Vitamin D pathway gene variants and prostate cancer prognosis

Abstract

Background Observational studies linking vitamin D deficiency with increased prostate cancer 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 prostate cancer. Increased understanding of relevant germline genetic variation with disease outcome could aid in 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-α-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 prostate cancer-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 prostate cancer. 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 prostate cancer death. Conclusions Genetic variations in vitamin D pathway genes were found to alter both risk of recurrence/progression and prostate cancer-specific mortality.

Associations of circulating 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and vitamin D pathway genes with prostate-specific antigen progression in men with localized prostate cancer undergoing active monitoring

“…Similarly, vitamin D pathway gene variants may be associated with both disease recurrence/progression and prostate-specific mortality (Holt et al, 2010). Our current study, however, found no evidence that circulating levels or vitamin D genotypes influence postdiagnosis PSA DT in men on active monitoring.…”

“…Vitamin D levels may be associated with the risk of disease progression (Chen et al, 2009;Holt et al, 2010) and the risk of progression may potentially be lowered by increasing a man's circulating vitamin D level (Gross et al, 1998).…”

Regulation of CYP3A4 and CYP3A5 expression and modulation of “intracrine” metabolism of androgens in prostate cells by liganded vitamin D receptor

“…Epidemiological evidence also link low serum levels of vitamin D metabolites and the expression of genetic variants within its hormonal pathway with increased risk of prostate cancer, its recurrence/progression and cancer-specific mortality (Schwartz and Hulka, 1990;Huang et al, 2006;Xu et al, 2003;Williams et al, 2004;Holt et al, 2010). In addition, the hormonally active form of vitamin D that is 1,25(OH) 2 D 3 (henceforth referred to as 1,25D) exerts well documented growth-regulatory effects upon prostate cancer cell lines that includes regulated expression of the cell cycle-related genes p21( waf/cip1 ) and p27( kip1 ) in addition to interference with growth factor signaling through induction of the IGFBP3 gene (Sinkkonen et al, 2005;Wu et al, 1997;Peng et al, 2004).…”

Association of vitamin D receptor gene polymorphism and calcium urolithiasis in the Chinese Han population

“…In our association study, we evaluated a novel VDR polymorphism detectable with Dde I restriction enzyme, which have reported a significant association in the prostate cancer [34]. However, it seems the Dde I polymorphism is not a candidate genetic marker for urinary stone disease.…”