Genetic factors in individual radiation sensitivity
Genetic factors in individual radiation sensitivity
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DOI：
10.1016/j.dnarep.2014.02.001
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发表时间：
2014-04-01
期刊：
影响因子：
3.8
通讯作者：
Gomolka, Maria
中科院分区：
文献类型：
--
作者：
Hornhardt, Sabine;Roessler, Ute;Gomolka, Maria
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。诱变剂或辐射敏感性和癌症易感性的个体间差异也可追溯到影响DNA修复能力等基因的多态性。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。我们研究了电离辐射对177例年轻肺癌患者和169例无癌对照的淋巴细胞的DNA损伤。我们还在175个家庭（总共798个人）的独立样本中寻求复制我们的发现。采用彗星试验的橄榄尾矩（OTM）评估DNA损伤。测定10、30和60 mm的DNA修复能力（DRC）。发现单链修复途径的基因（SSR，如XRCC1和MSH2）和双链修复途径的基因（DSR，如RAD50、XRCC4、MRE11和ATM）与DNA损伤相关。在病例和对照组中，XRCC1的标记rs3213334与基础DNA损伤(B)的相关性最为显著（p = 0.005）。对同一ld区rs1001581标记物的OTM对数有明显的加性效应（p = 0.039）： B-CC = -1.06 (95%-CI: 1.16 ~ -0.96), B-CT = -1.02 (95%-CI: -1.11 ~ -0.93), B-TT = -0.85 （95%-CI: -1.01 ~ -0.68）。在病例和对照组中，我们观察到RAD50（参与DSR）标记rs2237060 AA基因型携带者的DNA基础损伤显著增加（p = 0.007）。然而，这不能在家庭样本中重复（p = 0.781）。修复30分钟后，患者的DRC变化对于ATM标记物rs611646（参与DSR， p = 0.055）具有临界显著性，但在家庭样本中最显著（p = 0.009）。我们的数据表明，基因变异对DNA损伤和修复有可测量的影响，这表明至少部分影响辐射敏感性和肺癌易感性。(C) 2014 Elsevier B.V.版权所有
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, 60 mm 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): B-CC = -1.06 (95%-CI: 1.16 to -0.96), B-CT = -1.02 (95%-CI: -1.11 to -0.93) and B-TT = -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 30 min 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. (C) 2014 Elsevier B.V. All rights reserved.