Journal Article Genetic Analysis of T Cell Lymphomas in Carbon Ion-Irradiated Mice Reveals Frequent Interstitial Chromosome Deletions: Implications for Second Cancer Induction in Normal Tissues During Carbon Ion Radiotherapy

Benjamin, Blyth  ,  柿沼, 志津子  ,  砂押, 正章  ,  甘崎, 佳子  ,  坂入, しのぶ  ,  小川, 佳那依  ,  白神, 綾奈  ,  尚, 奕  ,  鶴岡, 千鶴  ,  西村, まゆみ  ,  島田, 義也

10 ( 6 )  , pp.e0130666-1 - e0130666-24 , 2015-06 , Public Library of Science
Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction innormal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, maleand female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam atthe Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumourvolume (average linear energy transfer = 13 keV.μm-1) during patient radiotherapy protocols. The mice were monitored for the remainderof their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following anequivalent dose of 137Cs gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved inradiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared thegenetic profile of the carbon ion- and gamma ray-induced tumours. The canonical set of genes previously associated with radiationinducedT cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhatdifferent between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most strikingfinding was the observation of large interstitial deletions at various sites across the genome in carbon ion-induced tumours, which wereonly seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristiclesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed inradiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing secondcancer risk in carbon ion radiotherapy patients.

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