Abstract
Sensitivity of T4 effector-memory (T4EM) lymphocytes to radiation-induced apoptosis shows heritability compatible with a Mendelian mode of transmission. Using gene expression studies and flow cytometry, we show a higher TNF-Related Apoptosis Inducing Ligand (TRAIL/TNFSF10) mRNA level and a higher level of membrane bound TRAIL (mTRAIL) on radiosensitive compared to radioresistant T4EM lymphocytes. Functionally, we show that mTRAIL mediates a pro-apoptotic autocrine signaling after irradiation of T4EM lymphocytes linking mTRAIL expression to T4EM radiosensitivity. Using single marker and multimarker Family-Based Association Testing, we identified 3 SNPs in the TRAIL gene that are significantly associated with T4EM lymphocytes radiosensitivity. Among these 3 SNPs, two are also associated with acute and subacute dermatitis after radiotherapy in breast cancer indicating that T4EM lymphocytes radiosensitivity may be used to predict response to radiotherapy. Altogether, these results show that mTRAIL level regulates the response of T4EM lymphocytes to ionizing radiation and suggest that TRAIL/TNFSF10 genetic variants hold promise as markers of individual radiosensitivity.
Highlights
Inter-individual differences in radiosensitivity are described since the discovery of the effects of ionizing radiation on human, and are associated with toxicity that patients treated with radiotherapy may experience
Exponential regression coefficients of dose-survival curves were used to classify human Peripheral blood mononuclear cells (PBMC) samples according to the radiosensitivity of their T4 effector-memory (T4EM) lymphocytes and radiosensitive and radioresistant samples were defined at the two ends of the T4EM lymphocytes radiosensitivity distribution
Using a radiosensitive to radioresistant ratio of more than 2, an expression level at least 3 times over background and p < 0.01, we identified 31 genes expressed at a higher level, and 33 genes expressed at a lower level in radiosensitive T4EM lymphocytes (Supplementary Table 1)
Summary
Inter-individual differences in radiosensitivity are described since the discovery of the effects of ionizing radiation on human, and are associated with toxicity that patients treated with radiotherapy may experience. No consensus exists on available biological tests that can be reliably used for prediction of early- and/ or late clinical adverse effects associated with radiotherapy [3, 4]. This absence of predictive tests for individual radiosensitivity together with deleterious side effects www.impactjournals.com/oncotarget observed in a minority of patients treated by radiotherapy led to limitation of the radiation dose used in radiotherapy. Beyond technical developments such as optimizing radiation delivery, improving radiotherapy outcome requires a better understanding of the underlying mechanisms of individual radiosensitivity [5] that will allow personalized radiotherapy
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