Genetic susceptibility to renal cell carcinoma: the role of DNA double-strand break repair pathway.
Genetic susceptibility to renal cell carcinoma: the role of DNA double-strand break repair pathway.
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DOI：
10.1158/1055-9965.epi-08-0259
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发表时间：
2008-09
期刊：
影响因子：
--
通讯作者：
Wu X
中科院分区：
文献类型：
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作者：
Margulis V;Lin J;Yang H;Wang W;Wood CG;Wu X
DNA修复基因的改变已被证明会导致宿主DNA修复能力的降低，并可能影响宿主对癌变的易感性。双链断裂（DSB）修复是dna修复的主要途径。本研究验证了DSB通路基因的共同序列变异使易感个体易患肾细胞癌（RCC）的假设。为此，我们在一项基于人群的病例对照研究中评估了DSB通路中10个候选基因中的13个单核苷酸多态性（SNP）与RCC风险的关系，该研究包括326名高加索RCC患者和335名对照。以纯合子野生型为参照组，我们观察到与NBS1纯合子变异基因型相关的RCC风险显著增加（rs1805794; OR 2.13； 95%可信区间（95% CI）， 1.17-3.86）。携带至少一个变异XRCC4等位基因拷贝也与风险显著增加相关（rs1805377； OR, 1.56; 95% CI, 1.08 - 2.26）。重要的是，在通路分析中，与对照组（≤1个不良等位基因）相比，携带2个（OR: 1.26; 95% CI: 0.83-1.91）、3个（OR: 1.00; 95% CI: 0.64-1.56）和3个以上不良等位基因（OR: 1.75; 95% CI: 1.03-2.98）的个体患RCC的风险增加，携带3个以上不良等位基因的个体患RCC的风险增加。这项研究的结果提供了证据，表明DBS修复途径中基因变异数量较多的个体患RCC的风险增加。这些发现需要在独立人群中进一步验证。
Alterations in DNA repair gene have been shown to cause a reduction in host DNA repair capacity and may influence host susceptibility to carcinogenesis. The double strand break (DSB) repair is a major DNA-repair pathway. This study tested the hypothesis that common sequence variants of the DSB pathway genes predispose susceptible individuals to increased risk of renal cell carcinoma (RCC). Towards this end, we evaluated the associations of 13 single nucleotide polymorphisms (SNP) in 10 candidate genes involved in the DSB pathway with RCC risk in a population-based case-control study that included 326 Caucasian RCC patients and 335 controls. Using the homozygous wild-type as the reference group, we observed a significantly increased RCC risk associated with the homozygous variant genotype of NBS1 (rs1805794; OR 2.13; 95% confidence interval (95% CI), 1.17-3.86). Carrying of at least one copy of the variant XRCC4 allele was also associated with a significantly increased risk (rs1805377; OR, 1.56; 95% CI, 1.08 - 2.26). Importantly, in pathway analysis, compared with the reference group (≤1 adverse alleles), individuals with 2 (OR: 1.26; 95% CI: 0.83-1.91), 3 (OR: 1.00; 95% CI: 0.64-1.56) and more than 3 adverse alleles (OR: 1.75; 95% CI: 1.03-2.98) were at increased risk of RCC with significant association in subjects carrying more than 3 adverse alleles. Results from this study provide evidence that individuals with a higher number of genetic variations in the DBS repair pathway are at an increased risk for RCC. These findings require further validation in independent populations.