Distinct vascular genomic response of proton and gamma radiation—A pilot investigation

Abstract

The cardiovascular biology of proton radiotherapy is not well understood. We aimed to compare the genomic dose-response to proton and gamma radiation of the mouse aorta to assess whether their vascular effects may diverge. We performed comparative RNA sequencing of the aorta following (4 hrs) total-body proton and gamma irradiation (0.5–200 cGy whole body dose, 10 dose levels) of conscious mice. A trend analysis identified genes that showed a dose response. While fewer genes were dose-responsive to proton than gamma radiation (29 vs. 194 genes; q-value ≤ 0.1), the magnitude of the effect was greater. Highly responsive genes were enriched for radiation response pathways (DNA damage, apoptosis, cellular stress and inflammation; p-value ≤ 0.01). Gamma, but not proton radiation induced additionally genes in vasculature specific pathways. Genes responsive to both radiation types showed almost perfectly superimposable dose-response relationships. Despite the activation of canonical radiation response pathways by both radiation types, we detected marked differences in the genomic response of the murine aorta. Models of cardiovascular risk based on photon radiation may not accurately predict the risk associated with proton radiation.

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“…It is, therefore, recommendable to incorporate new consensual contour atlases into routine clinical practice, for which self-segmentation computer tools may be of help, to ensure the homogeneity of the dosimetric data compiled [ 121 ]. Clinical trials are also required to identify differences in radiobiological responses of cardiovascular tissues to different particles (photons versus protons/others) and their possible clinical impact [ 122 ].…”

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“…Amongst others, this includes the development of proton minibeam therapy [28,29] and proton FLASH irradiation [50,57,218,219]. Further studies on normal tissue toxicities have focused on processes, such as the peripheral inflammatory response [220], radiation-induced thoracic injuries [19,221], radiation-induced abdominal injury [207,222], as well as tumor incidence after irradiation of a healthy brain [223] and dorsal skin [224].…”

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“…Moreover, when analyzing gene expression, the authors found differences in the magnitude and kinetics of DNA repair genes. Another study investigated gene expression profiles by RNA sequencing of proton- and γ whole-body irradiated mice [ 87 ]. Here, the investigators showed that γ-radiation responsive genes only partly overlapped with proton-responsive genes.…”