Hainaut P, Pfeifer G P
International Agency for Research on Cancer (WHO), 150 Cours Albert Thomas, 69372 Lyon cedex, France.
Carcinogenesis. 2001 Mar;22(3):367-74. doi: 10.1093/carcin/22.3.367.
It is unquestionable that the major cause of lung cancer is cigarette smoking. p53 mutations are common in lung cancers from smokers but less common in non-smokers. A large fraction of the p53 mutations in lung cancers are G-->T transversions, a type of mutation that is infrequent in other tumors aside from hepatocellular carcinoma. Previous studies have indicated that there is a good correlation between G-->T transversion hotspots in lung cancers and sites of preferential formation of polycyclic aromatic hydrocarbon (PAH) adducts along the p53 gene. The origin of p53 mutations in lung cancer has been questioned by recent reports suggesting that there are no significant differences in p53 mutation spectra between smokers and non-smokers and between lung cancers and non-lung cancers [S.N. Rodin and A.S. Rodin (2000) Human lung cancer and p53: The interplay between mutagenesis and selection. P:roc. Natl Acad. Sci. USA, 97, 12244-12249]. We have re-assessed these issues by using the latest update of the p53 mutation database of the International Agency for Research on Cancer (14 051 entries) as well as recent data from the primary literature on non-smokers. We come to the conclusion that the p53 mutation spectra are different between smokers and non-smokers and that this difference is highly statistically significant (G-->T transversions are 30 versus 10%; P < 0.0001, chi2 test). A similar difference is seen between lung cancers and non-lung cancers. At a number of mutational hotspots common to all cancers, a large fraction of the mutations are G-->T transversions in lung cancers but are almost exclusively G-->A transitions in non-lung cancers. Our data reinforce the notion that p53 mutations in lung cancers can be attributed to direct DNA damage from cigarette smoke carcinogens rather than to selection of pre-existing endogenous mutations.
毫无疑问，肺癌的主要病因是吸烟。p53突变在吸烟者的肺癌中很常见，但在不吸烟者中则较少见。肺癌中很大一部分p53突变是G→T颠换，这种突变类型除肝细胞癌外，在其他肿瘤中并不常见。先前的研究表明，肺癌中的G→T颠换热点与p53基因上多环芳烃（PAH）加合物优先形成的位点之间存在良好的相关性。最近的报告对肺癌中p53突变的起源提出了质疑，这些报告表明吸烟者与不吸烟者之间以及肺癌与非肺癌之间的p53突变谱没有显著差异[S.N. Rodin和A.S. Rodin（2000年）《人类肺癌与p53：诱变与选择之间的相互作用》。《美国国家科学院院刊》，97，12244 - 12249]。我们通过使用国际癌症研究机构p53突变数据库的最新更新版本（14051条记录）以及来自关于不吸烟者的原始文献的最新数据，重新评估了这些问题。我们得出的结论是，吸烟者与不吸烟者之间的p53突变谱不同，并且这种差异具有高度统计学意义（G→T颠换分别为30%和10%；P < 0.0001，卡方检验）。肺癌与非肺癌之间也存在类似的差异。在所有癌症共有的一些突变热点处，肺癌中的大部分突变是G→T颠换，而在非肺癌中几乎完全是G→A转换。我们的数据强化了这样一种观念，即肺癌中的p53突变可归因于香烟烟雾致癌物对DNA的直接损伤，而不是对预先存在的内源性突变的选择。
