Background: Observational studies linking vitamin D deficiency with increased prostate cancer (PCa) mortality and the pleiotropic anticancer effects of vitamin D in malignant prostate cell lines have initiated trials examining potential therapeutic benefits of vitamin D metabolites. There have been some successes but efforts have been hindered by risk of inducing hypercalcemia. A limited number of studies have investigated associations between variants in vitamin D pathway genes with aggressive forms of PCa. Increased understanding of relevant germline genetic variation with disease outcome could aid in the development of vitamin-D-based therapies.
Methods: We undertook a comprehensive analysis of 48 tagging single-nucleotide polymorphisms (tagSNPs) in genes encoding for vitamin D receptor (VDR), vitamin D activating enzyme 1-alpha-hydroxylase (CYP27B1), and deactivating enzyme 24-hydroxylase (CYP24A1) in a cohort of 1,294 Caucasian cases with an average of 8 years of follow-up. Disease recurrence/progression and PCa-specific mortality risks were estimated using adjusted Cox proportional hazards regression.
Results: There were 139 cases with recurrence/progression events and 57 cases who died of PCa. Significantly altered risks of recurrence/progression were observed in relation to genotype for two VDR tagSNPs (rs6823 and rs2071358) and two CYP24A1 tagSNPs (rs927650 and rs2762939). Three VDR tagSNPs (rs3782905, rs7299460, and rs11168314), one CYP27B1 tagSNP (rs3782130), and five CYP24A1 tagSNPs (rs3787557, rs4809960, rs2296241, rs2585428, and rs6022999) significantly altered risks of PCa death.
Conclusions: Genetic variations in vitamin D pathway genes were found to alter both risk of recurrence/progression and PCa-specific mortality.