Human lung cancer and p53:: The interplay between mutagenesis and selection
Human lung cancer and p53:: The interplay between mutagenesis and selection
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DOI：
10.1073/pnas.180320897
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发表时间：
2000-10-24
影响因子：
11.1
通讯作者：
Rodin, AS
中科院分区：
文献类型：
--
作者：
Rodin, SN;Rodin, AS
人们几乎一致认为，烟草烟雾的主要致癌风险在于其对癌症相关基因DNA的直接诱变作用。从p53肿瘤抑制基因的加合物谱中获得了推测吸烟诱导突变与肺癌相关的关键数据。我们对国际癌症研究机构p53数据库（1999年4月更新）和文献中p53突变的分析结果表明了不同的致病联系。我们新的分析测试集中在互补碱基替换上，并表明正是原发性病变的链特异性修复和所产生突变的位点特异性选择决定了肺癌特异性热点，即沿着p53基因沿着G：C到T：A的颠换，以及与烟雾不可及的组织相比，它们在肺组织中的丰度增加。然而，在p53 DNA的两条链中的每一条上，我们的测试显示吸烟者和非吸烟者之间在不同类型的突变的频率或它们沿p53基因沿着出现的频率上没有显著差异。此外，在吸烟者和非吸烟者中，具有沉默的p53突变的肺肿瘤的频率相同。因此，我们在这里提供了一个基于选择的解释，为什么非沉默p53突变的肺癌在吸烟者中比在非吸烟者中更常见。我们的结论是，吸烟加重的生理压力（不一定是遗传毒性）是p53相关的肺癌病因的主要危险因素。
It is an almost consensus opinion that the major carcinogenic risk of,tobacco smoke is in its direct mutagenic action on DNA of cancer-related genes. The key data supposedly linking smoke-induced mutations to lung cancer were obtained from the adduct spectrum of the p53 tumor suppressor gene. Results of our analysis of p53 mutations compiled from the International Agency for Research on Cancer p53 database (April 1999 update) and from the literature point to a different causative link. Our new analytical tests focused on complementary base substitutions and showed that it is strand-specific repair of primary lesions and site-specific selection of the resultant mutations that determine the lung cancer-specific hot spots of G:C to T:A transversions along the p53 gene and also their increased abundance in lung tissues as compared with smoke-inaccessible tissues. However, on each of the two strands of p53 DNA, our tests revealed no significant difference between smokers and nonsmokers, either in the frequency of different types of mutations or in the frequency of their occurrence along the p53 gene, Moreover, in both smokers and nonsmokers, there was the same frequency of lung tumors with silent p53 mutations. Accordingly, we offer here a selection-based explanation of why lung cancers with nonsilent p53 mutations are more common in smokers than in nonsmokers. We conclude that physiological stresses (not necessarily genotoxic) aggravated by smoking are the leading risk factor in the p53-associated etiology of lung cancer.