Journal Article The effect of age at exposure on the inactivating mechanisms and relative contributions of key tumor suppressor genes in radiation-induced mouse T-cell lymphomas

砂押, 正章  ,  甘崎, 佳子  ,  坂入, しのぶ  ,  Benjamin, Blyth  ,  森岡, 孝満  ,  上西, 睦美  ,  尚, 奕  ,  西村, まゆみ  ,  島田, 義也  ,  立花, 章  ,  柿沼, 志津子

Children are considered more sensitive to radiation-induced cancer than adults, yet any differences ingenomic alterations associated with age-at-exposure and their underlying mechanisms remain unclear.We assessed genome-wide DNA copy number and mutation of key tumor suppressor genes in T-celllymphomas arising after weekly irradiation of female B6C3F1 mice with 1.2 Gy X-rays for 4 consecutiveweeks starting during infancy (1 week old), adolescence (4 weeks old) or as young adults (8 weeks old).Although T-cell lymphoma incidence was similar, loss of heterozygosity at Cdkn2a on chromosome 4 andat Ikaros on chromosome 11 was more frequent in the two older groups, while loss at the Pten locus onchromosome 19 was more frequent in the infant-irradiated group. Cdkn2a and Ikaros mutation/loss wasa common feature of the young adult-irradiation group, with Ikaros frequently (50%) incurring multipleindependent hits (including deletions and mutations) or suffering a single hit predicted to result in adominant negative protein (such as those lacking exon 4, an isoform we have designated Ik12, whichlacks two DNA binding zinc-finger domains). Conversely, Pten mutations were more frequent after earlyirradiation (60%) than after young adult-irradiation (30%). Homozygous Pten mutations occurred withoutDNA copy number change after irradiation starting in infancy, suggesting duplication of the mutatedallele by chromosome mis-segregation or mitotic recombination. Our findings demonstrate that whiledeletions on chromosomes 4 and 11 affecting Cdkn2a and Ikaros are a prominent feature of young adultirradiation-induced T-cell lymphoma, tumors arising after irradiation from infancy suffer a second hit inPten by mis-segregation or recombination. This is the first report showing an influence of age-at-exposureon genomic alterations of tumor suppressor genes and their relative involvement in radiation-inducedT-cell lymphoma. These data are important for considering the risks associated with childhood exposureto radiation.

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