P53 mutations do not occur randomly but have certain mutation hotspots. These hotspots are within a domain of about 180 amino acids from codon 120 to 130. These are specifically G-to-T transversions in lung cancer, brain, breast, and colorectal cancers. The hotspot locations are important because they can allow the specific assignment of particular carcinogens to that mutated site. These specific sites can also be linked to specific cancers.  


p53 Mutations


For lung cancers, some of the specific mutational hotspots include codons 157,158,245,248, and 273 (mostly G to T mutations). 248 and 273 are the most common targets for the G to T transversions and are the most common for the entire p53 mutation database. When these are mutated, p53’s function is altered and aggregates p53’s ability to act as a transcription factor to activated other genes. 


Target codons for mutation

Carcinogens liken to target the tumor suppressor genes or oncogenes primarily. Mutations that occur on the p53 tumor suppressor gene are common in smokers and the lungs. An excess of G-to-T transversions occurs for these tumors that grow here. Around 30% of the point mutations that happen on this gene are the G-toT transversions (in smokers), as compared to 12% in non-smokers. Nonsmokers have an increased number of G to A transversions (47% to 27% smokers). 



State University of New York at Stony Brook

One of the most studied PAHs, benzo[a]pyrene (BaP) can cause genotoxic changes to DNA. When BaP enters the body it will be processed by enzymes which will allow it to become water soluble. These water soluble forms of the BaP will be called epoxides. Epoxides are good at binding to DNA and creating the bulky adducts. When adducts remain attached, they generally form in the lungs, mouth, and bladder for smoking-induced cancers. 

Benzo[a]pyrene 

Pfeifer, G. P., Denissenko, M. F., Olivier, M., Tretyakova, N., Hecht, S. S., & Hainaut, P. (2002). Tobacco smoke carcinogens, DNA damage and p53 mutations in smoking-associated cancers. Oncogene, 21(48), 7435–7451. https://doi.org/10.1038/sj.onc.1205803

Tobacco Smoke Carcinogens Reference

These adducts will form at guanine bases in DNA. Normally, guanine will pair with cytosine in the DNA helix, but when the DNA adduct has replicated the enzymes that do the copying will put an adenine base opposite of the guanine. These point mutations are called G-to-T transversions. Single purine bases are changed for a pyrimidine or vice versa. An abundance of these G-to-T transversions in DNA is an indicator of smoking-induced damage. 

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