title: TP53 and KRAS mutation load and types in lung cancers in relation to tobacco smoke: distinct patterns in never, former, and current smokers.
abstract: TP53 mutations are common in lung cancers of smokers, with high prevalence of G:C-to-T:A transversions generally interpreted as mutagen fingerprints of tobacco smoke. In this study, TP53 (exons 5-9) and KRAS (codon 12) were analyzed in primary lung tumors of never (n = 40), former (n = 27), and current smokers (n = 64; mainly heavy smokers). Expression of p53, cyclooxygenase-2 (Cox-2), and nitrotyrosine (N-Tyr), a marker of protein damage by nitric oxide, were analyzed by immunohistochemistry. TP53 mutations were detected in 47.5% never, 55.6% former, and 77.4% current smokers. The relative risk for mutation increased with tobacco consumption (P(linear trend) < 0.0001). G:C-to-T:A transversions (P = 0.06, current versus never smokers) and A:T-to-G:C transitions (P = 0.03, former versus never smokers) were consistently associated with smoking. In contrast, G:C-to-A:T transitions were associated with never smoking (P = 0.02). About half of mutations in current smokers fell within a particular domain of p53 protein, suggesting a common structural effect. KRAS mutations, detected in 20 of 131 (15.3%) cases, were rare in squamous cell carcinoma compared with adenocarcinoma [relative risk (RR), 0.2; 95% confidence interval (95% CI), 0.07-1] and were more frequent in former smokers than in other categories. No significant differences in Cox-2 expression were found between ever and never smokers. However, high levels of N-Tyr were more common in never than ever smokers (RR, 10; 95% CI, 1.6-50). These results support the notion that lung tumorigenesis proceeds through different molecular mechanisms according to smoking status. In never smokers, accumulation of N-Tyr suggests an etiology involving severe inflammation.
authors.affiliation: IARC, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez
authors.forename: Anush
authors.initials: A
authors.lastname: Mukeria
authors.forename: Jay D
authors.initials: JD
authors.lastname: Hunt
authors.forename: Olaf
authors.initials: O
authors.lastname: Kelm
authors.forename: Rayjean J
authors.initials: RJ
authors.lastname: Hung
authors.forename: Philippe
authors.initials: P
authors.lastname: Tanière
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: David G
authors.initials: DG
authors.lastname: Zaridze
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
mesh_terms: D000368:Aged; D051546:Cyclooxygenase 2; D005260:Female; D016158:Genes, p53 / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins; D008875:Middle Aged; D009154:Mutation; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis; D012907:Smoking / Q000009:adverse effects / Q000235:genetics* / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000096:biosynthesis
chemical_list: D008565:Membrane Proteins; D016159:Tumor Suppressor Protein p53; C002744:3-nitrotyrosine; D014443:Tyrosine; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D011451:Prostaglandin-Endoperoxide Synthases