Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival
Effects of functional genetic polymorphisms in the CYP19A1 gene on prostate cancer risk and survival
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DOI：
10.1002/ijc.28952
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发表时间：
2015-01-01
影响因子：
6.4
通讯作者：
Habuchi, Tomonori
中科院分区：
文献类型：
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作者：
Kanda, Sohei;Tsuchiya, Norihiko;Habuchi, Tomonori
CYP 19催化雄激素转化为雌激素，是影响性激素环境的关键酶。在这项研究中，我们研究了CYP 19 A1多态性的功能及其与前列腺癌风险和临床结局的关系。本病例对照研究评价了330例前列腺癌患者和354例正常对照中CYP 19 A1基因3个单核苷酸多态性（SNP）对前列腺癌风险的影响。在164名健康男性患者中评估每个SNP与性激素水平之间的关联。在PC 3和DU 145细胞系中通过报告基因测定确定SNPs的功能。在142例接受雄激素剥夺治疗的转移性前列腺癌患者中评估了前列腺特异性抗原最低值。在166例转移性前列腺癌患者中测定癌症特异性生存率（CSS），以评估三种SNP的影响。这三个SNP的每个变异等位基因都显著降低了前列腺癌的风险。单倍型分析显示T-A-G单倍型（对应rs 2470152-rs 10459592-rs 4775936）增加前列腺癌的风险，而C-C-A单倍型降低风险。雌酮/雄烯二酮比率在具有rs 2470152的C等位基因、rs 10459592的C等位基因和rs 4775936的A等位基因的男性中以基因剂量依赖的方式显著较高。在rs 4775936处具有变异等位基因的患者具有显著较短的CSS。这些结果表明，CYP 19 A1多态性可能会影响前列腺癌的风险和生存通过修改启动子的活性，与性激素环境的后续影响。
CYP19 catalyzes the conversion of androgens to estrogens and is a critical enzyme affecting the sex hormone milieu. In this study, we investigated the functions of CYP19A1 polymorphisms and their associations with prostate cancer risk and clinical outcome. This case-control study evaluated the effects of three single nucleotide polymorphisms (SNPs) in CYP19A1 on the risk of prostate cancer in 330 prostate cancer patients and 354 normal controls. The associations between each SNP and sex hormone levels were evaluated in 164 healthy male patients. The functions of the SNPs were determined by reporter gene assays in PC3 and DU145 cell lines. Prostate-specific antigen nadir was evaluated in 142 patients with metastatic prostate cancer treated with androgen deprivation therapy. Cancer-specific survival (CSS) was determined in 166 patients with metastatic prostate cancer, to evaluate the influence of the three SNPs. Each variant allele of the three SNPs significantly decreased the risk of prostate cancer. Haplotype analysis showed that the T-A-G haplotype (corresponding to rs2470152-rs10459592-rs4775936) increased the risk of prostate cancer, while the C-C-A haplotype decreased the risk. The estrone/androstenedione ratio was significantly higher in men with the C allele of rs2470152, the C allele of rs10459592, and the A allele of rs4775936 in a gene-dosage-dependent manner. Patients with the variant allele at rs4775936 had significantly shorter CSS. These results indicate that CYP19A1 polymorphisms may influence prostate cancer risk and survival by modifying promoter activity, with subsequent effects on the sex hormone milieu.