A test for sensitivity of normal tissue to radiation damage?

Researchers find genetic variations that could be used to help tailor radiotherapy doses to individual patients

Researchers in Denmark have identified specific changes in the basic building blocks of DNA that can affect how sensitive a patient is to radiotherapy. Their findings offer a glimmer of hope that it might be possible to develop gene-based predictive tests that would enable doctors to work out the highest dose a patient could tolerate, thereby improving the efficacy of radiotherapy treatment.

Dr Nicolaj Andreassen told a news conference at ECCO12 – The European Cancer Conference that he and his colleagues had studied five genes that were known to be involved in the body’s response to radiation. They had looked at the sequence of the four different nucleotides (A, T, G and C) that make up the DNA of each gene and found particular places in the genetic sequence where the sequence varied from the norm in a way that could affect the proteins that the gene was responsible for coding for (or making).

The spots on the genes where these variations are found are called single nucleotide polymorphisms (SNPs), and they represent sites where a number of people have a nucleotide that is different to the nucleotide that most people would have – for instance, a T instead of a C. SNPs mean that certain people may have a protein that works in a different way to the corresponding protein in other people, and these differences in protein function contribute to making us different to one another and with bodies that behave in different ways to external challenges such as radiotherapy.

Dr Andreassen, a research fellow at the Department of Experimental Clinical Oncology at Aarhus University Hospital, Denmark, found that in 41 women treated with radiotherapy after a mastectomy between 1978 and 1982, five SNPs in four genes correlated with different levels of two types of radiation damage: subcutaneous fibrosis (scarring under the skin) and telangiectasia (an increase in small blood vessels under the skin).

The XRCC1 and XRCC3 genes code for proteins involved in the repair of radiation-induced DNA damage; SOD2 is the gene for the protein that eliminates toxic reactive oxygen species, which are known to be generated in large quantities when tissues are irradiated; TGFB1 produces a protein that is assumed to play a major role in the development of tissue fibrosis. Dr Andreassen found that SNPs on the XRCC1, XRCC3, SOD2 and TGFB1 were all associated with the risk of radiation-induced subcutaneous fibrosis. The XRCC3 gene was also associated with the risk of telangiectasia.

Everyone has two copies of a gene, one inherited from the father and one from the mother. Dr Andreassen and colleagues placed their patients into three groups: two groups were for patients who had genes where both copies either had a certain variant of the SNP or did not (homozygous), and a third group for patients where one copy of the gene had the variant SNP and the other did not (heterozygous).

He said: “We observed that patients with two copies of one nucleotide (for instance, two Ts) were more radiosensitive than those with two copies of the other nucleotide (for instance, two Cs) whereas those with one of each nucleotide (for instance, a T and a C) at the polymorphic site exhibited intermediate radiosensitivity. This showed that the SNPs influence radiosensitivity, and that a particular genetic pattern at these sites correlates with increased or decreased radiosensitivity.

“For each of the polymorphisms that affected radiosensitivity significantly, we found that patients with two ’favourable copies’ tolerated a 15-25% higher radiation dose compared to those with two ’unfavourable copies’. Typically, those with one favourable and one unfavourable copy, at the polymorphic site, tolerated an approximately 10% higher radiation dose than those with two unfavourable copies, hence their radiosensitivity was intermediate.

“Our findings indicate that normal tissue radiosensitivity should be considered as a trait dependent on the combined effect of variations in several genes, and that SNPs could constitute a substantial proportion of such genetic determinants. This means that normal tissue radiosensitivity could be predicted from individual genetic patterns or profiles.”

Dr Andreassen said that although the results needed to be confirmed and more work was necessary, this could be the first step to developing tests that could predict the way individual patients would respond to radiotherapy and improving treatments.

At present, radiotherapy doses are often restricted by what the most radiosensitive patients can tolerate, keeping the risk of severe persistent normal tissue damage below 5-10%, despite the fact that many patients could tolerate a larger dose without severe tissue reactions.

“The aim of developing predictive assays is to enable individual tailoring of treatments. If normal tissue radiosensitivity could be reliably predicted prior to treatment, the radioresistant patients could be offered a somewhat higher dose. In many cases this would increase the chances of cure substantially. Occasionally, more than one treatment strategy exists for the same disease. In such situations predictive assays could be used to decide whether radiotherapy should be included in the treatment,” explained Dr Andreassen.

“Even though our results should be regarded as preliminary, we consider them very interesting and important. They shed new light on the genetic basis that seems to underlie differences in normal tissue radiosensitivity and provide backing for the concept of gene-based predictive tests for patients.”

The research will be fed into the ESTRO project GENEPI, which aims to collect biological specimens and clinical data from European radiotherapy patients with the intention of establishing correlations between genetic markers and clinical outcome. The project should give researchers important information about the influence of genetic factors on normal tissue radiosensitivity so that findings from this and other research can be put to good use in the clinic to improve treatments for patients.

Note: The study was supported by grants from the Danish Cancer Society, the Clinical Research Unit at the Department of Oncology, Aarhus University Hospital, the Danish Medical Research Council and ’Max og Inger Wørzners Mindelegat’.

Further information:
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