ABNORMAL CHROMOSOME REPAIR AND RISK OF DEVELOPING CANCER

Several scientists have proposed that DNA repair deficiencies and the induction of a mutator phenotype are responsible for the generation of Multiple mutagenic alterations in cancer cells. I propose that exposure to environmental carcinogens can induce DNA lesions, elicit infidelity of DNA repair, and cause the instability phenomenon and the subsequent consequences. Using cell lines derived from mammary glands of irradiated mice, my laboratory conducted sequential studies to document genetic events leading to the development of malignant cells in vitro. We found that aneuploidy and extensive chromosome breaks and rearrangements occurred early. This is followed by inactivation of the retinoblastoma tumor-suppressor gene, amplification of the myc oncogene, and expression of the tumorigenic phenotype. Our observation of chromosome instability at the early phase of transformation is consistent with the mutator phenotype. We suggest that a cause of the instability is infidelity of DNA repair, and we have developed a challenge assay to elucidate this phenomenon. In this assay, cells are challenged to repair radiation-induced DNA lesions. In one of our studies, lymphocytes from cigarette smokers and nonsmokers were exposed to gamma rays in vitro. Cells from smokers had significantly more rearranged chromosomes than cells from nonsmokers after the challenge. These data suggest that smokers have infidelity of DNA repair and that this repair problem is a cause of health effects in smokers. In an in vitro study, lymphocytes were exposed to mitomycin C or to nickel acetate and then irradiated with gamma rays. Significantly increased frequencies of rearranged chromosomes were detected with low doses of mitomycin and nickel, which do not cause chromosome damage by themselves. Lymphocytes from patients with epidermodysplasia verruciformis were found to have infidelity of DNA repair after exposure to UV-light in our challenge assay. This sensitivity is consistent with the predisposition to skin cancer after exposure to sunlight. Our studies suggest that infidelity of chromosome/DNA repair can generate an unstable genome, which allows genetic alterations relevant to the development of cancer to evolve. Furthermore, infidelity of chromosome/DNA repair allows the generation of multiple genetic alterations in the multistep carcinogenic process.