Key Laboratory of Developmental Genes and Human Diseases, Ministry of Education, Southeast University, Nanjing 210009, China.
BMC Med. 2010 Feb 3;8:12. doi: 10.1186/1741-7015-8-12.
DNA-methyltransferase (DNMT)-3A plays an important role in the development of embryogenesis and the generation of aberrant methylation in carcinogenesis. The aim of this study was to investigate the role of a DNMT3A promoter genetic variant on its transcriptional activity and to evaluate the association between DNMT3A gene polymorphism and the susceptibility to gastric cancer (GC) and oesophagus carcinoma (EC) in the Chinese population.
We selected one of the single nucleotide polymorphisms (SNPs) -448A>G in the DNMT3A promoter region and evaluated its effect on activity using a luciferase assay. -448A>G polymorphisms of DNMT3A were determined by polymerase chain reaction/restriction fragment length polymorphism and confirmed by sequencing. The distribution of -448A>G polymorphisms was detected in 208 GC patients and 346 healthy controls matched for age and gender. The distribution of -448A>G polymorphisms was also detected in 96 EC patients and matched 241 healthy controls. The association of -448A>G polymorphisms of DNMT3A and the risk of GC and EC was evaluated by stratified analysis according to the patient's age and gender.
In a promoter assay, carriage of the -448 A allele showed a significantly higher promoter activity (> two fold) compared with the -448G allele (P < 0.001). The allele frequency of -448A among GC patients and controls was 32.9% versus 19.9%, respectively. Overall, we found that, compared with GG carriers, the DNMT3A -448AA homozygotes has a > six fold increased risk of GC. Stratification analysis showed that AA homozygotes have a more profound risk in the subgroups of individuals at the age range <or= 60 years in GC. However, individuals with -448AG and -448AA were not statistically significantly associated with an increased risk of EC compared with those carried the -448GG genotype.
The DNMT3A -448A>G polymorphism is a novel functional SNP and contributes to its genetic susceptibility to GC. -448A>G can be used as a stratification marker to predict an individual's susceptibility to GC, especially in the subgroups of individuals at the age range <or= 60 years. However, the relative distribution of -448A>G in EC can not be used as a prediction marker in order to evaluate an individual's susceptibility to EC.
DNA 甲基转移酶（DNMT）-3A 在胚胎发生发育和致癌作用中异常甲基化的产生中发挥重要作用。本研究旨在探讨 DNMT3A 启动子遗传变异对其转录活性的影响，并评估 DNMT3A 基因多态性与中国人胃癌（GC）和食管癌（EC）易感性之间的关系。
我们选择了 DNMT3A 启动子区域的一个单核苷酸多态性（SNP）-448A>G，并使用荧光素酶测定法评估其对活性的影响。通过聚合酶链反应/限制性片段长度多态性确定 DNMT3A 的-448A>G 多态性，并通过测序确认。在 208 例 GC 患者和 346 例年龄和性别匹配的健康对照者中检测了-448A>G 多态性。在 96 例 EC 患者和 241 例匹配的健康对照者中也检测了-448A>G 多态性。根据患者的年龄和性别进行分层分析，评估 DNMT3A-448A>G 多态性与 GC 和 EC 风险的相关性。
在启动子测定中，携带-448A 等位基因的个体表现出明显更高的启动子活性（>两倍），与-448G 等位基因相比（P<0.001）。GC 患者和对照组中-448A 的等位基因频率分别为 32.9%和 19.9%。总体而言，与 GG 携带者相比，DNMT3A-448AA 纯合子患 GC 的风险增加了>六倍。分层分析显示，在<or=60 岁的 GC 亚组中，AA 纯合子的风险更为显著。然而，与携带-448GG 基因型的个体相比，携带-448AG 和-448AA 的个体患 EC 的风险并未显著增加。
DNMT3A-448A>G 多态性是一种新的功能 SNP，有助于其遗传易感性 GC。-448A>G 可作为分层标记物，预测个体对 GC 的易感性，尤其是在<or=60 岁的个体亚组中。然而，EC 中-448A>G 的相对分布不能作为预测标记物，以评估个体对 EC 的易感性。
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