Gao Wei-Min, Romkes Marjorie, Siegfried Jill M, Luketich James D, Keohavong Phouthone
Department of Environmental and Occupational Health, University of Pittsburgh, Pittsburgh, Pennsylvania 15219, USA.
Mol Carcinog. 2006 Nov;45(11):828-32. doi: 10.1002/mc.20208.
The etiology of lung cancer in population with little or no tobacco exposure is not well understood. Individual genetic susceptibility factors have been suggested to contribute to lung cancer risk in this population. Mutations in the p53 tumor suppressor gene are implicated in the development of lung cancer as they are frequently found in lung tumors from both smokers and never-smokers. In order to determine whether genetic polymorphisms affecting DNA repair capacity modulate p53 mutations in lung tumors from never-smokers, we compared p53 mutations with genotypes of XPD 312, XPD 751, and XRCC1 399 in lung tumors from 43 lifetime never-smokers. p53 mutations were identified in 10 (23%) cases and consisted mostly of G/C to A/T transitions. No statistically significant association was found between p53 mutations and genotypes of XPD 312 or XPD 751. However, patients with the XRCC1 399 Gln allele, that results in a lower base excision repair capacity, were more likely to have p53 mutations, compared with patients the wild-type Arg allele (P = 0.03). In addition, the p53 mutation frequency increased with an increasing number of combined genotypes associated with a lower DNA repair capacity of XPD 312, XPD 751, and XRCC1 399 (P = 0.02). These results suggest that individuals who never smoked and had XRCC1 399 Gln allele may be at a greater risk of p53 mutations, especially if combined with the genotypes of XPD 312 and XPD 751 that may result in a lower DNA repair capacity.
在很少或没有烟草暴露的人群中，肺癌的病因尚未完全明确。有研究表明个体遗传易感性因素可能导致该人群患肺癌的风险增加。p53肿瘤抑制基因的突变与肺癌的发生有关，因为在吸烟者和从不吸烟者的肺肿瘤中都经常发现这些突变。为了确定影响DNA修复能力的基因多态性是否会调节从不吸烟者肺肿瘤中的p53突变，我们比较了43名终生不吸烟者肺肿瘤中p53突变与XPD 312、XPD 751和XRCC1 399的基因型。在10例（23%）病例中发现了p53突变，主要为G/C到A/T的转换。未发现p53突变与XPD 312或XPD 751基因型之间存在统计学显著关联。然而，与野生型Arg等位基因的患者相比，携带导致碱基切除修复能力较低的XRCC1 399 Gln等位基因的患者更有可能发生p53突变（P = 0.03）。此外，随着与XPD 312、XPD 751和XRCC1 399较低DNA修复能力相关的联合基因型数量增加，p53突变频率也增加（P = 0.02）。这些结果表明，从不吸烟且携带XRCC1 399 Gln等位基因的个体可能有更大的p53突变风险，特别是如果与可能导致较低DNA修复能力的XPD 312和XPD 751基因型相结合。
