Somatic Cell Mutations at the Glycophorin A Locus in Erythrocytes of Atomic Bomb Survivors: Implications for Radiation Carcinogenesis

Abstract

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.

Lessons learned from the study of immigrants to Israel from areas of Russia, Belarus, and Ukraine contaminated by the Chernobyl accident.

“…Increases in the frequency of variants have been found after exposure to mutagenic drugs as well as in cancer-susceptible patients with ataxia telangectasia (32,33) and Bloom's syndrome (34). The GPA somatic mutation assay therefore has been suggested to be useful for assessing cancer risk (30,35).…”

“…The GPA assay has been used to show elevated levels of red cell variants due to somatic mutation in human groups exposed to radiation such as those from Hiroshima and Nagasaki (28)(29)(30) and victims of the Goiania radiation exposure accident (31). Increases in the frequency of variants have been found after exposure to mutagenic drugs as well as in cancer-susceptible patients with ataxia telangectasia (32,33) and Bloom's syndrome (34).…”

Somatic Mutations at the Glycophorin A (GPA) Locus Measured in Red Cells of Chernobyl Liquidators Who Immigrated to Israel

“…Increases in the frequency of variants have been found after exposure to mutagenic drugs (23) as well as in cancer-susceptible patients with ataxia telangiectasia (24) and Bloom's syndrome (25,26). It has been suggested, therefore, that the GPA somatic mutation assay has value for the assessment of cancer risk (20,27 Kyoizumi et al (20) reported a slightly greater frequency of GPA N0 cells in males than in females (by -10%) in unexposed survivors in Hiroshima and Nagasaki, but no effect of sex on dose response was observed. Although control groups contained a lower proportion of males, compared to the liquidator group, the marked difference reported between liquidators and controls is not explainable on the basis of the natural male-to-female difference in N0 frequency.…”

“…The GPA assay was used to show elevated levels of red cell variants due to somatic mutation in human groups exposed to radiation such as that from Hiroshima and Nagasaki (2,3,(19)(20)(21)(22) and from the Goiania radiation exposure accident (4). Increases in the frequency of variants have been found after exposure to mutagenic drugs (23) as well as in cancer-susceptible patients with ataxia telangiectasia (24) and Bloom's syndrome (25,26).…”

Individual Variation of Somatic Gene Mutability in Relation to Cancer Susceptibility: Prospective Study on Erythrocyte Glycophorin A Gene Mutations of Atomic Bomb Survivors

“…Because the atomic bomb (A-bomb) survivor population is an epidemiologically well-controlled cohort in terms of dose estimation (14) and cancer follow-up (15), such an analysis is feasible in this population. We previously measured hemizygous GPA Mf in f1,200 heterozygous A-bomb survivors in Hiroshima and Nagasaki between 1988 and 1993 and analyzed the dose response of GPA Mf and the relationship between GPA Mf and cancer risk (16). It was found that the doubling dose of GPA Mf was similar to that of solid-cancer incidence in A-bomb survivors.…”