Institution:Spanish National Cancer Research Centre (CNIO)
Researcher: Núria Malats
Experimental, clinical, and epidemiologic evidence suggests that 25-hydroxyvitamin D [25(OH)D], the best biomarker of vitamin D status, may protect against the development of different types of cancer as well as of their progression. However, there is limited data on the association between 25(OH)D and risk and prognosis of bladder cancer. Furthermore, the mechanisms through which it may impact on bladder carcinogenesis are not fully understood.
We aimed at:
Evaluating the association between concentrations of 25(OH)D in plasma and risk of bladder cancer overall and for sub-phenotypes
Analyzing 25(OH)D*candidate-SNPs interactions
Assessing the independent prognostic role of 25(OH)D in bladder cancer
Performing a genome wide association study (GWAS) with 25(OH)D levels.
The study considered 1,125 cases of bladder cancer and 1,028 hospital controls with available plasma samples recruited in the Spanish Bladder Cancer/EPICURO Study. Concentrations of 25(OH)D were determined by a chemiluminescence immunoassay. Odds ratios (ORs) and 95% confidence intervals (CIs) for main effects and interactions were calculated using logistic regression, adjusting for potential confounders.
Multivariable Cox proportional-hazards regression models were applied to assess the risk of tumour recurrence, progression and disease-specific survival. Analyses were further stratified by tumour invasiveness-grade and FGFR3 expression levels, in addition to smoking status.
Objective 1: A significant increased risk of bladder cancer was observed among those subjects presenting the lowest concentrations of 25(OH)D [< 10 ng/ml 25(OH)D vs. ≥ 30 ng/ml; ORadj= 1.83, 95%CI 1.19-2.82, P=0.006], showing a dose-response effect (P-trend=0.004). The association of 25(OH)D was higher with muscle-invasive tumours and especially among those expressing lower levels of FGFR3 [ORadj=5.26, 95%CI 1.73-16.04, P=0.003].
Objective 2: Interesting 25(OH)D*SNP interactions were observed for UGT1A3 and RXRA variants (P<0.005), they are now being further studied.
Objective 3: A significant decrease in the risk of bladder cancer progression was observed among patients with non-muscle invasive bladder cancer with increasing concentrations of 25(OH)D (P = 0.02). Concentrations of 25(OH)D were not associated with recurrence among individuals with NMIBC or progression or disease-specific death among MIBC.
Objective 4: While preliminary, this wide-genome assessment replicated previous published results on genetic variants associated with 25(OH)D levels and identify new polymorphisms that need further evaluation.
These findings support the role of vitamin D in the pathogenesis and progression of bladder cancer and suggest that individuals with lower levels of plasma 25(OH)D are at high risk of more aggressive forms of bladder tumours. Since vitamin D status is modifiable, new recommendations on vitamin D intake should be considered upon replication of this association.