Polymorphisms In The Nitric-Oxide Synthase 2 Gene And Prostate Cancer Pathogenesis

Abstract

Nitric-oxide synthase (NOS)-polymorphisms influence the cellular amount of NO, and are associated with disease-risk in many disorders. We investigated 145 SNP-polymorphisms and a (CCTTT)n-microsatellite in the NOS2-gene in 3161 prostate-cancer patients and 2149 controls from a Swedish population-based GWAS-study. To analyze possible associations between NOS2-polymorphisms, prostate cancer, and prostate cancer pathogenesis. Two groups were analyzed, those with advanced tumours (Gleason≥6), and those with tumours of mixed Gleason-statues. Affymetrix 5.0-chip (SNP-polymorphisms), DNA Fragment-analysis and Sequencing ((CCTTT)n-microsatellite) were used for genotyping. Genotypes were combined with information on tumour stage, Gleason, PSA, metastases and cancer-specific death, using clinical follow-up. We divided the (CCTTT)n-alleles into short (S, n≤10), intermediate (M, n=11-12) and long (L, n≥13). Patients homozygous for longer repeats (LL) had decreased risk of highly aggressive (Gleason ≥7;PSA>20;T3+) tumours (OR:0.40;CI:0.14-1.08;p=0.071), but, once ill they showed a threefold increased risk of dying in prostate cancer (HR:3.31;CI:0.85-12.85;p=0.084), compared to SS-homozygotes. The SNP-alleles that co-varied with the (CCTTT)l-allele also had lower risk of aggressive tumours, as well as, once ill, a 2-4 times higher risk of dying (p=0.009). Also the proportion of patients with lymph node metastases increased with length of the (CCTTT)n-alleles of the patients (SS<SM<SL<MM<ML <LL)(trend analysis; p=0.033). Nitric oxide can induce proliferation as well as apoptosis depending on cellular context. Our results suggest that NOS2 polymorphisms may influence the risk of aggressive prostate cancer and that these polymorphisms could have an impact on disease pathogenesis, possibly by affecting intracellular nitric oxide levels.