Carcinogen-induced site-specific mutagenesis and genetic susceptibility in squamous cell carcinoma of the head and neck.
Tobacco and alcohol have been identified as the most important risk factors for squamous cell carcinomas of the head and neck (HNSCC). Especially for tobacco, some of the carcinogen-induced mutations that trigger transformation have been identified. Much attempt has been made to show a relationship between the mutations of growth regulatory genes, i.e. tumor suppressor- or oncogenes, and the exposure to specific exogeneous mutagens. One of the best examined genes - harboring the most DNA damages (DNA adducts) - caused by xenobiotics is p53. This tumor suppressor gene is an important regulator of cell cycle and apoptosis and is mutated in 40-60% of all HNSCC. Further studies link specific mutations of the ras oncogene to definite carcinogens. The question of why these mutations lead to cancer in some smokers but not in others, i.e. the individual's susceptibility to external carcinogens, remains unclear. One possibility is the individual's ability (or non-ability) of detoxifying carcinogenic xenobiotics or repairing the DNA damages they caused. There are several known polymorphisms of enzymes involved in detoxification as well as in DNA repair - which might explain the interindividual variable susceptibility to HNSCC in smokers and drinkers. However, the results of several examined polymorphisms are diverse or even controversial. The diversity might be due to ethnical differences, study populations, tumor localizations as well as intratumoral heterogeneity. In this review, we attempt to discuss the carcinogen-specific mutations as well as the genetic polymorphisms, which may transfer an enhanced susceptibility to suffer HNSCC.
Weber
A
A
Klinik für Hals-Nasen-Ohren-Heilkunde/Plastische Operationen, Universitätsklinikum Leipzig, Germany. Anette.Weber@t-online.de
Tannapfel
A
A
Wittekind
C
C
Bootz
F
F
D000428:Alcohol Drinking / Q000009:adverse effects*; D002273:Carcinogens / Q000009:adverse effects* / Q000493:pharmacokinetics; D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D004249:DNA Damage / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D008658:Inactivation, Metabolic / Q000235:genetics; D016297:Mutagenesis, Site-Directed / Q000235:genetics*; D010039:Otorhinolaryngologic Neoplasms / Q000235:genetics*; D012307:Risk Factors; D012907:Smoking / Q000009:adverse effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D002273:Carcinogens; D016159:Tumor Suppressor Protein p53