Among genetic alterations, the activation of proto-oncogenes and inactivation of tumour suppressor genes in affected cells are considered to be the core molecular events that provide a selective growth advantage and clonal expansion during the multistep process of
carcinogenesis. The TP53 tumour suppressor gene is mutated in about half of all human
cancer cases. The p53
protein modulates multiple cellular functions, such as gene transcription,
DNA synthesis and repair, cell cycle arrest, senescence and apoptosis. Mutations in the TP53 gene can abrogate these functions, leading to genetic instability and progression to
cancer. The molecular archaeology of the TP53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of each type of
cancer. The spectrum of somatic mutations in the TP53 gene, of which 75% are missense mutations, implicates
environmental carcinogens and endogenous processes in the etiology of human
cancer. The presence of a characteristic TP53 mutation can also manifest a molecular link between exposure to a particular
carcinogen and a specific type of human
cancer, e.g. exposure to
aflatoxin B1 (AFB1) and
codon 249 mutations in
hepatocellular carcinoma; exposure to ultraviolet (UV) light and C:C-->T:T tandem mutations in
skin cancer; and cigarette smoking and the prevalence of G-->T transversions in
lung cancer. Although exogenous
carcinogens have been shown to target p53 selectively, evidence supporting the endogenous insult of TP53 from oxyradicals and
nitrogen-oxyradicals is also accumulating. TP53 mutations can be a
biomarker of
carcinogen effect. Determining the characteristic TP53 mutation load in non-tumorous tissue, using a highly sensitive mutation assay, can indicate exposure to a specific
carcinogen and may also help in identifying individuals at an increased risk of
cancer.