Vitamin D and bladder cancer risk, recurrence and progression

  • Topic:
  • Institution: Spanish National Cancer Research Centre (CNIO)
  • Country: Spain
  • Status: Completed

Scientific abstract

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Background

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.

Objectives

We aimed at:

  1. Evaluating the association between concentrations of 25(OH)D in plasma and risk of bladder cancer overall and for sub-phenotypes
  2. Analyzing 25(OH)D*candidate-SNPs interactions
  3. Assessing the independent prognostic role of 25(OH)D in bladder cancer
  4. Performing a genome wide association study (GWAS) with 25(OH)D levels.

Methods

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.

Results

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.

Conclusions

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.

Plain language abstract

Hypothesis

We hypothesised that individuals having low levels of serum 25(OH)D (the best marker of vitamin D) would be at an increased risk of developing bladder cancer globally, and more specifically, of an aggressive type of bladder cancer characterised by its invasion of the muscle layer of the urinary bladder and the lack of FGFR3 expression.

We also think that specific inherited genetic profiles in gens belonging to the vitamin D pathway would modify the effect of 25(OH)D on bladder cancer, either by increasing or decreasing the risk.

Furthermore, we hypothesised that bladder cancer in patients with high levels of 25(OH)D would progress less than in patients with low levels of 25(OH)D.

Background

Urinary bladder cancer is an important health problem with a high incidence in most developed countries, where men are more affected than women. Its main risk factors are smoking, occupational exposure to aromatic amines, and arsenic. These factors explain a large proportion of the etiological scenario of bladder cancer but there is still a fraction of the disease that remains unexplained.

Previous 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.

Methods

The study used the resources gathered by the Spanish Bladder Cancer/EPICURO Study conducted during 1998-2001 in 18 hospitals. It considered 1,125 cases with a newly diagnosed bladder cancer and 1,028 hospital controls with available plasma samples. Patients have been followed up for more than 10 years to assess the evolution of their tumours.

Concentrations of 25(OH)D were determined by a chemiluminescence immunoassay. The risk for the main effects of 25(OH)D and for its interactions with the inherited genetic profile of the study subjects were calculated controlling for potential confounders. Similarly, the risk of progression as well as the risk of dying of bladder cancer was estimated. Analyses were done separately by levels of tumour invasiveness and expression of FGFR3, in addition to smoking status.

Key findings

A significant increased risk of bladder cancer was observed among those subjects presenting the lowest concentrations of 25(OH)D. These individuals almost doubled the risk of developing bladder cancer. The association of 25(OH)D was higher for the aggressive tumours according to their invasiveness of the muscle layer of the urinary bladder and the absence of FGFR3 expression. Smokers with low levels of 25(OH)D presented a slightly higher risk than non-smokers with low levels, though this difference was not statistically different.

We also observed that individuals harbouring variants in the UGT1A3 and RXRA genes modified the effect of 25(OH)D*SNP on bladder cancer risk.

In addition, the bladder tumours of patients with high levels of 25(OH)D were less prone to progress than those from patients with low levels 25(OH)D.

Grant publications