Smoking, P53 Mutation, and Lung Cancer

Overview

Journal Mol Cancer Res

Specialty Cell Biology

Date 2014 Jan 21

PMID 24442106

Citations 131

Authors

Don L Gibbons

Lauren A Byers

Jonathan M Kurie

Affiliations

Soon will be listed here.

Abstract

This issue marks the 50th anniversary of the release of the U.S. Surgeon General's Report on Smoking and Health. Perhaps no other singular event has done more to highlight the effects of smoking on the development of cancer. Tobacco exposure is the leading cause of cancers involving the oral cavity, conductive airways, and the lung. Owing to the many carcinogens in tobacco smoke, smoking-related malignancies have a high genome-wide burden of mutations, including in the gene encoding for p53. The p53 protein is the most frequently mutated tumor suppressor in cancer, responsible for a range of critical cellular functions that are compromised by the presence of a mutation. Herein, we review the epidemiologic connection between tobacco exposure and cancer, the molecular basis of p53 mutation in lung cancer, and the normal molecular and cellular roles of p53 that are abrogated during lung tumor development and progression as defined by in vitro and in vivo studies. We also consider the therapeutic potential of targeting mutant p53 in a clinical setting based upon the cellular role of mutant p53 and data from genetic murine models.

Citing Articles

The epigenetic landscape shapes smoking-induced mutagenesis by modulating DNA damage susceptibility and repair efficiency.

Heilbrun E, Tseitline D, Wasserman H, Kirshenbaum A, Cohen Y, Gordan R Nucleic Acids Res. 2025; 53(4).

PMID: 39933696 PMC: 11811737. DOI: 10.1093/nar/gkaf048.

Organoid modeling reveals the tumorigenic potential of the alveolar progenitor cell state.

Li J, Dang S, Sengupta S, Schurmann P, Dost A, Moye A EMBO J. 2025; .

PMID: 39930268 DOI: 10.1038/s44318-025-00376-6.

The Role of Behavioral Factors on Chronic Diseases-Practice and Knowledge Gaps.

Rahelic V, Perkovic T, Romic L, Perkovic P, Klobucar S, Pavic E Healthcare (Basel). 2025; 12(24.

PMID: 39765947 PMC: 11675894. DOI: 10.3390/healthcare12242520.

Understanding the molecular regulatory mechanisms of autophagy in lung disease pathogenesis.

Lin L, Lin Y, Han Z, Wang K, Zhou S, Wang Z Front Immunol. 2024; 15:1460023.

PMID: 39544928 PMC: 11560454. DOI: 10.3389/fimmu.2024.1460023.

Final Analysis Data and Exploratory Biomarker Analysis of a Randomized Phase 2 Study of Osimertinib Plus Bevacizumab Versus Osimertinib Monotherapy for Untreated Patients With Nonsquamous NSCLC Harboring EGFR Mutations: The WJOG9717L Study.

Kenmotsu H, Sakai K, Mori K, Kato T, Sugawara S, Kirita K JTO Clin Res Rep. 2024; 5(11):100716.

PMID: 39399795 PMC: 11470244. DOI: 10.1016/j.jtocrr.2024.100716.

References

Winslow M, Dayton T, Verhaak R, Kim-Kiselak C, Snyder E, Feldser D . Suppression of lung adenocarcinoma progression by Nkx2-1. Nature. 2011; 473(7345):101-4. PMC: 3088778. DOI: 10.1038/nature09881. View

Brauch H, Johnson B, Hovis J, Yano T, Gazdar A, Pettengill O . Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung. N Engl J Med. 1987; 317(18):1109-13. DOI: 10.1056/NEJM198710293171803. View

Finlay C, Hinds P, Levine A . The p53 proto-oncogene can act as a suppressor of transformation. Cell. 1989; 57(7):1083-93. DOI: 10.1016/0092-8674(89)90045-7. View

Xue W, Zender L, Miething C, Dickins R, Hernando E, Krizhanovsky V . Senescence and tumour clearance is triggered by p53 restoration in murine liver carcinomas. Nature. 2007; 445(7128):656-60. PMC: 4601097. DOI: 10.1038/nature05529. View

Malkin D, Li F, Strong L, Fraumeni Jr J, Nelson C, Kim D . Germ line p53 mutations in a familial syndrome of breast cancer, sarcomas, and other neoplasms. Science. 1990; 250(4985):1233-8. DOI: 10.1126/science.1978757. View

Feldser D, Kostova K, Winslow M, Taylor S, Cashman C, Whittaker C . Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature. 2010; 468(7323):572-5. PMC: 3003305. DOI: 10.1038/nature09535. View

Meylan E, Dooley A, Feldser D, Shen L, Turk E, OuYang C . Requirement for NF-kappaB signalling in a mouse model of lung adenocarcinoma. Nature. 2009; 462(7269):104-7. PMC: 2780341. DOI: 10.1038/nature08462. View

Hussain S, Amstad P, Raja K, Sawyer M, Hofseth L, Shields P . Mutability of p53 hotspot codons to benzo(a)pyrene diol epoxide (BPDE) and the frequency of p53 mutations in nontumorous human lung. Cancer Res. 2001; 61(17):6350-5. View

Donehower L, Harvey M, Slagle B, McArthur M, Montgomery Jr C, Butel J . Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature. 1992; 356(6366):215-21. DOI: 10.1038/356215a0. View

10.

Lawrence M, Stojanov P, Polak P, Kryukov G, Cibulskis K, Sivachenko A . Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature. 2013; 499(7457):214-218. PMC: 3919509. DOI: 10.1038/nature12213. View

11.

Williams B, Remington L, Albert D, Mukai S, Bronson R, Jacks T . Cooperative tumorigenic effects of germline mutations in Rb and p53. Nat Genet. 1994; 7(4):480-4. DOI: 10.1038/ng0894-480. View

12.

Schlereth K, Heyl C, Krampitz A, Mernberger M, Finkernagel F, Scharfe M . Characterization of the p53 cistrome--DNA binding cooperativity dissects p53's tumor suppressor functions. PLoS Genet. 2013; 9(8):e1003726. PMC: 3744428. DOI: 10.1371/journal.pgen.1003726. View

13.

Gaiddon C, Lokshin M, Ahn J, Zhang T, Prives C . A subset of tumor-derived mutant forms of p53 down-regulate p63 and p73 through a direct interaction with the p53 core domain. Mol Cell Biol. 2001; 21(5):1874-87. PMC: 86759. DOI: 10.1128/MCB.21.5.1874-1887.2001. View

14.

Jackson E, Olive K, Tuveson D, Bronson R, Crowley D, Brown M . The differential effects of mutant p53 alleles on advanced murine lung cancer. Cancer Res. 2005; 65(22):10280-8. DOI: 10.1158/0008-5472.CAN-05-2193. View

15.

Govindan R, Ding L, Griffith M, Subramanian J, Dees N, Kanchi K . Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell. 2012; 150(6):1121-34. PMC: 3656590. DOI: 10.1016/j.cell.2012.08.024. View

16.

Junttila M, Karnezis A, Garcia D, Madriles F, Kortlever R, Rostker F . Selective activation of p53-mediated tumour suppression in high-grade tumours. Nature. 2010; 468(7323):567-71. PMC: 3011233. DOI: 10.1038/nature09526. View

17.

Harris C, Autrup H, Connor R, Barrett L, McDowell E, Trump B . Interindividual variation in binding of benzo[a]pyrene to DNA in cultured human bronchi. Science. 1976; 194(4269):1067-9. DOI: 10.1126/science.982061. View

18.

Sato M, Larsen J, Lee W, Sun H, Shames D, Dalvi M . Human lung epithelial cells progressed to malignancy through specific oncogenic manipulations. Mol Cancer Res. 2013; 11(6):638-50. PMC: 3687022. DOI: 10.1158/1541-7786.MCR-12-0634-T. View

19.

Eliyahu D, Raz A, Gruss P, Givol D, Oren M . Participation of p53 cellular tumour antigen in transformation of normal embryonic cells. Nature. 1984; 312(5995):646-9. DOI: 10.1038/312646a0. View

20.

Ventura A, Kirsch D, McLaughlin M, Tuveson D, Grimm J, Lintault L . Restoration of p53 function leads to tumour regression in vivo. Nature. 2007; 445(7128):661-5. DOI: 10.1038/nature05541. View