Hatt Lotte, Loft Steffen, Risom Lotte, Møller Peter, Sørensen Mette, Raaschou-Nielsen Ole, Overvad Kim, Tjønneland Anne, Vogel Ulla
Institute of Public Health, Department of Environmental Health, Copenhagen, Denmark.
Mutat Res. 2008 Mar 1;639(1-2):45-54. doi: 10.1016/j.mrfmmm.2007.11.002. Epub 2007 Nov 19.
Oxidative DNA damage is believed to be implicated in lung carcinogenesis. 8-OxodG is a mutagenic and abundant oxidative modification induced in DNA. OGG1, NEIL1 and MUTYH are all involved in the repair and prevention of 8-oxodG-derived mutations and may be up-regulated by oxidative stress. The polymorphism OGG1 Ser326Cys has in some studies been associated with risk of lung cancer. In a population-based cohort of 57,053 Danes, we examined associations between mRNA levels of OGG1, NEIL1, MUTYH and NUDT in buffy coat material and subsequent lung cancer risk. 260 cases with lung cancer were identified and a sub-cohort of 263 individuals was matched on sex, age and smoking duration. We found that OGG1 mRNA levels in healthy individuals were not associated with risk of subsequent getting lung cancer. However, subjects with the OGG1 Cys326/Cys326 genotype had a higher expression level of OGG1 mRNA than wildtype-allele carriers. For homozygous Cys326 carriers, the incidence rate ratio (IRR) was 1.51 (95% CI: 1.09-2.08) for a doubling of the OGG1 mRNA level and there was a statistically significant interaction between the genotype and mRNA level. Among never-smokers, the IRR was 4.29 (1.09-16.9) per doubling of the OGG1 mRNA level, which was not found among smokers. Furthermore, we found a positive correlation between OGG1 mRNA expression and urinary excretion of 8-oxodG (RS=0.18; p<0.005). NUDT1 mRNA levels were omitted due to low and unreliable expression levels. The results suggest that OGG1 mRNA levels should be regarded as a biomarker of exposure to oxidative stress with induction of DNA rather than a marker of inborn DNA repair capacity.
氧化DNA损伤被认为与肺癌发生有关。8-氧代脱氧鸟苷（8-OxodG）是DNA中诱导产生的一种具有致突变性且含量丰富的氧化修饰。OGG1、NEIL1和MUTYH均参与8-氧代脱氧鸟苷衍生突变的修复和预防，并且可能会因氧化应激而上调。在一些研究中，OGG1 Ser326Cys多态性与肺癌风险相关。在一项基于人群的57053名丹麦人的队列研究中，我们检测了血沉棕黄层样本中OGG1、NEIL1、MUTYH和NUDT的mRNA水平与后续肺癌风险之间的关联。共识别出260例肺癌病例，并选取了263名个体作为亚队列，根据性别、年龄和吸烟时长进行匹配。我们发现，健康个体中的OGG1 mRNA水平与后续患肺癌的风险无关。然而，具有OGG1 Cys326/Cys326基因型的受试者的OGG1 mRNA表达水平高于野生型等位基因携带者。对于纯合Cys326携带者，OGG1 mRNA水平翻倍时的发病率比（IRR）为1.51（95%置信区间：1.09 - 2.08），并且基因型与mRNA水平之间存在统计学显著的相互作用。在从不吸烟者中，OGG1 mRNA水平每翻倍，IRR为4.29（1.09 - 16.9），而在吸烟者中未发现此现象。此外，我们发现OGG1 mRNA表达与8-氧代脱氧鸟苷的尿排泄量之间存在正相关（斯皮尔曼相关系数RS = 0.18；p < 0.005）。由于表达水平低且不可靠，未纳入NUDT1 mRNA水平。结果表明，OGG1 mRNA水平应被视为DNA诱导氧化应激暴露的生物标志物，而非先天性DNA修复能力的标志物。
