title: 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.
abstract: Monitoring mice exposed to carbon ion radiotherapy provides an indirect method to evaluate the potential for second cancer induction in normal tissues outside the radiotherapy target volume, since such estimates are not yet possible from historical patient data. Here, male and female B6C3F1 mice were given single or fractionated whole-body exposure(s) to a monoenergetic carbon ion radiotherapy beam at the Heavy Ion Medical Accelerator in Chiba, Japan, matching the radiation quality delivered to the normal tissue ahead of the tumour volume (average linear energy transfer = 13 keV x μm(-1)) during patient radiotherapy protocols. The mice were monitored for the remainder of their lifespan, and a large number of T cell lymphomas that arose in these mice were analysed alongside those arising following an equivalent dose of 137Cs gamma ray-irradiation. Using genome-wide DNA copy number analysis to identify genomic loci involved in radiation-induced lymphomagenesis and subsequent detailed analysis of Notch1, Ikzf1, Pten, Trp53 and Bcl11b genes, we compared the genetic profile of the carbon ion- and gamma ray-induced tumours. The canonical set of genes previously associated with radiation-induced T cell lymphoma was identified in both radiation groups. While the pattern of disruption of the various pathways was somewhat different between the radiation types, most notably Pten mutation frequency and loss of heterozygosity flanking Bcl11b, the most striking finding was the observation of large interstitial deletions at various sites across the genome in carbon ion-induced tumours, which were only seen infrequently in the gamma ray-induced tumours analysed. If such large interstitial chromosomal deletions are a characteristic lesion of carbon ion irradiation, even when using the low linear energy transfer radiation to which normal tissues are exposed in radiotherapy patients, understanding the dose-response and tissue specificity of such DNA damage could prove key to assessing second cancer risk in carbon ion radiotherapy patients.
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blyth
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Shizuko
authors.initials: S
authors.lastname: Kakinuma
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Masaaki
authors.initials: M
authors.lastname: Sunaoshi
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Amasaki
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Shinobu
authors.initials: S
authors.lastname: Hirano-Sakairi
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Kanae
authors.initials: K
authors.lastname: Ogawa
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Ayana
authors.initials: A
authors.lastname: Shirakami
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yi
authors.initials: Y
authors.lastname: Shang
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Chizuru
authors.initials: C
authors.lastname: Tsuruoka
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Mayumi
authors.initials: M
authors.lastname: Nishimura
authors.affiliation: Radiobiology for Children's Health Program, Research Center for Radiation Protection, National Institute of Radiological Sciences, Chiba, Japan.
authors.forename: Yoshiya
authors.initials: Y
authors.lastname: Shimada
mesh_terms: D000818:Animals; D002872:Chromosome Deletion; D004249:DNA Damage / Q000235:genetics / Q000528:radiation effects; D004307:Dose-Response Relationship, Radiation; D005260:Female; D005720:Gamma Rays / Q000009:adverse effects; D005820:Genetic Testing / Q000379:methods; D063193:Heavy Ion Radiotherapy / Q000009:adverse effects*; D020450:Heavy Ions / Q000009:adverse effects; D007564:Japan; D016399:Lymphoma, T-Cell / Q000235:genetics* / Q000532:radiotherapy*; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D009381:Neoplasms, Radiation-Induced / Q000235:genetics*; D016609:Neoplasms, Second Primary / Q000235:genetics*