Polymorphisms in genes involved in homologous recombination repair interact to increase the risk of developing acute myeloid leukemia
Polymorphisms in genes involved in homologous recombination repair interact to increase the risk of developing acute myeloid leukemia
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DOI：
10.1158/1078-0432.ccr-03-0372
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发表时间：
2004-04-15
影响因子：
11.5
通讯作者：
Russell, N
中科院分区：
文献类型：
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作者：
Seedhouse, C;Faulkner, R;Russell, N
目的：通过同源重组进行双链断裂修复对维持遗传完整性至关重要。RAD 51和XRCC 3通过该途径参与DNA的修复，并且已经在RAD 51（RAD 51-G135 C）和XRCC 3（XRCC 3-Thr 241 Met）基因中鉴定出多态性。本研究的目的是检测这些多态性是否可以调节急性髓细胞白血病（AML）的易感性，AML是一种以遗传不稳定性为特征的疾病。我们研究了216例初治AML，51例治疗相关AML（t-AML），对照组186例，采用PCR及限制性内切酶酶切。结果：当RAD 51 - 135 C和XRCC 3 - 241 Met等位基因同时存在时，AML发生的危险性显著增加[比值比（OR），3.77; 95%置信区间（CI），1.39 - 10.24]，而t-AML发展的风险甚至更高（OR，8.11; 95% CI，2.22-29.68），可能是因为这些患者在暴露于放疗或化疗后接受了大量的遗传毒性损伤。如果我们进一步将AML组分为DNA损伤负担增加的患者，由于GSTM 1基因的缺失，AML发展的风险进一步增加（OR，15.26; 95%CI，1.83-127.27）。结论：这些结果强烈表明，DNA双链断裂及其修复在新发和t-AML的发病机制中都是重要的。
Purpose: Double-strand break repair via homologous recombination is essential in maintaining genetic integrity. RAD51 and XRCC3 are involved in the repair of DNA by this pathway, and polymorphisms have been identified in both the RAD51 (RAD51-G135C) and XRCC3 (XRCC3-Thr241Met) genes. The object of this study was to examine whether these polymorphisms may modulate susceptibility to the development of acute myeloid leukemia (AML), a disease that is characterized by genetic instability.Experimental Design: We studied the distribution of polymorphisms in RAD51 and XRCC3 in 216 cases of de novo AML, 51 cases of therapy-related AML (t-AML), and 186 control subjects using PCR followed by restriction enzyme digestion. The polymorphic deletion of the detoxification gene glutathione S-transferase M1 (GSTM1) was also examined by PCR.Results: The risk of the development of AML was found to be significantly increased when both variant RAD51-135C and XRCC3-241Met alleles are present [odds ratio (OR), 3.77; 95 % confidence interval (CI), 1.39 -10.24], whereas the risk of t-AML development is even higher (OR, 8.11; 95% CI, 2.22-29.68), presumably because of the large genotoxic insult these patients receive after their exposure to radiotherapy or chemotherapy. If we further divide the AML group into patients in which the burden of DNA damage is increased, because of the deletion of the GSTM1 gene, the risk of development of AML is further increased (OR, 15.26; 95% CI, 1.83-127.27).Conclusions: These results strongly suggest that DNA double-strand breaks and their repair are important in the pathogenesis of both de novo and t-AML.