8-Oxoguanine incision activity is impaired in lung tissues of NSCLC patients with the polymorphism of OGG1 and XRCC1 genes
8-Oxoguanine incision activity is impaired in lung tissues of NSCLC patients with the polymorphism of OGG1 and XRCC1 genes
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DOI：
10.1016/j.mrfmmm.2011.02.009
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发表时间：
2011-05-10
影响因子：
2.3
通讯作者：
Speina, Elzbieta
中科院分区：
文献类型：
--
作者：
Janik, Justyna;Swoboda, Maja;Speina, Elzbieta
氧化性DNA损伤的修复减少是发展某些人类恶性肿瘤的危险因素。我们以前发现，8-氧代-7，8-二氢鸟嘌呤的修复能力在NSCLC患者的白细胞中低于对照组。为了解释这些观察结果，我们在88名NSCLC患者和79名对照中寻找OGG 1基因的突变和多态性。1例患者在外显子1中表现出杂合突变，导致Arg 46 Gln替换。携带这种突变的正常肺和肿瘤组织显示出明显低于所有患者的平均值的8-oxoG切割活性。OGG 1基因的主要多态性位点为Ser 326 Cys。在NSCLC患者和对照人群之间观察到OGG 1变异体的频率存在显著差异。Cys 326等位基因频率和Cys 326 Cys纯合子数量在患者中高于对照组。无论是Ser 326 Cys或Cys 326 Cys基因型8-oxoG切口率的个人低于那些与Ser 326等位基因，无论是在肺或白细胞。此外，8-oxodG水平较高，在肺组织和白细胞的患者携带两个Cys 326等位基因和白细胞的患者与Ser 326 Cys基因型。我们还筛选了XRCC 1基因的多态性。仅XRCC 1变体Arg 194 Trp的杂合子。Arg 280 His和Arg 399 Gln在患者和对照组中均有发现，Arg 280 His的频率在患者中显著较高。携带Arg 280 His或Arg 399 Gln多态性的NSCLC患者在肺组织中显示较低的8-oxoG切割活性，但在白细胞中没有。我们可以得出结论，OGG 1 Ser 326 Cys多态性可能会影响人体8-oxoG切割的效率，XRCC 1 His 280和GIn 399可能会影响暴露于慢性氧化/炎症应激的组织中的OGG 1活性。NSCLC患者中OGG 1 Cys 326等位基因的频率较高，可能部分解释了在其白细胞中观察到的8-oxoG修复受损。(C)2011爱思唯尔有限公司版权所有。
Decreased repair of oxidative DNA damage is a risk factor for developing certain human malignancies. We have previously found that the capacity of 8-oxo-7,8-dihydroguanine repair was lower in leukocytes of NSCLC patients than in controls. To explain these observations, we searched for mutations and polymorphisms in the OGG1 gene among 88 NSCLC patients and 79 controls. One patient exhibited a heterozygous mutation in exon 1, which resulted in Arg46GIn substitution. Normal lung and tumor tissue carrying this mutation showed markedly lower 8-oxoG incision activity than the mean for all patients. The predominant polymorphism of OGG1 was Ser326Cys. A significant difference was observed in the frequencies of the OGG1 variants between populations of NSCLC patients and controls. The frequency of the Cys326 allele and the number of Cys326Cys homozygotes was higher among patients than controls. In individuals with either Ser326Cys or Cys326Cys genotype 8-oxoG incision rate was lower than in those with both Ser326 alleles, either in lung or leukocytes. Moreover, 8-oxodG level was higher in lung tissue and leukocytes of patients carrying two Cys326 alleles and in leukocytes of patients with the Ser326Cys genotype. We also screened for polymorphisms of the XRCC1 gene. Only heterozygotes of the XRCC1 variants Arg194Trp. Arg280His and Arg399GIn were found among patients and controls, with the frequency of Arg280His being significantly higher among patients. NSCLC patients with Arg280His or Arg399GIn polymorphism revealed lower 8-oxoG incision activity in their lung tissues, but not in leukocytes. We can conclude that the OGG1 Ser326Cys polymorphisms may have an impact on the efficiency of 8-oxoG incision in humans and the XRCC1 His280 and GIn399 may influence the OGG1 activity in tissues exposed to chronic oxidative/inflammatory stress. Higher frequency of the OGG1 Cys326 allele among NSCLC patients may partially explain the impairment of the 8-oxoG repair observed in their leukocytes. (C) 2011 Elsevier B.V. All rights reserved.