Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Centre, Madrid, Spain.
J Natl Cancer Inst. 2012 Dec 19;104(24):1897-904. doi: 10.1093/jnci/djs444. Epub 2012 Oct 29.
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.
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).
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.
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.
先前的证据表明 25-羟维生素 D（3）[25（OH）D（3）]可预防多种癌症。然而，关于尿路上皮膀胱癌（UBC）的了解甚少。我们分析了血浆 25（OH）D（3）与 UBC 总体风险之间的关联，以及根据分期和 FGFR3 分子亚表型的关联。
通过化学发光免疫分析法测定 1125 例 UBC 患者和 1028 例对照者的血浆 25（OH）D（3）浓度。评估肿瘤组织中 FGFR3 的突变状态和表达。通过 logistic 回归调整潜在混杂因素后计算比值比（OR）和 95%置信区间（CI）。根据肿瘤侵袭性和分级、FGFR3 表达和吸烟状态进一步分层分析。在培养有 1α，25-二羟维生素 D（3）的人 UBC 细胞系中测量细胞增殖。
在血浆 25（OH）D（3）浓度最低的患者中，UBC 的发病风险呈统计学显著增加（OR（adj）= 1.83；95%CI = 1.19 至 2.82；P =.006），呈现出剂量反应效应（P（趋势）=.004）。这种关联在肌肉浸润性肿瘤患者中更强，尤其是在低 FGFR3 表达者中（OR（adj）= 5.94；95%CI = 1.72 至 20.45；P =.005）。这些关联的生物学合理性得到了支持，即体外，1α，25-二羟维生素 D（3）上调低水平野生型 FGFR3 的 UBC 细胞系中 FGFR3 的表达。
这些发现支持维生素 D 在 UBC 发病机制中的作用，并表明 25（OH）D（3）水平与肿瘤中的 FGFR3 表达有关。由于 FGFR3 突变和过表达是预后较好的标志物，我们的发现表明，血浆 25（OH）D（3）水平较低的个体可能处于更具侵袭性 UBC 形式的高风险中。
