Smoking, p53 mutation, and lung cancer

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.

Figure 1

Genome-wide mutation density from the TCGA datasets for lung adenocarcinoma and squamous cell carcinoma. Plot of mutations/megabase of the genome, with the X-axis representing the probability density. Current smokers were grouped with those reformed for less than 15 years, while those reformed greater than 15 years and lifelong non-smokers are presented separately. Since 96% of the squamous cell lung cancer group was identified as a smoker, this group was not further segregated.

Figure 2

p53 mutation spectrum from the TCGA lung squamous and lung adenocarcinoma datasets. A graphical representation is shown of the percent with p53 mutations (colored) versus wild-type p53 (grey). The mutations within a 5 residue stretch are grouped and colored to represent one of four hotspot regions, around amino acid 157 (orange), 175 (green), 248 (red) and 273 (yellow). Mutations outside of these four hotspots are grouped and colored blue.

Figure 3

Domain structure of the p53 protein. (A) The functional domains and some of the sites of post-translational modification are illustrated. The concentration of N-terminal Ser/Thr phosphorylation sites is schematically shown. The major sites of lysine acetylation are shown in green arrows at K120 and K164, while the cluster of 6 lysines in the TD and CRD that can be ubiquitinated or acetylated are schematically indicated with blue arrows. (B) The amino acid residues in the four mutational hotspot regions of the DNA binding domain are shown.