Vitamin D pathway gene variants and prostate cancer prognosis.
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.
Holt
Sarah K
SK
Division of Public Health Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA. skholt@fhcrc.org
Kwon
Erika M
EM
Koopmeiners
Joseph S
JS
Lin
Daniel W
DW
Feng
Ziding
Z
Ostrander
Elaine A
EA
Peters
Ulrike
U
Stanford
Janet L
JL
D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase / Q000235:genetics*; D000483:Alleles; D016022:Case-Control Studies; D018450:Disease Progression; D005787:Gene Frequency; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D016016:Proportional Hazards Models; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality*; D012372:ROC Curve; D018167:Receptors, Calcitriol / Q000235:genetics*; D013250:Steroid Hydroxylases / Q000235:genetics*; D065668:Vitamin D3 24-Hydroxylase; D044465:White People
D018167:Receptors, Calcitriol; D013250:Steroid Hydroxylases; C585549:CYP24A1 protein, human; D065668:Vitamin D3 24-Hydroxylase; D015090:25-Hydroxyvitamin D3 1-alpha-Hydroxylase