Abnormal chromosome repair and risk of developing cancer.
- 1 October 1993
- journal article
- review article
- Published by Environmental Health Perspectives in Environmental Health Perspectives
- Vol. 101 (suppl 3), 303-308
- https://doi.org/10.1289/ehp.93101s3303
Abstract
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 C and nickel, which do not cause chromosome damage by themselves.(ABSTRACT TRUNCATED AT 250 WORDS)Keywords
This publication has 36 references indexed in Scilit:
- p53 Mutations in Human CancersScience, 1991
- Heterogeneity of DNA repair at the gene levelMutation Research, 1991
- Tumor Suppressor Genes: New Prospects for Cancer ResearchJNCI Journal of the National Cancer Institute, 1991
- Mechanism of clastogenic and co-clastogenic activity of cremophore with benzene hi miceCarcinogenesis: Integrative Cancer Research, 1991
- A genetic model for colorectal tumorigenesisCell, 1990
- Non‐genotoxic environmental carcinogensEnvironmental Carcinogenesis Reviews, 1990
- Effect of dimethyl sulfoxide on the genotoxicity and metabolism of benzene in vivoCarcinogenesis: Integrative Cancer Research, 1989
- Structural Evidence for the Authenticity of the Human Retinoblastoma GeneScience, 1987
- Breast and Other Cancers in Families with Ataxia-TelangiectasiaNew England Journal of Medicine, 1987
- Mutation and Cancer: Statistical Study of RetinoblastomaProceedings of the National Academy of Sciences, 1971