Prognostic significance of HIF-1 alpha polymorphisms in transitional cell carcinoma of the bladder

Recently, two single nucleotide polymorphisms in the hypoxia-inducible factor-1 alpha (HIF-1 alpha) gene, P582S and A588T, were shown to cause significantly higher transcriptional activity than the wild type. We investigated the association between the HIF-1 alpha polymorphisms and the incidence and progression of transitional cell carcinoma of the bladder, and the relationship between the polymorphisms and the tissue vascular endothelial growth factor (VEGF) level or microvessel density (MVD). A total of 219 patients with bladder cancer and 464 healthy native Japanese control subjects were enrolled. Tissue VEGF and HIF-1 alpha expression levels and the mean MVD were evaluated in 73 radical cystectomy specimens by immunohistochemistry. The HIF-1 alpha genotype did not significantly influence the incidence or disease status of bladder cancer. Among patients who underwent radical cystectomy, those with a variant allele had significantly worse disease-free survival (p = 0.001) and disease-specific survival (p = 0.006) than those without a variant allele. Multivariate analysis using a Cox proportional hazard model revealed that the presence of a variant allele was an independent predictor of disease-free survival (HR = 3.10, 95%CI = 1.38-6.99, p = 0.006). Although not statistically significant, the moderate/high expression levels of VEGF in tumor tissues were more frequently observed in patients with a HIF-1 alpha variant allele (11/13, 84.6%) than in those without (33/60, 55%, p = 0.063). The HIF-1 alpha polymorphisms may have a significant influence on the poor prognosis of the patients undergoing radical cystectomy for bladder cancer, while they seem to have no relation to the bladder cancer occurrence.