Abstract
Following recent developments, the RENEB network (Running the European Network of biological dosimetry and physical retrospective dosimetry) is in an excellent position to carry out large scale molecular epidemiological studies of ionizing radiation effects, with validated expertise in the dicentric, fluorescent in situ hybridization (FISH)-translocation, micronucleus, premature chromosome condensation, gamma-H2AX foci and gene expression assays. Large scale human health effects studies present complex challenges such as the practical aspects of sample logistics, assay costs, effort, effect modifiers and quality control/assurance measures. At Public Health England, the dicentric, automated micronucleus and gamma-H2AX radiation-induced foci assays have been tested for use in a large health effects study. The results of the study and the experience gained in carrying out such a large scale investigation provide valuable information that could help minimise random and systematic errors in biomarker data sets for health surveillance analyses going forward.
Highlights
One of the hallmarks of ionizing radiation is its ability to induce DNA double-strand breaks, lesions that are difficult to repair and prone to mis-repair, resulting in mutations and chromosomal aberrations such as dicentrics or acentric fragments [1]
These biomarkers of radiation exposure and effect are key tools to (i) support the clinical management of critically exposed individuals and reassure the ‘worried well’ following a radiation accident or incident, e.g., [3]; (ii) support counselling on the likelihood of long-term health radiation-induced effects such as cancer, e.g., [4]; (iii) provide dose estimates in epidemiological studies of health risks associated with radiation exposure, e.g., [5]; and (iv) predict the response of a tumour and the patient’s normal tissues to radiotherapy in order to personalise treatment and maximise the probability of complication-free tumour control, e.g., [6]
CHHIP (Conventional Hypofractionated High Dose Intensity Modulated Radiotherapy for Prostate Cancer (ICRCTN97182923)) is a randomised trial to see whether hypofractionated radiotherapy schedules for localised prostate cancer could improve the therapeutic ratio by either improving tumour control or reducing normal tissue side effects [19]
Summary
One of the hallmarks of ionizing radiation is its ability to induce DNA double-strand breaks, lesions that are difficult to repair and prone to mis-repair, resulting in mutations and chromosomal aberrations such as dicentrics or acentric fragments [1]. The modification or accumulation of DNA damage response proteins at the site of DNA double-strand breaks can be visualised as gamma-H2AX and 53BP1 foci [2] These biomarkers of radiation exposure and effect are key tools to (i) support the clinical management of critically exposed individuals and reassure the ‘worried well’ following a radiation accident or incident, e.g., [3]; (ii) support counselling on the likelihood of long-term health radiation-induced effects such as cancer, e.g., [4]; (iii) provide dose estimates in epidemiological studies of health risks associated with radiation exposure, e.g., [5]; and (iv) predict the response of a tumour and the patient’s normal tissues to radiotherapy in order to personalise treatment and maximise the probability of complication-free tumour control, e.g., [6]. Progress in the area of predictive markers of individual response to radiation exposure has been much more limited, a number of small scale studies (7–10 patients plus matched controls) and recently larger studies (42–>1000 patients) have suggested an association of DNA double-strand break-related markers or apoptosis with clinical radiosensitivity in non-syndromic patients [8,9,10,11,12,13]
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