p53 mutational spectra and the role of methylated CpG sequences

The occurrence of tumor-specific mutational spectra in the p53 mutation dat abase provides indirect evidence that implicates certain exogenous and poss ibly endogenous mutagenic events in human carcinogenesis. In some cases, th e distribution of DNA damage along the p53 gene caused by environmental car cinogens can be correlated with the mutational spectra, i.e. hotspots and t ypes of mutations of certain cancers, most notably for nonmelanoma skin can cers and lung cancers in smokers. This concept has been validated by experi ments with sunlight and cigarette smoke components representing the polycyc lic aromatic hydrocarbon class of carcinogens. A disproportionally high num ber of mutations in p53 (and other genes) are found at methylated CpG dinuc leotides. These sequences are particularly prone to mutagenesis involving e ndogenous events as well as modification by exogenous carcinogens. (C) 2000 Elsevier Science B.V. All rights reserved.