Cellular oncogenes and tumor suppressor genes are two of the critical DNA targets for chemical carcinogens, leading to activation of oncogenes and the inactivation of suppressor genes. This will be discussed further in Chapter 5, but a few examples will be given here.
Carcinogens can activate cellular oncogenes (proto-oncogenes) by a variety of mechanisms including base substitution (point) mutations, chromosomal translocations, and gene amplification. One fairly common example is the activation of ras proto-oncogenes by chemical and physical carcinogens in both cultured mammalian cells and animal models (reviewed in Ref. 24). H-ras and K-ras proto-oncogene mutations, for example, have been observed in rodent models of skin, liver, lung, and mammary carcinogenesis. The observed mutations in the tumors correlate with expected base adducts formed by the carcinogen: G?A base transitions with alkylating agents (e.g., NMU and MNNG), G?T transversions for benzo(a)pyrene, A?T transversions for 7,12 dimethylbenzanthracene, G?T transversions and G?A transitions for aflatoxin B1.24 These mutations appear to reflect similar base substitution mutations in human tumors.
The best documented example of a tumor suppressor gene being inactivated during car-cinogenesis is the p53 gene. Mutations of the p53 gene have been observed in animal tumors and in a wide variety of human cancers. Most of the mutations are point mutations involving ''hot spots" in exons 5 through 8. Interestingly, these are the most highly conserved domains of these exons. In human colon tumors, the majority of the mutations are G?A transitions (just as for ras); however, other types of base alterations of p53 are seen in other human cancers.
Perhaps the most interesting observation is the finding of a high incidence of p53 point mutations in hepatocellular carcinomas in patients from parts of China and southern Africa where exposure to aflatoxin B1 is endemic.25,26 Most of these are at a single site, the third base of codon 249, and are G?T transversions. Moreover, hepatocellular carcinomas from low-aflatoxin exposure areas appear to only rarely have this mutation.
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