The TCR/CD3 complex plays a central role in antigen recognition and activation of mature T cells, and, therefore, abnormalities in the expression of the complex should induce unresponsiveness of T cells to antigen stimulus. Using flow cytometry, we detected and enumerated variant cells with loss or alteration of the surface TCR/CD3 expression among human mature CD4+ T cells. The presence of variant CD4+ T cells was demonstrated by isolating and cloning them from peripheral blood, and their abnormalities can be accounted for by alterations in TCR expression such as defects of protein expression and partial protein deletion. The variant frequency in peripheral blood increased with aging in normal donors and was highly elevated in patients with ataxia telangiectasia, an autosomal recessive inherited disease with defective DNA repair and variable T cell immunodeficiency. These findings suggest that such alterations in TCR expression are induced by somatic mutagenesis of TCR genes and can be important factors related to age-dependent and genetic disease-associated T cell dysfunction.
To clarify the relationship between somatic cell mutations and radiation exposure, the frequency of hemizygous mutant erythrocytes at the glycophorin A (GPA) locus was measured by flow cytometry for 1,226 heterozygous atomic bomb (A-bomb) survivors in Hiroshima and Nagasaki. For statistical analysis, both GPA mutant frequency and radiation dose were log-transformed to normalize skewed distributions of these variables. The GPA mutant frequency increased slightly but significantly with age at testing and with the number of cigarettes smoked. Also, mutant frequency was significantly higher in males than in females even with adjustment for smoking and was higher in Hiroshima than in Nagasaki. These characteristics of background GPA mutant frequency are qualitatively similar to those of background solid cancer incidence or mortality obtained from previous epidemiological studies of survivors. An analysis of the mutant frequency dose response using a descriptive model showed that the doubling dose is about 1.20 Sv [95% confidence interval (CI): 0.95-1.56], whereas the minimum dose for detecting a significant increase in mutant frequency is about 0.24 Sv (95% CI: 0.041-0.51). No significant effects of sex, city or age at the time of exposure on the dose response were detected. Interestingly, the doubling dose of the GPA mutant frequency was similar to that of solid cancer incidence in A-bomb survivors. This observation is in line with the hypothesis that radiation-induced somatic cell mutations are the major cause of excess cancer risk after radiation exposure. Furthermore, the dose response was significantly higher in persons previously or subsequently diagnosed with cancer than in cancer-free individuals. This may suggest an earlier onset of cancer due to elevated mutant frequency or a higher radiation sensitivity in the cancer group, although the possibility of dosimetry errors should be considered. The findings obtained in the present study suggest that the GPA mutant frequency may reflect the cancer risk among people exposed to radiation.
The somatic-mutation theory of carcinogenesis has received strong scientific support from results of recent studies on tumor-suppressor genes. We anticipated that people among the high risk for cancer group, either through exposure to various ionizing radiations or by virtue of unique genotypes, would also manifest increased frequencies of somatic mutation. This report presents the results of two somatic-mutation assays--at the erythrocyte glycophorin A (GPA) and lymphocyte T-cell receptor (TCR) genes--in various groups at high risk for cancer development, including atomic-bomb survivors, patients with various cancers, patients administered Thorotrast, and patients with genetic disorders that make them cancer prone. Although neither the GPA-mutation nor the TCR-mutation assay detects gene mutations directly related to carcinogenesis, increased mutation frequencies were detected by both assays in many individuals among the high-risk groups and among cancer patients. We have continued to follow up those individuals who show values of about three times higher than those of the control group. Thus, these assays may prove useful for identifying high-risk cancer groups and for estimating the effects of mutagens. Such information would constitute a valuable data base for epidemiological studies.
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