2004 Fiscal Year Final Research Report Summary
Genetic alterations in radiation-induced colorectal cancers and susceptibility to irradiation
| Project/Area Number |
13470263
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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 |
Digestive surgery
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| Research Institution | Japanese Foundation for Cancer Research |
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Principal Investigator |
ARAI Masami The Cancer Institute of Japanese Foundation for Cancer Research, Associate, 癌研究所, 研究員 (20232027)
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| Co-Investigator(Kenkyū-buntansha) |
MIKI Yoshio Tokyo Medical and Dental University, Medical Research Institute, Department of Molecular Genetics, Professor, 難治疾患研究所, 教授 (10281594)
KATO You The Cancer Institute of Japanese Foundation for Cancer Research, Department of Pathology, Chief, 癌研究所・病理部, 部長 (20010473)
YANAGISAWA Akio Graduate school of Kyoto Prefectural University of Medicine, Department of Pathology, Professor, 大学院・医学系研究科, 教授 (30137963)
UTSUNOMIYA Jyoji The Cancer Institute of Japanese Foundation for Cancer Research, Associate, 癌研究所, 研究員 (70013901)
MUTO Tetsuichiro The Cancer Institute of Japanese Foundation for Cancer Research, Chief, 癌研究所, 部長 (20110695)
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| Project Period (FY) |
2001 – 2004
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| Keywords | Radiation induced colorectal cancer / microsatellite instability / radiosensitivity / SNP |
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| Research Abstract |
1.Mlh1-/- mice irradiated with 2 Gy at 10 weeks old had a significantly increased number of gastrointestinal tumors (GITs). The effect of irradiation at 2 weeks of age was less than that at 10 weeks. Irradiation did not promote tumorigenesis in Mlh1+/- mice. GITs developing after irradiation showed a high frequency of overexpression of P53 protein on immunohistochemical analysis. This characteristic is commonly found in human radiation-induced colorectal cancers.
2.SNP typing was performed to identify genetic factors responsible for the severe side effects of radiation therapy. Fifty patients who had previously received radiation therapy for their primary tumors (mainly uterine cervical cancers) were studied. The occurrence of severe side effects such as radiation colitis was retrospectively examined. Nineteen patients had severe side effects and 31 did not. Genotypes of 2,988 SNPs covering 490 genes of each patient were determined by invader assay. Genotype frequencies were compared be
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tween the two groups. Nineteen SNPs were found to correlate with adverse effects of irradiation (p<0.01). To elucidate specific haplotypes harboring genetic polymorphisms associated with adverse effects, the haplotype block structures of 19 genes were determined, and association analyses using the haplotype information were performed. These analyses showed a strong correlation between adverse effects and a haplotype in a gene related to interleukin receptor (p<0.00001). The identified haplotype appeared to protect against adverse effects of irradiation. Because the involved gene is related to the response to interleukin, our results suggested that the presence and absence of the identified haplotype is related to different responses to interleukin and individual differences in susceptibility to severe adverse effects of radiation therapy.
(Finding 1 is based on the results of a collaborative study with Yoshiya Shimada, Ph.D., Low dose radiation research project, National Institute of Radiological Science.) Less
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