Gene expression following ionising radiation: Identification of biomarkers for dose estimation and prediction of individual response

Abstract

Purpose: To establish a panel of highly radiation responsive genes suitable for biological dosimetry and to explore inter-individual variation in response to ionising radiation exposure.

Materials and methods: Analysis of gene expression in response to radiation was carried out using three independent techniques (Microarray, Multiplex Quantitative Real-Time Polymerase Chain Reaction (MQRT- PCR) and nCounter® Analysis System) in human dividing lymphocytes in culture and peripheral blood leukocytes exposed ex vivo from the same donors.

Results: Variations in transcriptional response to exposure to ionising radiation analysed by microarray allowed the identification of genes which can be measured accurately using MQRT PCR and another technique allowing direct count of mRNA copies. We have identified genes which are consistently up-regulated following exposure to 2 or 4 Gy of X-rays at different time points, for all individuals in blood and cultured lymphocytes. Down-regulated genes including cyclins, centromeric and mitotic checkpoint genes, particularly those associated with chromosome instability and cancer could be detected in dividing lymphocytes only.

Conclusions: The data provide evidence that there are a number of genes which seem suitable for biological dosimetry using peripheral blood, including sestrin 1 (SESN1), growth arrest and DNA damage inducible 45 alpha (GADD45A), cyclin-dependent kinase inhibitor 1A (CDKN1A), cyclin G1 (CCNG1), ferredoxin reductase (FDXR), p53 up-regulated mediator of apoptosis (BBC3) and Mdm2 p53 binding protein homolog (MDM2). These biomarkers could potentially be used for triage after large-scale radiological incidents and for monitoring radiation exposure during radiotherapy.

Keywords:

• ionising radiation
• biodosimetry
• individual response
• gene expression
• biomarkers
• peripheral blood lymphocytes

Acknowledgements

We thank Richard Doull (MRC Harwell) for irradiations. This work was supported in part by Cancer Research UK (C181/A6976) and Breakthrough Breast Cancer.

Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.