Molecular Life Sciences (2014)
Mutation and cancer
One of the reasons why the study of DNA damage is of high interest is in relation to cancer. Many of the accepted human carcinogens are believed to use mutagenesis as a mode of action.
Although it is not possible to establish exactly what fraction of human cancer is due to DNA damage and somatic mutation, there are several major reasons to believe that DNA damage is a cause of human cancer. The reasons are not necessarily given in order.
Individuals with established deficiencies in DNA repair are very prone to cancer. Some examples include xeroderma pigmentosum, Cockayne’s syndrome, and trichothiodystrophy.
There is strong evidence that UV light damage causes skin cancer in humans. This is generally accepted to be the result of various DNA lesions produced by cyclization and other reactions. Further, the deficiencies in DNA repair (see above) are linked with this damage.
Animal studies on chemical carcinogens show strong associations between the extent of DNA adduct formation and the incidence of tumors (Bechtel 1989).
Some of the classic epidemiological studies of chemicals causing human cancer are best under- stood in the context of DNA adducts that are known to be formed from these agents. Examples include arylamines (Rehn 1895), afiatoxin B1 (Busby and Wogan 1984), and vinyl chloride (Creech and Johnson 1974). Strongly suggestive associations can also be made for tobacco-induced causes (Hecht 2008).
The ability of DNA adducts to cause mutations can be demonstrated experimentally. It is possible to prepare oligonucleotides with many defined DNA lesions (see “fi Synthesis of Modified Oligo- nucleotides”). Replication can be done with DNA polymerases, and the patterns of misincorporation can be established by several methods. An even more powerful approach induces site-specific mutagenesis, in which the modified oligonucleotide is added to a cell and errors in replication can be detected.
Collectively, these arguments provide strong evidence that this DNA damage is an issue in human cancer. This somatic mutation theory of cancer was proposed by Bauer in 1928 (Bauer 1928).
The assignment of chemicals to a list of human carcinogens is not a trivial process, and these lists can be provocative, due to economic considerations or medical needs for a drug. The list of “Known Human Carcinogens” for the US National Toxicology Program includes (in alphabetical order): afiatoxins, alcoholic beverage consumption, 4-aminobiphenyl, analgesic mixtures containing phen- acetin, inorganic arsenic compounds, asbestos, azathioprine, benzene, benzidine, beryllium and beryllium compounds, 1,3-butadiene, 1,4-butanediol dimethanesulfonate (Myleran®), cadmium and cadmium compounds, chlorambucil, 1-(2-chloroethyl)-3-(4-methylcyclohexyl)-1-nitrosourea (MeCCNU), bis(chloromethyl) ether and technical-grade chloromethyl methyl ether, chromium hexavalent compounds, coal tar pitches, coal tars, coke oven emissions, cyclophosphamide, cyclosporin A, diethylstilbestrol, dyes metabolized to benzidine, environmental (second-hand) tobacco smoke, erionite, estrogens (steroidal), ethylene oxide, hepatitis B virus, hepatitis C virus, human papilloma viruses (some genital-mucosal types), melphalan, methoxsalen with ultraviolet A therapy (PUVA), mineral oils (untreated and mildly treated), mustard gas, 2-naphthylamine, neutrons (ionizing radiation), nickel compounds, radon, crystalline silica (respirable size), smoke- less tobacco, solar radiation, soots, strong inorganic acid mists containing sulfuric acid, exposure to sunlamps or sunbeds, tamoxifen, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD, “dioxin”), thiotepa, thorium dioxide, tobacco smoking, vinyl chloride, ultraviolet radiation (broad spectrum UV radia- tion), wood dust, and X-radiation and gamma-radiation.
Usually the assignment is based on either strong epidemiological evidence (in humans) or extensive experience with multiple experimental models.
In another classification system (e.g., International Agency for Research on Cancer), there are five categories: group 1 “Carcinogenic to humans” (107 compounds), group 2A “Probably carcinogenic to humans” (58 compounds), group 2B “Possibly carcinogenic to humans” (249 compounds), group 3 “Not classifiable as to its carcinogenicity to humans” (512 compounds), and group 4 “Probably not carcinogenic to humans” (1 compound).
Bauer KH (1928) Mutationstheorie der Geschwulstenstehung. Springer, Berlin
Bechtel DH (1989) Molecular dosimetry of hepatic afiatoxin B1-DNA adducts: linear correlation with hepatic cancer risk. Regul Toxicol Pharmacol 10:74–81
Busby WF, Wogan GN (1984) Afiatoxins. In: Searle CE (ed) Chemical carcinogens, vol 2, 2nd edn. American Chemical Society, Washington, DC, pp 945–1136
Creech JL Jr, Johnson MN (1974) Angiosarcoma of liver in the manufacture of polyvinyl chloride. J Occup Med 16:150–151
Hecht SS (2008) Progress and challenges in selected areas of tobacco carcinogenesis. Chem Res Toxicol 21:160–171
Rehn L (1895) UЂ ber Blasentumoren bei Fuchsinarbeitern. Archiv Clin Chirgurie 50:588–600