A Meta-Analysis of the Effects of High-LET Ionizing Radiations in Human Gene Expression

Abstract

The use of high linear energy transfer (LET) ionizing radiation (IR) is progressively being incorporated in radiation therapy due to its precise dose localization and high relative biological effectiveness. At the same time, these benefits of particle radiation become a high risk for astronauts in the case of inevitable cosmic radiation exposure. Nonetheless, DNA Damage Response (DDR) activated via complex DNA damage in healthy tissue, occurring from such types of radiation, may be instrumental in the induction of various chronic and late effects. An approach to elucidating the possible underlying mechanisms is studying alterations in gene expression. To this end, we identified differentially expressed genes (DEGs) in high Z and high energy (HZE) particle-, γ-ray- and X-ray-exposed healthy human tissues, utilizing microarray data available in public repositories. Differential gene expression analysis (DGEA) was conducted using the R programming language. Consequently, four separate meta-analyses were conducted, after DEG lists were grouped depending on radiation type, radiation dose and time of collection post-irradiation. To highlight the biological background of each meta-analysis group, functional enrichment analysis and biological network construction were conducted. For HZE particle exposure at 8–24 h post-irradiation, the most interesting finding is the variety of DNA repair mechanisms that were downregulated, a fact that is probably correlated with complex DNA damage formation. Simultaneously, after X-ray exposure during the same hours after irradiation, DNA repair mechanisms continue to take place. Finally, in a further comparison of low- and high-LET radiation effects, the most prominent result is that autophagy mechanisms seem to persist and that adaptive immune induction seems to be present. Such bioinformatics approaches may aid in obtaining an overview of the cellular response to high-LET particles. Understanding these response mechanisms can consequently aid in the development of countermeasures for future space missions and ameliorate heavy ion treatments.

Radiation Type- and Dose-Specific Transcriptional Responses across Healthy and Diseased Mammalian Tissues

“…In general, different types of radiation trigger distinct gene transcription programs associated with divergent cellular responses both in cancer and normal cells. Although radiation type-specific transcriptional changes have been examined sporadically [ 13 , 14 , 15 , 16 , 17 , 18 ], to our knowledge, there is no systematic effort to characterize the effects of several high-LET or low-LET radiation types and doses of radiation in normal or diseased tissues, which would set a basis to untangle their side effects from their beneficial cytotoxic and immunogenic properties. Simultaneous screening of the transcriptomes across irradiated cancer and normal tissues would require large-scale experiments for each radiation type and/or dose.…”

Radiation-Induced Fibrotic Tumor Microenvironment Regulates Anti-Tumor Immune Response

“…Several previous works have suggested that high and low LET irradiation produce distinct effects [32][33][34]. However, the specific molecular changes within the TME following high and low LET radiation therapy have remained unclear.…”

Cancer Studies under Space Conditions: Finding Answers Abroad

“…Numerous studies have shown that high-linear energy transfer (LET) radiation is more damaging than low-LET radiation because the latter produces more complex and hard-to-repair DNA damage [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 , 71 , 72 , 73 , 74 , 75 ]. While less complex DNA lesions can easily be repaired by our DNA damage repair mechanisms, this complex DNA damage bogs down these repair mechanisms and induces frequent errors and mis-repairs.…”

“…While the DNA damage repair mechanisms can repair the less complex DNA damage caused by low-LET radiation, these complex DNA lesions take more time to repair, bogging down the repair mechanisms while inducing frequent errors during the repair. This leads to increased apoptosis, or the cell goes through its cell cycle, chromosome aberrations, and cumulative DNA damage [ 63 , 64 , 66 , 67 , 69 , 70 , 71 , 72 , 73 , 76 ]. This accumulation of DNA damage, in turn, causes higher incidences and grades of cancer, mainly if these DNA lesions occur in critical genes, such as tumour-suppressor genes or oncogenes [ 70 ].…”