DNMT3A基因R882H突变与结肠癌遗传易感性的关系

Association between DNMT3A gene R882H mutation and susceptibility of colorectal cancer in Chinese patients

目的探讨DNMT3A基因R882H突变在结肠癌患者中的分布，以及此突变与结肠癌发生的关系。方法收集86例结肠癌患者，124例普通对照人群的外周血标本。采用PCR扩增然后测序分析法检测外周血DNMT3A基因R882H位点的基因多态性。同时采用RT—PCR检测各基因型结肠癌患者正常结肠黏膜的DNMT3A基因mRNA表达。结果散发结肠癌患者DNMT3A基因R882位点A等位基因频率明显高于普通人群，P=0．028，OR=4．3，95％CI：1．67～8．37。各基因型结肠癌患者正常结肠黏膜的DNMT3A基因mRNA表达差异无统计学意义。结论DN—MT3A基因R882H突变是我国散发结肠癌的遗传易感因素。R882H突变不是通过下调DNMT3A表达，可能是增加DNMT3A酶的活性来诱导肿瘤形成的。

Objective The causative role of the methylation pathway,such as DNMT3A gene, is well established in hereditary colorectal cancer（CRC）. DNMT3A variant R882H（2645 locus G-A mutation） is reported to be associated with CRC in vitro. This association,however,is not detected in clinical cases. Thus,our aim is to study the possible etiological role of DNMT3A gene 2645 locus G--A mutation in sporadic CRC patients from Chinese. Methods From March 2006 to May 2009,86 sporadic CRC pa- tients and 124 normal people as controls were collected from Hubei Cancer Hospital. Genomic DNA was extracted from peripheral blood of normal people and CRC patients. Gene mutation was analyzed by PCR - RFLP. And DNMT3A mRNA expression of colorectal mucosal in different genotypes was analyzed by RT - PCR. Results The frequency of DNMT3A gene C/C genotype was significantly higher in sporadic CRC patients than that in controls （ P = 0. 035 ; OR = 5.29,95 % CI ： 1.07 - 26.04 ）. In CRC families, the C al- lele frequency of CRC and their relatives were increased, compared with sporadic CRC （ P = 0. 003 ） and normal controls （ P = 0. 006 ） , respectively . DNMT3A mRNA expression of colorectal mucosal was similar in different genotypes. Conclusion DNMT3A gene 2645 locus G--A mutation may be a genetic suscepti- bility to sporadic CRC in Chinese. The mutation might increase the enzyme activity of DNMT3A but downregulate DNMT3A mRNA expression to induce CRC formation.