Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer
Association of the DNA repair gene XPD Asp312Asn polymorphism with p53 gene mutations in tobacco-related non-small cell lung cancer
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DOI：
10.1093/carcin/bgg115
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发表时间：
2003-10-01
期刊：
影响因子：
4.7
通讯作者：
Keohavong, P
中科院分区：
文献类型：
--
作者：
Gao, WM;Romkes, M;Keohavong, P
肺癌是一种主要与烟草烟雾暴露有关的疾病，也是工业化国家癌症相关死亡的主要原因，通常与p53肿瘤抑制基因突变有关。导致DNA修复能力个体间变异的遗传差异可能部分解释了细胞对遗传毒性剂的易感性，导致体细胞突变，包括p53突变，并最终将正常细胞转化为恶性表型。本研究旨在探讨DNA修复基因核苷酸切除修复着色性干皮病D组（XPD）基因（密码子312和751）和碱基切除修复X射线修复交叉互补组1（XRCC 1）基因（密码子399）多态性与肺癌患者p53突变的关系。分析了204例吸烟者非小细胞肺癌（NSCLC）患者的肺肿瘤中p53基因第5-8外显子的突变以及XPD和XRCC 1基因型。20%（40/204）的患者存在p53突变。携带XPD密码子312 Asn等位基因的患者发生p53突变的可能性（13.8%）低于XPD 312 Asp/Asp（27.3%）[比值比（OR）0.43，95%置信区间（CI）0.20-0.89，P = 0.023]。未发现p53突变与XPD Lys 751 Gln或XRCC 1 Arg 399 Gln之间存在关联。然而，在XPD 312 WT（Asp/Asp）、XPD 751 VT（Lys/Gln或Gln/Gln）或XRCC 1 399 VT（Arg/Gln或Gln/Gln）中，p53突变频率随着组合基因型数目的增加而增加（P = 0.01，趋势检验）。这些结果表明，吸烟并具有XPD密码子312 Asp/Asp基因型的个体可能具有更大的p53突变风险，特别是如果与可能导致DNA修复缺陷的其他多态性相结合。
Lung cancer, a disease related mostly to tobacco smoke exposure and a leading cause of cancer-related death in industrialized countries, is frequently associated with mutations in the p53 tumor suppressor gene. Genetic differences resulting in inter-individual variation in DNA repair capacity may in part account for susceptibility of a cell to genotoxic agents leading to somatic mutations, including p53 mutations, and eventual transformation of a normal cell into a malignant phenotype. The objective of this study is to investigate the relationship between the polymorphisms of two DNA repair genes, the nucleotide excision repair xeroderma pigmentosum group D (XPD) gene (codons 312 and 751) and the base excision repair X-ray repair cross-complementing group 1 (XRCC1) gene (codon 399), and p53 mutations among lung cancer patients. Lung tumors from 204 smokers with non-small cell lung cancer (NSCLC) were analyzed for mutations in exons 5-8 of the p53 gene and genotypes of XPD and XRCC1. p53 mutations were found in 20% (40/204) of the patients. Patients with the XPD codon 312 Asn allele were less likely to have p53 mutations (13.8%) than XPD 312 Asp/Asp (27.3%) [odds ratio (OR) 0.43, 95% confidence interval (CI) 0.20-0.89, P = 0.023]. No association was found between p53 mutations and either XPD Lys751Gln or XRCC1 Arg399Gln. However, the p53 mutation frequency increased with the increased number of the combined genotypes among XPD 312WT (Asp/Asp), XPD 751VT (Lys/Gln or Gln/Gln) or XRCC1 399VT (Arg/Gln or Gln/Gln) (P = 0.01, trend test). These results suggest that individuals who smoke and have the XPD codon 312 Asp/Asp genotype may be at a greater risk of p53 mutations, especially if combined with other polymorphisms that may result in deficient DNA repair.