Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment.
The p53 tumor 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 p53 gene can abrogate these functions and may lead to genetic instability and progress to cancer. The molecular archeology of the p53 mutation spectrum generates hypotheses concerning the etiology and molecular pathogenesis of cancer. The spectrum of somatic mutations in the p53 gene implicates environmental carcinogens and endogenous processes in the etiology of human cancer. The presence of a characteristic p53 mutation also can manifest a molecular link between exposure to a particular carcinogen and a specific type of human cancer, e.g. aflatoxin B1 (AFB1) exposure and codon 249ser mutations in hepatocellular carcinoma, ultraviolet (UV) exposure and CC to TT tandem mutations in skin cancer, and cigarette smoke and the prevalence of G to T transversions in lung cancer. Although several different exogenous carcinogens have been shown to selectively target p53, evidence supporting the endogenous insult of p53 from oxyradical and nitrogen-oxyradicals is accumulating. p53 mutations can be a biomarker of carcinogen effect. Determining the characteristic p53 mutation load in nontumorous tissue, with a highly sensitive mutation assay, can indicate a specific carcinogen exposure and also may help in identifying individuals at an increased risk of cancer.
Hussain
S P
SP
Laboratory of Human Carcinogenesis, National Cancer Institute, NIH, 37 Convent Drive, MSC 4255, Bethesda, MD 20892, USA.
Hofseth
L J
LJ
Harris
C C
CC
D002273:Carcinogens / Q000009:adverse effects*; D002471:Cell Transformation, Neoplastic; D016166:Free Radical Scavengers / Q000009:adverse effects; D016147:Genes, Tumor Suppressor; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005820:Genetic Testing; D006801:Humans; D008175:Lung Neoplasms / Q000209:etiology / Q000235:genetics*; D009569:Nitric Oxide / Q000009:adverse effects; D018384:Oxidative Stress; D017354:Point Mutation; D018570:Risk Assessment; D012878:Skin Neoplasms / Q000209:etiology / Q000235:genetics; D012907:Smoking / Q000009:adverse effects
D002273:Carcinogens; D016166:Free Radical Scavengers; D009569:Nitric Oxide