Polymorphisms In The Nitric-Oxide Synthase 2 Gene And Prostate Cancer Pathogenesis.
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.
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Charlotta
C
Ryk
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Petra
P
de Verdier
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Emmie
E
Montgomery
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
N
N
Peter Wiklund
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Fredrik
F
Wiklund
Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Henrik
H
Grönberg
D055106:Genome-Wide Association Study; D006801:Humans; D008297:Male; D018895:Microsatellite Repeats; D009363:Neoplasm Proteins / Q000235:genetics* / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II / Q000235:genetics* / Q000378:metabolism; D020641:Polymorphism, Single Nucleotide; D011471:Prostatic Neoplasms / Q000201:enzymology / Q000235:genetics*; D013548:Sweden
D009363:Neoplasm Proteins; C496319:NOS2 protein, human; D052247:Nitric Oxide Synthase Type II