title: Plasma 25-hydroxyvitamin D(3) and bladder cancer risk according to tumor stage and FGFR3 status: a mechanism-based epidemiological study.
abstract: BACKGROUND
  Previous evidence suggests that 25-hydroxyvitamin D(3) [25(OH)D(3)] protects against several cancers. However, little is known regarding urothelial bladder cancer (UBC). We analyzed the association between plasma 25(OH)D(3) and overall risk of UBC, as well as according to stage and FGFR3 molecular subphenotypes.
  
  
  METHODS
  Plasma concentrations of 25(OH)D(3) in 1125 cases with UBC and 1028 control subjects were determined by a chemiluminescence immunoassay. FGFR3 mutational status and expression in tumor tissue were assessed. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by logistic regression adjusting for potential confounders. Analyses were further stratified by tumor invasiveness and grade, FGFR3 expression, and smoking status. Cell proliferation was measured in human UBC cell lines cultured with 1α,25-dihydroxyvitamin D(3).
  
  
  RESULTS
  A statistically significantly increased risk of UBC was observed among subjects presenting the lowest concentrations of 25(OH)D(3) (OR(adj) = 1.83; 95% CI = 1.19 to 2.82; P = .006), showing a dose-response effect (P (trend) = .004). The association was stronger for patients with muscle-invasive tumors, especially among low-FGFR3 expressers (OR(adj) = 5.94; 95% CI = 1.72 to 20.45; P = .005). The biological plausibility of these associations is supported by the fact that, in vitro, 1α,25-dihydroxyvitamin D(3) upregulates FGFR3 expression in UBC cell lines with low levels of wild-type FGFR3.
  
  
  CONCLUSIONS
  These findings support a role of vitamin D in the pathogenesis of UBC and show that 25(OH)D(3) levels are associated with FGFR3 expression in the tumor. Because FGFR3 mutation and overexpression are markers of better outcome, our findings suggest that individuals with low levels of plasma 25(OH)D(3) may be at high risk of more aggressive forms of UBC.
authors.affiliation: Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain.
authors.forename: André F S
authors.initials: AF
authors.lastname: Amaral
authors.forename: Marinela
authors.initials: M
authors.lastname: Méndez-Pertuz
authors.forename: Alberto
authors.initials: A
authors.lastname: Muñoz
authors.forename: Debra T
authors.initials: DT
authors.lastname: Silverman
authors.forename: Yves
authors.initials: Y
authors.lastname: Allory
authors.forename: Manolis
authors.initials: M
authors.lastname: Kogevinas
authors.forename: Josep
authors.initials: J
authors.lastname: Lloreta
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Alfredo
authors.initials: A
authors.lastname: Carrato
authors.forename: Manuel
authors.initials: M
authors.lastname: Rivas del Fresno
authors.forename: Francisco X
authors.initials: FX
authors.lastname: Real
authors.forename: Núria
authors.initials: N
authors.lastname: Malats
mesh_terms: D000328:Adult; D000368:Aged; D016588:Anticarcinogenic Agents / Q000097:blood*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D015153:Blotting, Western; D002112:Calcifediol / Q000097:blood*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D005060:Europe / Q000453:epidemiology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007118:Immunoassay / Q000379:methods; D016015:Logistic Models; D008163:Luminescent Measurements; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016017:Odds Ratio; D012333:RNA, Messenger / Q000378:metabolism; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism*; D018570:Risk Assessment; D012307:Risk Factors; D013030:Spain / Q000453:epidemiology; D015854:Up-Regulation; D001749:Urinary Bladder Neoplasms / Q000097:blood / Q000737:chemistry / Q000453:epidemiology* / Q000473:pathology* / Q000517:prevention & control
chemical_list: D016588:Anticarcinogenic Agents; D014408:Biomarkers, Tumor; D012333:RNA, Messenger; C496365:FGFR3 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D002112:Calcifediol