Two survivin polymorphisms are cooperatively associated with bladder cancer susceptibility.

Abnormal survivin expression has been reported to be involved in many types of cancer. A single-nucleotide polymorphism (SNP), C-31G, located in the promoter region of survivin reportedly may alter the mRNA level, while the significance of the nonsynonymous SNP A9194G in exon 4 has not yet been clarified. Here, the association between the two survivin SNPs and bladder cancer susceptibility and progression was investigated in 235 patients with bladder cancer and 346 healthy controls. Regarding the C-31G SNP, subjects with the CC genotype had a significantly higher risk of bladder cancer compared to those with the GG + CG genotype [odds ratio (OR) = 1.85, p = 0.001]. Regarding the A9194G SNP, the presence of the G allele was associated with a significantly reduced risk with a gene dosage effect (OR = 0.69, p = 0.002). Using the C-A haplotype as a reference, the G-G haplotype was associated with a significantly lower risk (OR = 0.11, p = 0.00006), indicating the cooperative effect of the two SNPs. Immunohistological evaluation of surgical specimens showed that cancer cells of the C-31G CC genotype had significantly higher nuclear survivin expression than those of the C-31G GG + CG genotype. With reverse transcriptase-polymerase chain reaction analysis, a significantly higher survivin mRNA expression level was observed in surgical specimens with an increase in the number of the C-31G C allele (p = 0.016). These results indicate that the two SNPs have a significant and cooperative influence on bladder cancer susceptibility.