Hornhardt Sabine, Rößler Ute, Sauter Wiebke, Rosenberger Albert, Illig Thomas, Bickeböller Heike, Wichmann Hans-Erich, Gomolka Maria
Department of Radiation Protection and Health, Federal Office for Radiation Protection, Ingolstaedter Landstr.1, 85764 Oberschleissheim,Germany.
Institute of Epidemiology, Helmholtz Center Munich, 85764 Neuherberg, Germany.
DNA Repair (Amst). 2014 Apr;16:54-65. doi: 10.1016/j.dnarep.2014.02.001. Epub 2014 Mar 4.
Cancer risk and radiation sensitivity are often associated with alterations in DNA repair, cell cycle, or apoptotic pathways. Interindividual variability in mutagen or radiation sensitivity and in cancer susceptibility may also be traced back to polymorphisms of genes affecting e.g. DNA repair capacity. We studied possible associations between 70 polymorphisms of 12 DNA repair genes with basal and initial DNA damage and with repair thereof. We investigated DNA damage induced by ionizing radiation in lymphocytes isolated from 177 young lung cancer patients and 169 cancer-free controls. We also sought replication of our findings in an independent sample of 175 families (in total 798 individuals). DNA damage was assessed by the Olive tail moment (OTM) of the comet assay. DNA repair capacity (DRC) was determined for 10, 30 and, 60min of repair. Genes involved in the single-strand-repair pathway (SSR; like XRCC1 and MSH2) as well as genes involved in the double-strand-repair pathway (DSR; like RAD50, XRCC4, MRE11 and ATM) were found to be associated with DNA damage. The most significant association was observed for marker rs3213334 (p=0.005) of XRCC1 with basal DNA damage (B), in both cases and controls. A clear additive effect on the logarithm of OTM was identified for the marker rs1001581 of the same LD-block (p=0.039): BCC=-1.06 (95%-CI: -1.16 to -0.96), BCT=-1.02 (95%-CI: -1.11 to -0.93) and BTT=-0.85 (95%-CI: -1.01 to -0.68). In both cases and controls, we observed significantly higher DNA basal damage (p=0.007) for carriers of the genotype AA of marker rs2237060 of RAD50 (involved in DSR). However, this could not be replicated in the sample of families (p=0.781). An alteration to DRC after 30min of repair with respect to cases was observed as borderline significant for marker rs611646 of ATM (involved in DSR; p=0.055), but was the most significant finding in the sample of families (p=0.009). Our data indicate that gene variation impacts measurably on DNA damage and repair, suggesting at least a partial contribution to radiation sensitivity and lung cancer susceptibility.
癌症风险和辐射敏感性通常与DNA修复、细胞周期或凋亡途径的改变有关。个体间在诱变剂或辐射敏感性以及癌症易感性方面的差异也可能追溯到影响例如DNA修复能力的基因多态性。我们研究了12个DNA修复基因的70个多态性与基础和初始DNA损伤及其修复之间的可能关联。我们调查了从177名年轻肺癌患者和169名无癌对照者中分离出的淋巴细胞中电离辐射诱导的DNA损伤。我们还在一个由175个家庭（共798人）组成的独立样本中寻求对我们研究结果的验证。通过彗星试验的橄榄尾矩（OTM）评估DNA损伤。在修复10分钟、30分钟和60分钟时测定DNA修复能力（DRC）。发现参与单链修复途径（SSR；如XRCC1和MSH2）的基因以及参与双链修复途径（DSR；如RAD50、XRCC4、MRE11和ATM）的基因与DNA损伤有关。在病例组和对照组中，均观察到XRCC1的标记rs3213334与基础DNA损伤（B）之间的最显著关联（p = 0.005）。对于同一连锁不平衡区域的标记rs1001581，在OTM对数上发现了明显的加性效应（p = 0.039）：病例组与对照组比较（BCC）=-1.06（95%置信区间：-1.16至-0.96），病例组与病例组比较（BCT）=-1.02（95%置信区间：-1.11至-0.93），对照组与对照组比较（BTT）=-0.85（95%置信区间：-1.01至-0.68）。在病例组和对照组中，我们观察到RAD50（参与DSR）的标记rs2237060的AA基因型携带者的DNA基础损伤显著更高（p = 0.007）。然而，这在家庭样本中无法得到验证（p = 0.781）。对于ATM的标记rs611646（参与DSR），在病例组中观察到修复30分钟后DRC的改变接近显著（p = 0.055），但这是家庭样本中最显著的发现（p = 0.009）。我们的数据表明基因变异对DNA损伤和修复有显著影响，这表明基因变异至少对辐射敏感性和肺癌易感性有部分贡献。
