Ser608Leu polymorphisms in the nitric oxide synthase-2 gene may influence urinary bladder cancer pathogenesis

Abstract

Objective. The aim of this study was to analyse whether the exonic Ser608Leu (rs2297518) polymorphism in nitric oxide synthase-2 (NOS2) influences urinarybladder cancer risk and pathogenesis. Material and methods. Genotyping of 359 bladder cancer patients from a population-based cohort and 164 population controls was carried out by allelic discrimination and sequencing. Genotypes were combined with information on tumour stage, grade, stage progression and cancer-specific death, from a 5-year clinical follow-up. Results. For the Ser608Leu polymorphism, TT homozygotes had three-fold higher odds for bladder cancer (p = 0.081), but once ill, a lower risk for stage progression (p = 0.031) and a better prognosis. Conclusions. The data indicate that the Tallele of the NOS2 Ser608Leu polymorphism is an initial risk factor for developing urinary bladder cancer. Among bladder cancer patients, however, individuals who are TT homozygous have a lower risk of developing muscle-invasive disease and a higher cancer-specific survival. Depending on the cellular context, nitric oxide can induce proliferation as well as apoptosis. The results from this and previous studies suggest that NOS2 polymorphisms may influence both the risk of contracting bladder cancer and the aggressiveness of the disease.

Key Words::

• genetic polymorphisms
• nitric oxide
• nitric oxide synthase-2
• urinary bladder cancer

Acknowledgements

Grants were obtained from the Swedish Cancer Association (Cancerfonden CAN2007/649), the regional agreement on medical training and clinical research between Stockholm County Council and Karolinska Institutet (ALF) and the Swedish Society of Medicine. The authors wish to thank Professor Bo Lambert for generously providing the population controls.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.