenesis (Bistulfi et al, 2010)
Average weekly alcohol consumption was associated with increased prostate cancer risk when folate intake, methylenetetrahydrofolate reductase (MTHFR) C677T genotype, and their multiplicative interaction were accounted for
Summary
Prostate cancer is the second most common malignancy among men (Ferlay et al, 2010). With 5–10% attributable to family history and genetic susceptibility (National Cancer Institute, 2004), etiology of prostate cancer is largely unknown (International Agency for Research on Cancer, 2008). Deficient folate levels have been shown in murine prostate cancer models to result in CpG island hypermethylation and misincorporation of uracil into DNA strands, leading to genetic and epigenetic instability that is characteristic of carcinogenesis (Bistulfi et al, 2010). Folate deficiency can halt progression of pre-existing tumors in the murine model (Tomaszewski et al, 2011) and high serum folate concentrations have been associated with an increased rate of progression among men with existing prostate cancer (Collin et al, 2010a). Conflicting results from epidemiological research may reflect this potential dualistic role of folate in prostate carcinogenesis
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