2001 Fiscal Year Final Research Report Summary
Epidemiological and molecular biological study of myelodysplastic syndrome (MDS) among atomic bomb survivors
| Project/Area Number |
11480141
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
環境影響評価(含放射線生物学)
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
KIMURA Akiro Hiroshima University, Research Institute for Radiation Biology and Medicine, Professor, 原爆放射能医学研究所, 教授 (70127645)
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| Co-Investigator(Kenkyū-buntansha) |
TANAKA Hideo Hiroshima University, Research Institute for Radiation Biology and Medicine, Associate Professor, 原爆放射能医学研究所, 助教授 (50243613)
HAYAKAWA Norihiko Hiroshima University, Research Institute for Radiation Biology and Medicine, Professor, 原爆放射能医学研究所, 教授 (40022834)
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| Project Period (FY) |
1999 – 2001
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| Keywords | MDS / Atomic bomb / Radiation / AML 1 / DNA repair / 放射線 / 被爆 |
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| Research Abstract |
To study the effect of radiation exposure on MDS development among Hiroshima A bomb survivors, patients with definite individual radiation dose were examined between 1985 and 1999. The dose was estimated according to ABS 93 dosimetry system. Among 735 patients without malignancy, 26 patients aged from 48 to 88 (median : 75) had diagnosis of MDS, including 16 RA, 2 RARS, 4 RAEB and 4 RAEBt. We analyzed the relative risk in relation to exposed radiation dose using a multiple regression with Cox proportional hazard model. Highly significant dose-effect on the risk of MDS was found. The relative risk was 2.53 (95 % CI : 1.49-4.30) at the dose of 100 cSv against 0 cSv (P = 0.0006). Age at the time of bombing showed significant effects on the risk (P = 0.0000). This is the first time that the incidence of hematological disease other than leukemia was found to be radiation dose dependent.
In order to clarify the molecular mechanism of A bomb radiation-induced MDS/AML, we studied the mutations of AML 1 which plays important roles in the definitive hematopoiesis by forming the transcription factor complex with CBF β. We have analyzed the DNA-binding domain (the runt domain) of AML 1 gene for mutations by PCR-SSCP assay using genomic DNA from bone marrow samples followed by sequence analysis. AML 1 mutations were identified in 46 % (6/13) of A bomb radiation-exposed MDS patients. Two cases had silent mutations (P157syn and T101syn), 3 cases had missense mutations (G42R, D171N and G42R), and one case had a frame shift/nonsense mutation (L70del 1bp to stop). In addition, missense mutations were found in 2/3 radiotherapy-related MDS/AML patients. On the other hand, AML 1 mutations were found in only 2.9 % (2/70) of sporadic MDS cases. The high incidence of AML 1 gene mutations in radiation-associated MDS/AML suggested that dysregulation of AML 1 function plays pivotal roles in this category of hematopoietic disorders.
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