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.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.
Highlights
One of the rationales for the use of heavy ion radiotherapy in cancer treatment is the ability to minimise the adverse effects in normal tissue by minimizing the radiation dose received outside the target volume [1, 2]
The accelerated heavy particles in carbon ion radiotherapy are ranged to stop within the target volume delivering their energy with high linear energy transfer (LET)–which underlies the increased tumour control per unit dose–the same particles first pass through normal tissues ahead of the target
It is exposure of normal tissue to the lower LET component of the carbon ion radiation LET-depth curve which poses the risk for induction of second cancers following high LET carbon radiotherapy [6]
Summary
One of the rationales for the use of heavy ion radiotherapy in cancer treatment is the ability to minimise the adverse effects in normal tissue by minimizing the radiation dose received outside the target volume [1, 2]. The accelerated heavy particles in carbon ion radiotherapy are ranged to stop within the target volume delivering their energy with high linear energy transfer (LET)–which underlies the increased tumour control per unit dose–the same particles first pass through normal (non-target) tissues ahead of the target (reviewed in [5]). During their transit through the normal tissue the particles’ greater initial energy results in fewer interactions per unit distance, and they have a lower LET than when depositing energy within the target volume. It is exposure of normal tissue to the lower LET component of the carbon ion radiation LET-depth curve which poses the risk for induction of second cancers following high LET carbon radiotherapy [6]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
