Huang Yu-Chuen, Lee Cheng-Ming, Chen Marcelo, Chung Ming-Yi, Chang Yen-Hwa, Huang William Ji-Shian, Ho Donald Ming-Tak, Pan Chin-Chen, Wu Tony T, Yang Stone, Lin Ming-Wei, Hsieh Jer-Tsong, Chen Yi-Ming Arthur
Division of Preventive Medicine, Institute of Public Health, National Yang-Ming University, Taipei, Taiwan.
Clin Cancer Res. 2007 Mar 1;13(5):1412-20. doi: 10.1158/1078-0432.CCR-06-1551.
Glycine N-methyltransferase (GNMT) affects genetic stability by regulating DNA methylation and interacting with environmental carcinogens. In a previous study, we showed that GNMT acts as a susceptibility gene for hepatocellular carcinoma. Here, we report on our efforts to characterize the haplotypes, loss of heterozygosity (LOH), and expression levels of the GNMT in prostate cancer.
Peripheral blood mononuclear cell DNA collected from 326 prostate cancer patients and 327 age-matched controls was used to determine GNMT haplotypes. Luciferase reporter constructs were used to compare the promoter activity of different GNMT haplotypes. GNMT LOH rates in tumorous specimens were investigated via a comparison with peripheral blood mononuclear cell genotypes. Immunohistochemical staining was used to analyze GNMT expression in tissue specimens collected from 5 normal individuals, 33 benign prostatic hyperplasia patients, and 45 prostate cancer patients.
Three major GNMT haplotypes were identified in 92% of the participants: A, 16GAs/DEL/C (58%); B, 10GAs/INS/C (19.9%); and C, 10GAs/INS/T (14.5%). Haplotype C carriers had significantly lower risk for prostate cancer compared with individuals with haplotype A (odds ratio, 0.68; 95% confidence interval, 0.48-0.95). Results from a phenotypic analysis showed that haplotype C exhibited the highest promoter activity (P < 0.05, ANOVA test). In addition, 36.4% (8 of 22) of the prostatic tumor tissues had LOH of the GNMT gene. Immunohistochemical staining results showed abundant GNMT expression in normal prostatic and benign prostatic hyperplasia tissues, whereas it was diminished in 82.2% (37 of 45) of the prostate cancer tissues.
Our findings suggest that GNMT is a tumor susceptibility gene for prostate cancer.
甘氨酸N-甲基转移酶（GNMT）通过调节DNA甲基化以及与环境致癌物相互作用来影响遗传稳定性。在之前的一项研究中，我们表明GNMT作为肝细胞癌的一个易感基因发挥作用。在此，我们报告我们在前列腺癌中对GNMT的单倍型、杂合性缺失（LOH）及表达水平进行特征分析的工作。
从326例前列腺癌患者和327例年龄匹配的对照者收集外周血单个核细胞DNA，用于确定GNMT单倍型。使用荧光素酶报告基因构建体比较不同GNMT单倍型的启动子活性。通过与外周血单个核细胞基因型比较，研究肿瘤标本中GNMT的LOH率。免疫组织化学染色用于分析从5例正常个体、33例良性前列腺增生患者和45例前列腺癌患者收集的组织标本中的GNMT表达。
在92%的参与者中鉴定出三种主要的GNMT单倍型：A，16GAs/DEL/C（58%）；B，10GAs/INS/C（19.9%）；C，10GAs/INS/T（14.5%）。与单倍型A的个体相比，单倍型C携带者患前列腺癌的风险显著更低（优势比，0.68；95%置信区间，0.48 - 0.95）。表型分析结果显示单倍型C表现出最高的启动子活性（P < 0.05，方差分析检验）。此外，22例前列腺肿瘤组织中有36.4%（8例）存在GNMT基因的杂合性缺失。免疫组织化学染色结果显示，GNMT在正常前列腺和良性前列腺增生组织中表达丰富，而在82.2%（45例中的37例）的前列腺癌组织中表达减少。
我们的研究结果表明GNMT是前列腺癌的一个肿瘤易感基因。
