Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers

Abstract

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 tobaccorelated 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 CpGmethylated 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.

Cigarette smoke condensate-induced level of adenomatous polyposis coli blocks long-patch base excision repair in breast epithelial cells

“…Furthermore, it has been found that in lung cancer cells, approximately 30% of GC to TA transversions occur at the hot spot codon 248 and 273 of TP53 gene and at codon 12, 13 or 61 of K-ras gene (Slebos et al, 1991;Husgafvel-Pursiainen et al, 1993;Westra et al, 1993;Greenblatt et al, 1994). A similar mutation spectrum has been detected in the TP53 gene of bronchial epithelial cells treated with B[a]P-7,8-diol-9,10-epoxide (Pfeifer et al, 2002). GC to TA transversions have also been found in Salmonella typhimurium strains by CSC treatment, suggesting a role of PAHs in inducing this class of mutations (DeMarini et al, 1995).…”

Nicotine coregulates multiple pathways involved in protein modification/degradation in rat brain

“…Previous studies also have suggested that nicotine, directly or indirectly, modulates the amount of DNA repair and/or DNA damage tolerance [30,44,46]. For example, nicotine increases the repair of plasmid DNA damaged by free radicals in the presence of whole-cell protein extracts from adult myocytes [30].…”

Epidemiology of Lung Cancer

“…First, polycyclic aromatic hydrocarbons, carcinogenic compounds present in tobacco smoke, induce mutations in the p53 gene that are crucial for cell cycle dysregulation and carcinogenesis. 34 G to T transversions within the gene have been linked to a molecular signature of tobacco mutagens in smokingassociated lung cancers. Second, the N-nitroso compounds are another major group of chemicals found in tobacco smoke, several of which are potent animal carcinogens.…”