The (CCTTT)n microsatellite polymorphism in the nitric oxide synthase 2 gene may influence bladder cancer pathogenesis

Purpose: We analyzed whether the NOS2 promoter microsatellite (CCTTT)n polymorphism influences bladder cancer pathogenesis.

Materials and methods: We genotyped 359 patients with bladder cancer in a population based cohort and 164 population controls by DNA fragment analysis and sequencing. Genotypes were combined with information on tumor stage, grade and stage, grade progression and cancer specific death. Clinical followup was 5 years.

Results: We divided (CCTTT)n alleles into short-10 or fewer, intermediate-11 or 12 and long-13 or greater repeats. Patients homozygous for 13 or longer (CCTTT)n repeats were at decreased odds ratio for bladder cancer (p = 0.010). However, after illness developed they were at 3-fold increased hazard ratio for stage progression (p = 0.062) and 4-fold increased hazard ratio for death from bladder cancer (p = 0.056). We discovered what is to our knowledge a previously undescribed polymorphism at position 23105343 (C/T). There was no difference in frequency between bladder cancer cases and population controls for this polymorphism. No associations were found between tumor stage, grade or stage and grade progression. However, patients with bladder cancer with the heterozygous CT genotype were at 3-fold increased hazard ratio of death from cancer (p = 0.011).

Conclusions: Nitric oxide can induce proliferation or apoptosis depending on the cellular context. Results suggest that the (CCTTT)n NOS2 microsatellite may influence bladder cancer risk and aggressiveness. This polymorphism may have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.