Singal Rakesh, Das Partha M, Manoharan Murugesan, Reis Isildinha M, Schlesselman James J
Division of Hematology/Oncology, University of Miami Sylvester Comprehensive Cancer Center, 1475 NW 12th Avenue (D8-4), Suite 3300, Miami, FL 33136, USA.
Oncol Rep. 2005 Aug;14(2):569-73.
Inactivation of tumor suppressor genes by promoter methylation is an important mechanism of tumorigenesis. Increased expression of DNA methyltransferases has been commonly observed in cancer. A C/T polymorphism in the DNA methyltransferase 3b (DNMT3b) promoter region results in increased activity and has recently been identified as a risk factor for lung cancer. In this study, we examined the C/T polymorphism of the DNMT3b gene in specimens from 81 patients with prostate cancer and 42 controls selected from patients with benign prostatic hypertrophy (BPH). Genomic DNA was isolated from archived formaldehyde-fixed and paraffin-embedded tissue blocks. DNMT3b genotypes were determined by restriction-fragment-length-polymorphism polymerase chain reaction. The DNMT3b polymorphism frequencies in the prostate cancer and BPH specimens were, respectively, 20 and 26% for CC, 42 and 52% for CT, and 38 and 21% for TT. Although such differences fall within the realm of chance variation (P>0.05), the data suggest that the TT genotype may be associated with an increased risk of prostate cancer: the age-adjusted odds ratio (aOR) was 2.6 [95% confidence interval: 0.8-8.0]; the increase in odds ratio was seen in both blacks and whites (aOR=4.3 in blacks, and 2.0 in whites). The samples used in this study have previously been examined for methylation index (MI) based on the number of genes methylated, the range being 0 to 5. A trend toward an increase in MI was detected for the DNMT3b polymorphisms in prostate cancer patients but not for BPH subjects (mean MI 2.6, 2.9, 3.1 for CC, CT, and TT genotype in prostate cancer; 0.8, 0.8, 0.7 for CC, CT, and TT genotype in BPH subjects). These findings suggest that the DNMT3b polymorphisms may be associated with an increase in promoter methylation of tumor-suppressor genes related to the development of prostate cancer, and may thereby increase the risk of this disease.
启动子甲基化导致肿瘤抑制基因失活是肿瘤发生的重要机制。癌症中普遍观察到DNA甲基转移酶的表达增加。DNA甲基转移酶3b（DNMT3b）启动子区域的C/T多态性导致活性增加，最近被确定为肺癌的一个危险因素。在本研究中，我们检测了81例前列腺癌患者和42例选自良性前列腺增生（BPH）患者的对照样本中DNMT3b基因的C/T多态性。从存档的甲醛固定石蜡包埋组织块中分离基因组DNA。通过限制性片段长度多态性聚合酶链反应确定DNMT3b基因型。前列腺癌和BPH样本中DNMT3b多态性频率分别为：CC型20%和26%，CT型42%和52%，TT型38%和21%。尽管这些差异属于随机变异范围（P>0.05），但数据表明TT基因型可能与前列腺癌风险增加相关：年龄调整后的优势比（aOR）为2.6[95%置信区间：0.8 - 8.0]；黑人和白人的优势比均有增加（黑人aOR = 4.3，白人aOR = 2.0）。本研究中使用的样本此前已根据甲基化基因数量检测了甲基化指数（MI），范围为0至5。在前列腺癌患者中检测到DNMT3b多态性的MI有增加趋势，但在BPH受试者中未检测到（前列腺癌患者CC、CT和TT基因型的平均MI分别为2.6、2.9、3.1；BPH受试者CC、CT和TT基因型的平均MI分别为0.8、0.8、0.7）。这些发现表明，DNMT3b多态性可能与前列腺癌发生相关的肿瘤抑制基因启动子甲基化增加有关，从而可能增加该疾病的风险。
