Plasma 25-Hydroxyvitamin D3 and Bladder Cancer Risk According to Tumor Stage and FGFR3 Status: A Mechanism-Based Epidemiological Study.
J Natl Cancer Inst. 2012 Oct 29.
Amaral AF, Méndez-Pertuz M, Muñoz A, Silverman DT, Allory Y, Kogevinas M, Lloreta J, Rothman N, Carrato A, Rivas Del Fresno M, Real FX, Malats N.
Affiliations of authors: Genetic and Molecular Epidemiology Group (AFSA, NM) and Epithelial Carcinogenesis Group (MM-P, FXR), Spanish National Cancer Research Centre, Madrid, Spain; Instituto de Investigaciones Biomédicas "Alberto Sols," Consejo Superior de Investigaciones Científicas-Universidad Autónoma de Madrid, Madrid, Spain (AM); Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD (DTS, NR); INSERM, U955, Institut Mondor de Recherche Biomédicale, Créteil, France (YA); Centre for Research in Environmental Epidemiology and Hospital del Mar Research Institute and CIBER Epidemiologia y Salud Pública, Barcelona, Spain (MK); National School of Public Health, Athens, Greece (MK); Departament de Patologia, Hospital del Mar-Parc de Salut Mar, Barcelona, Spain (JL); Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain (JL, FXR); Hospital General Universitario de Elche, Elche, Spain (AC); Hospital Ramon y Cajal, Madrid, Spain (AC); Hospital de Cabueñes, Gijón, Spain (MRF).
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) = 1.8395% 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.
Conclusion 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.