Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.
Redox Biol. 2015 Aug;5:419. doi: 10.1016/j.redox.2015.09.029. Epub 2015 Dec 30.
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.
一氧化氮合酶（NOS）-多态性影响细胞内一氧化氮的含量，并与许多疾病的疾病风险相关。我们在一项瑞典人群基于 GWAS 的研究中，调查了 3161 例前列腺癌患者和 2149 例对照中的 145 个 SNP 多态性和 NOS2 基因中的（CCTTT）n 微卫星。
分析 NOS2 多态性与前列腺癌和前列腺癌发病机制之间的可能关联。
分析了两组患者，一组为晚期肿瘤（Gleason≥6），另一组为混合 Gleason 分期肿瘤。Affymetrix 5.0 芯片（SNP 多态性）、DNA 片段分析和测序（（CCTTT）n 微卫星）用于基因分型。将基因型与肿瘤分期、Gleason、PSA、转移和癌症特异性死亡的信息结合起来，进行临床随访。
我们将（CCTTT）n 等位基因分为短（S，n≤10）、中（M，n=11-12）和长（L，n≥13）。纯合较长重复（LL）的患者患高度侵袭性（Gleason≥7；PSA>20；T3+）肿瘤的风险降低（OR：0.40；CI：0.14-1.08；p=0.071），但一旦患病，死于前列腺癌的风险增加三倍（HR：3.31；CI：0.85-12.85；p=0.084），与 SS 纯合子相比。与（CCTTT）l 等位基因共变异的 SNP 等位基因也降低了侵袭性肿瘤的风险，以及患病后 2-4 倍的死亡风险（p=0.009）。同样，患者的淋巴结转移比例也随患者（SS<SM<SL<MM<ML<LL）（趋势分析；p=0.033）中（CCTTT）n 等位基因的长度而增加。
一氧化氮可以根据细胞环境诱导增殖和凋亡。我们的结果表明，NOS2 多态性可能影响侵袭性前列腺癌的风险，这些多态性可能通过影响细胞内一氧化氮水平对疾病发病机制产生影响。
