The association between bladder cancer and a single nucleotide polymorphism (rs2854744) in the insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3) gene

Abstract

Insulin-like growth factors (IGF) regulate growth and development and enhance cellular proliferation. IGF-binding protein-3 (IGFBP-3) inhibits IGF action by competitively binding IGFs that prevents their binding to the IGF cell surface receptor. Altered expression and serum levels of IGFBP-3 are associated with a number of malignancies. Study addressing the effect of IGFBP-3 gene polymorphism on bladder cancer is lacking. The aim of this study was to examine the effect of -202 A/C polymorphism of IGFBP-3 gene on development of bladder transitional cell carcinoma (TCC) and its correlation with serum concentration of IGF-1 and IGFBP-3 and with clinicopathological characteristics. One single nucleotide polymorphism (rs2854744) was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RLFP) technique. One hundred and sixty-two bladder cancer patients were genotyped for this SNP. The genotypes were compared with those of a random sample of 324 age-matched controls of the general population. Serum levels of IGF-I and IGFBP-3 were also determined. We found statistically significant differences in the genotypic distribution between the cases and the control subject (χ(2)=6.43, df=2.0, P=0.028). Using CC genotype as a reference, the odds ratio for the subjects with AC genotype was 1.76 (95% CI: 1.27-2.84; P=0.038). We detected a significantly decreased risk of bladder cancer associated with the AA genotype (adjusted OR=0.48; 95% CI=0.24-0.64; P=0.001) compared with the CC genotype. This decreased risk was more pronounced for invasive bladder cancer. Age-adjusted mean serum IGFBP-3 levels were lowest in the individuals with the CC genotype. We found a positive correlation between age-adjusted serum IGFBP-3 levels and circulating IGF-1 concentrations (16% difference in IGFBP-3 in top vs. bottom tertiles of IGF-1, P for trend=0.001), which was comparable across genotypes at the -202 IGFBP-3 locus (interaction term, F=0.10, P=0.87). Genetic polymorphism of the IGFBP-3 gene may be involved in the etiology of bladder TCC, and our results need further confirmation by larger studies.