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TP53 and KRAS Mutation Load and Types in Lung Cancers in Relation to Tobacco Smoke: Distinct Patterns in Never, Former, and Current Smokers
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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 (Plinear 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.
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“Unlike other clinically actionable genomic alterations found in NSCLCs (such as EGFR and ALK aberrations), KRAS mutations, particularly KRASG12C and KRASG12V, are strongly associated with smoking29–31.”
From The current state of the art and future trends in RAS-targeted cancer therapies (2022) · cites this paper as [31]
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Metadata
- Authors
- Le Calvez, F., Mukeria, A., Hunt, J. D., Kelm, O., Hung, R. J., Tanière, P., Brennan, P., Boffetta, P., Zaridze, D. G., & Hainaut, P.
- Affiliations
- 1IARC, Lyon, France;
- Russian Cancer Research Center NN Blokhin (RU)
- Centre international de recherche sur le cancer (FR)
- 4Department of Cellular Pathology, The Medical School, University of Birmingham, Egbaston, Birmingham, United Kingdom
- ORCID
- Venue
- Cancer Research
- Published
- 2005-06-15
- Volume
- 65
- Issue
- 12
- Pages
- 5076-5083
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2149459560
- Cited by
- 273
- References
- 54
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 8 · 2023: 12 · 2022: 11 · 2021: 12 · 2020: 9 · 2019: 15 · 2018: 4 · 2017: 10 · 2016: 11 · 2015: 9 · 2014: 11 · 2013: 14 · 2012: 27
- FWCI
- 13.85
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- Funders
- European Commission (IC15-CT96-0313)
- National Institutes of Health (5k01es000358-03)
- National Institute of Environmental Health Sciences (K01‐ES00358)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Smoking Behavior and Cessation
- Keywords
- TP53 mutation, KRAS mutation, lung cancer, smoking, mutation patterns, G:C to T:A transversions, cyclooxygenase-2, nitrotyrosine, nitric oxide, inflammation, never smokers, former smokers, squamous cell carcinoma, adenocarcinoma, lung carcinogenesis
- MeSH terms
- Aged, Female, Humans, Immunohistochemistry, Lung Neoplasms, Male, Membrane Proteins, Middle Aged, Mutation, Prostaglandin-Endoperoxide Synthases, Genes, ras, Smoking, Tyrosine, Genes, p53, Tumor Suppressor Protein p53, Cyclooxygenase 2
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