Department of Molecular Biology, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawińskiego 5a, 02-106 Warsaw, Poland.
Mutat Res. 2011 May 10;709-710:21-31. doi: 10.1016/j.mrfmmm.2011.02.009. Epub 2011 Mar 3.
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 Arg46Gln 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 Arg399Gln were found among patients and controls, with the frequency of Arg280His being significantly higher among patients. NSCLC patients with Arg280His or Arg399Gln 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 Gln399 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.
氧化 DNA 损伤修复能力降低是某些人类恶性肿瘤发生的危险因素。我们之前发现，非小细胞肺癌 (NSCLC) 患者白细胞中的 8-氧-7,8-二氢鸟嘌呤修复能力低于对照组。为了解释这些观察结果，我们在 88 名 NSCLC 患者和 79 名对照者中搜索 OGG1 基因的突变和多态性。一名患者在exon 1 中表现出杂合突变，导致 Arg46Gln 取代。携带这种突变的正常肺组织和肿瘤组织的 8-氧鸟嘌呤切口活性明显低于所有患者的平均值。OGG1 的主要多态性是 Ser326Cys。在 NSCLC 患者和对照组人群中，OGG1 变体的频率存在显著差异。与对照组相比，Cys326 等位基因和 Cys326Cys 纯合子的数量在患者中更高。在具有 Ser326Cys 或 Cys326Cys 基因型的个体中，无论是在肺组织还是白细胞中，8-氧鸟嘌呤切口率均低于具有两个 Ser326 等位基因的个体。此外，携带两个 Cys326 等位基因的患者的肺组织和白细胞中的 8-氧脱氧鸟嘌呤水平以及具有 Ser326Cys 基因型的患者的白细胞中的 8-氧脱氧鸟嘌呤水平均较高。我们还筛选了 XRCC1 基因的多态性。仅在患者和对照组中发现 XRCC1 变体 Arg194Trp、Arg280His 和 Arg399Gln 的杂合子，并且患者中 Arg280His 的频率明显更高。在肺组织中，具有 Arg280His 或 Arg399Gln 多态性的 NSCLC 患者的 8-氧鸟嘌呤切口活性较低，但在白细胞中则没有。我们可以得出结论，OGG1 Ser326Cys 多态性可能对人类 8-氧鸟嘌呤切口的效率有影响，而 XRCC1 His280 和 Gln399 可能影响暴露于慢性氧化/炎症应激的组织中的 OGG1 活性。NSCLC 患者中 OGG1 Cys326 等位基因的较高频率可能部分解释了在其白细胞中观察到的 8-氧鸟嘌呤修复受损。
