PubMed · 10048946
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G A Boorman. 1998. EMF working group.. https://doi.org/10.1289/ehp.106-1533239
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It is estimated that cigarette smoking kills over 1 000 000 people each year by causing lung cancer as well as many other neoplasmas. p53 mutations are frequent in tobacco-related cancers and the mutation load is often higher in cancers from smokers than from nonsmokers. In lung cancers, the p53 mutational patterns are different between smokers and nonsmokers with an excess of G to T transversions in smoking-associated cancers. The prevalence of G to T transversions is 30% in smokers' lung cancer but only 12% in lung cancers of nonsmokers. A similar trend exists, albeit less marked, in laryngeal cancers and in head and neck cancers. This type of mutation is infrequent in most other tumors aside from hepatocellular carcinoma. At several p53 mutational hotspots common to all cancers, such as codons 248 and 273, a large fraction of the mutations are G to T events in lung cancers but are almost exclusively G to A transitions in non-tobacco-related cancers. Two important classes of tobacco smoke carcinogens are the polycyclic aromatic hydrocarbons (PAH) and the nicotine-derived nitrosamines. Recent studies have indicated that there is a strong coincidence of G to T transversion hotspots in lung cancers and sites of preferential formation of PAH adducts along the p53 gene. Endogenously methylated CpG dinucleotides are the preferred sites for G to T transversions, accounting for more than 50% of such mutations in lung tumors. The same dinucleotide, when present within CpG-methylated mutational reporter genes, is the target of G to T transversion hotspots in cells exposed to the model PAH compound benzo[a]pyrene-7,8-diol-9,10-epoxide. As summarized here, a number of other tobacco smoke carcinogens also can cause G to T transversion mutations. The available data suggest 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.
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Lung cancer is the single most common cause of death, and almost all of it is due to tobacco smoking. Before the widespread use of cigarettes in this century, lung cancer was a rare illness. Tobacco smoke is a complex mixture of numerous mutagens and carcinogens. Over the last 40 years, the type of cigarettes most frequently used has been changing, namely the increased use of low tar and nicotine cigarettes. This has been accompanied by an increased risk of lung cancer due to a smokers' need to maintain blood nicotine levels, which in turn causes the need for smoking more cigarettes per day and deeper inhalation. This phenomena has led to the increasing rates of lung adenocarcinoma, compared to squamous cell carcinoma. It also probably explains, in part, the greater risk of lung cancer in women compared to men (in addition to some biological differences). The study of lung cancer involves many types of biomarkers, including those that measure exposure, the biologically effective dose and harm. The use of these has allowed us to understand many parts of lung carcinogenesis. Genetic susceptibilities play a large role in lung cancer risk. They govern smoking behavior (affecting dopamine reward mechanisms due to nicotine and nicotine metabolism), carcinogen metabolism and detoxification, DNA repair, cell cycle control and other cellular responses. The need for the study of lung cancer is highlighted by the need to improve cessation rates and reduce exposure among persons who cannot quit smoking, for better prevention strategies for former smokers and an understanding of environmental tobacco smoke risk.