Gene expression following ionising radiation: Identification of biomarkers for dose estimation and prediction of individual response
Sylwia Dziwura1, Alan Mackay2, Paul Finnon1, Simon Bouffler1, Christophe Badie1
1Health Protection Agency, Chilton, Didcot, Oxfordshire, UK, 2The breakthrough Breast Cancer Research centre at the Institute of Cancer Research, London, UK
Ionising Radiation (IR) is widely used in cancer treatment and is a well-known environmental carcinogen. In response to IR, DNA damage activates the DNA Damage Response network which maintains genomic stability by activating cell-cycle checkpoints and other pathways. ATM (Ataxia Telangiectasia Mutated) plays a central role in the cellular response to IR. Post-translational modifications of ATM associate with changes in gene expression which impact on cell fate in the short term as well as the long term [1]. Numerous studies demonstrate the successful use of gene expression profiling in cancer research to characterise tumour subtypes or predict the therapeutic response to drugs or IR. We recently showed [2] that CDKN1A transcriptional response associates with abnormal sensitivity to radiation treatment.
In this study, we compared gene expression response to IR in stimulated T-lymphocytes and whole blood from normal individuals and an AT patient to identify biomarkers of radiation exposure. Analysis of micro RNA responses to IR is also underway.
Microarray analysis identified hundreds of gene expression changes in response to IR. Responses were very heterogeneous between donors and between whole blood and stimulated lymphocytes. Nevertheless, we identified four genes which respond to radiation in all individuals, at all time points (2 hours to 24 hours) and at different doses in both blood and lymphocytes. Amongst them, CDKN1A and GADD45A, which are good candidate biomarkers of radiation response, are involved in signal transduction and damage response. They provide research tools to examine in vivo dosimetry, therapeutic response and mechanisms of radiation tumorigenesis.
References
[1]Badie C. et al. Molecular and Cellular Biology 2000 Apr;20(7):2358-66
[2]Badie C. et al. British Journal of Cancer 2008 Accepted for publication
