Radiation protection of low dose ionizing radiation is currently based on linear extrapolation from high doses. Estimates of risk from radiation exposure are based on the mean exposure to a population. The effectiveness of radiotherapy (RT) for many tumours is dose limited to minimise late effects in normal tissue. Clinical observations of adverse effects indicate large variations in individuals. Strategies linking normal tissue and various phenotypical responses at high doses to predict individual risk of normal tissue response have not been successful. The internationally-leading, EU funded GENEPI-ENTB provides a valuable resource on normal tissue effects in a large cohort of RT patients. The objective is to couple analysis of cellular responses at low dose with the GENEPI bio-bank, providing an ideal opportunity to address whether differential genome-wide expression responses induced at low dose and inter-individual genetic differences are associated with the development of severe, normal tissue effects. A team of leading European clinical and basic scientists will address the following objectives:

The overall objectives

• Explore links between the development of severe, normal tissue toxicity following radiotherapy with transcriptional changes and modulation of gene expression induced at low doses and
• Identify links between individual radiosensitivity and genetic factors.

Approaches that will be used to address the objectives

• Identify two groups of breast cancer patients who are statistically different in their normal tissue response to radiotherapy, e.g. non- and over responders.
• With due consideration of applicable regulations and ethical guidelines and appropriate patient consent, the required number of patients (~50 in each Group) will be identified to obtain anonymised skin biopsies from a non-irradiated field and blood samples to establish fibroblast and T-cells.
• Undertake a pilot study to standardise and optimise the assays using primary fibroblasts already availably with different radiation doses and assayed at various times post-irradiation.
• Undertake genotyping and functional analysis after low dose radiation (around 0.1 Gy from the pilot study) on the cells obtained and identify inter-cellular differences in gene expression and functionality.
• Retrospective analysis for any correlation between the genetic and functional findings to the severity of normal tissue responses of the patients and individual susceptibility.

The main deliverable is to provide knowledge for better quantification of non-cancer health risks and identify potential genetic components of relevance to occupational, environmental and medical exposure to radiation.

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