Patterns of p53 G -> T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke

It is unquestionable that the major cause of lung cancer is cigarette smoki ng. p53 mutations are common in lung cancers from smokers but less common i n 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 as ide from hepatocellular carcinoma. Previous studies have indicated that the re is a good correlation between G-->T transversion hotspots in lung cancer s and sites of preferential formation of polycyclic aromatic hydrocarbon (P AH) adducts along the p53 gene, The origin of p53 mutations in lung cancer has been questioned by recent reports suggesting that there are no signific ant 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, Proc. Natl Acad, Sci, USA, 97, 12244-12249]. We have reassessed these issu es by using the latest update of the p53 mutation database of the Internati onal 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 transversio ns are 30 versus 10%; P < 0.0001, <chi>(2) test). A similar difference is s een between lung cancers and non-lung cancers. At a number of mutational ho tspots common to all cancers, a large fraction of the mutations are G-->T t ransversions in lung cancers but are almost exclusively G-->A transitions i n non-lung cancers, Our data reinforce the notion that p53 mutations in lun g cancers can be attributed to direct DNA damage from cigarette smoke carci nogens rather than to selection of pre-existing endogenous mutations.