@misc{oai:repo.qst.go.jp:00070786,
 author = {Sunaoshi, Masaaki and Amasaki, Yoshiko and Hirano, Shinobu and Takabatake, Takashi and Morioka, Takamitsu and Nishimura, Mayumi and Shimada, Yoshiya and Tachibana, Akira and Kakinuma, Shizuko and 砂押 正章 and 甘崎 佳子 and 坂入 しのぶ and 高畠 貴志 and 森岡 孝満 and 西村 まゆみ and 島田 義也 and 立花 章 and 柿沼 志津子},
 month = {Apr},
 note = {Background: Radiation carcinogenesis is greatly dependent on the age-at-exposure. Previous studies on the survivors of A-bombing and Chernobyl accident have indicated that there is an age difference in incidence and causal gene involved in both leukemia and thyroid cancer. The data on underlying mechanism of age dependency, however, is still limited. In this study, mouse T-cell lymphoma (TL) model was used for investigating the different effect of ionizing radiation to infant age and young adult age-at-exposure. We aimed to clarify the age dependent change of the affected molecular pathways of radiation-induced mouse T-cell lymphomagenesis.
Materials and Methods: We analyzed the three groups of TLs developed after irradiation to female B6C3F1 mice weekly to 1.2 Gy X-ray for 4 consecutive weeks starting at infant (1 week of age), prepubertal (4 weeks of age) and adult (8 weeks of age). Loss of heterozygosity (LOH) analyses on chromosome 11, 12 and 19 were performed by PCR using genomic DNA of TLs. Mutations of the Ikaros and Pten were analyzed by sequencing of cDNA and genomic DNA, Western blotting, and array CGH.
Results and Discussion: The frequency of LOH on chromosome 11 in 1W-TLs (27%; 4/15) was lower than those in 4W (46%; 6/13) and 8W-TLs (63%; 5/8). In contrast, the frequency of LOH on chromosome 19 in 1W-TLs (60%; 9/15) was higher than those in 4W-TLs (31%; 4/13) and 8W-TLs (13%; 1/8). Thus, LOH frequency was altered dependent on the age-at-exposure. Array CGH analysis revealed that intragenic deletion within Ikaros locus, which is mapped on chromosome 11, was characteristic in 1W-TLs, which produced aberrant Ikaros isoform, a lack of exon 5. On the other hand, different size deletions were found in each allele in 8W-TLs; one is intragenic deletion and the other is wide deletion including whole Ikaros locus. This type deletion caused null expression of Ikaros. In 4W-TLs, either type of deletion was found. Thus, deletion type in Ikaros region was different depend on the age-at-exposure. Array-CGH analysis revealed that the genomic copy number of the defined region of chromosome 19 in 1W-TLs was unchanged despite LOH, suggesting the LOH was caused by mitotic recombination. Therefore, it is considered that one allele deletion or intragenic mutation was formed at first and then the mitotic recombination occurred, resulting in homozygous deletion or homozygous intragenic mutations in 1W-TLs. Mutation frequency of Pten was higher than that in 4W- and 8W-TLs.
Conclusion: Ikaros mutation was more involved in older age-at-exposure for T-cell lymphomagenesis, while Pten mutation was more involved in younger age-at-exposure. These results suggest that a target gene of radiation-induced T-cell lymphomagenesis and molecular mechanism of mutation change as a function of age-at-exposure., Childhood Cancer 2012 -International scientific conference on early exposure and childhood cancer-},
 title = {Age dependency of Ikaros and Pten alterations in radiation-induced T-cell lymphoma},
 year = {2012}
}