Genetic Profiling of Carbon Ion Radiation-Induced Thymic Lymphomas

Secondary cancer risk following carbon ion radiotherapy is a key consideration for its use in children over conventional photon radiotherapy. Understanding not only the relative carcinogenic risk of carbon ion therapy, but also the potentially different carcinogenic mechanisms is a primary goal of the Radiobiology for Children\u27s Health Program at the National Institute of Radiological Sciences, Japan.The research program has undertaken a large-scale study over the past 9 years, for which cohorts of irradiated B6C3F1 mice are followed throughout their natural life for tumour development. The study includes groups which vary in their age-at-exposure, as well as radiation source, quality, fractionation and total dose. From this study, a sub-cohort of mice was selected for detailed genetic analysis of radiation-induced thymic lymphomas. This included all mice irradiated with 4 or 4.8 Gy carbon ions (HIMAC: mono-energetic beam, 290 MeV/n, average LET 13 keV/micron) starting at one week of age (either in a single exposure, or four weekly fractions), which had been sacrificed in a moribund state with a cause of death at autopsy of thymic lymphoma (n = 102 mice). Gross genomic changes at common thymic lymphoma tumour suppressor loci including Pten, Bcl11b, Trp53 and Ikzf1 are being assessed by loss of heterozygosity (LOH) analysis using PCR of sites polymorphic for sequence length between the parental strains. High-resolution copy number variation analysis is being conducted on selected tumour samples using a customized comparative genome hybridization array to identify further sites of genomic loss/gain. Smaller genetic alterations are being further assessed by exon sequencing of Pten, Bcl11b, Trp53 and Ikzf1 to identify small insertions/deletions and point-mutations. The features observed in the carbon ion-irradiated sub-cohort are being compared to those in a reference population of tumours in mice irradiated with corresponding regimes of gamma-radiation.Mechanistic insight into carbon ion-induced carcinogenesis will be vital in assessing the long-term safety of carbon ion radiotherapy for children.The 59th Annual Meeting of the Radiation Research Societ