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

Departments of ¹ Radiobiology/Molecular Epidemiology, ² Clinical Studies, and ³ Statistics, Radiation Effects Research Foundation, Hiroshima, Japan

Requests for reprints: Yoichiro Kusunoki, Department of Radiobiology/Molecular Epidemiology, Radiation Effects Research Foundation, 5-2 Hijiyama Park, Minami-ku, 732-0815 Hiroshima, Japan. Phone: 81-82-261-3131; Fax: 81-82-261-3170; E-mail: ykusunok{at}rerf.or.jp.

It has previously been reported that hemizygous mutant fraction (Mf) at the glycophorin A (GPA) locus in erythrocytes increased with radiation dose in heterozygotes among Hiroshima and Nagasaki atomic bomb survivors. In the present study, we analyzed the relationship between GPA Mf and cancer risk using newly developed cancers among previously cancer-free subjects whose GPA Mf had been measured between 1988 and 1996. Among 1,723 survivors (1,117 in Hiroshima and 606 in Nagasaki), we identified 186 subjects who developed a first cancer by the end of 2000. We compared the radiation dose responses of GPA Mf between cancer and cancer-free groups using a linear-quadratic model fit by multiple regression analysis in combination with age, sex, and city. The slope of the GPA Mf dose-response curve was significantly higher in the cancer group than in the cancer-free group among Hiroshima subjects. Moreover, no significant difference of GPA Mf between cancer and cancer-free groups was found in unexposed controls in the two cities. The same conclusions were obtained using a linear dose-response model and by further analysis using Cox regression of cancer incidence. These findings suggest that there might be interindividual variation in mutability of somatic genes and that Hiroshima survivors who have higher mutability in response to radiation exposure would be expected to have a higher probability of suffering radiation-related cancer.