Vinita Chauhan, Andrew Williams, Carole L. Yauk
Overall, TGx-DDI demonstrated proof of concept by identifying radiation-associated transcriptional activation of DDR at moderate to high doses, while revealing differences in DDR-associated transcriptional responses across donors at low doses. This study represents the first application of TGx-DDI at the individual level, providing preliminary evidence that transcriptomic biomarkers may be used for individualized radiation response profiling in future studies.
PURPOSE: The DNA damage response (DDR) and repair pathways are well-characterized mechanisms that maintain genomic integrity following genotoxic stress. However, the dose at which these pathways are transcriptionally activated for ionizing radiation and how they vary across individuals remains an important area for investigation. The TGx-DDI transcriptomic biomarker panel, a 64-gene signature originally developed in TK6 lymphoblastic cells, was designed to distinguish DNA damage-inducing (DDI) from non-DDI agents through key transcriptional responses in the DDR pathway. While validated for chemical exposures, its application to ionizing radiation remains limited. Here, we evaluate whether TGx-DDI can detect coordinated DDR-associated transcriptional activation following X-ray exposure at the individual donor level across a range of radiation doses and dose-rates. MATERIALS AND METHODS: platform. RESULTS: TGx-DDI classification outcomes of the dataset showed clear dose- and dose-rate dependencies. Under both dose rate conditions, DDI classifications were observed at most doses across donors, although non-DDI- calls occurred at lower doses in a subset of individuals. More TGx-DDI responsive donors exhibited detectable DDI responses at very low doses (as low as 0.05 Gy), whereas less TGx-DDI responsive donors showed responses only at higher doses (≥1 Gy) or were non-responsive. CONCLUSION: Overall, TGx-DDI demonstrated proof of concept by identifying radiation-associated transcriptional activation of DDR at moderate to high doses, while revealing differences in DDR-associated transcriptional responses across donors at low doses. This study represents the first application of TGx-DDI at the individual level, providing preliminary evidence that transcriptomic biomarkers may be used for individualized radiation response profiling in future studies.