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April 2002 Volume 4, Issue 10:
ASK THE EXPERTS: Genetic Testing to Determine the Cause and Outcome of Myeloma
By Gareth J. Morgan, PhD
"DNA damage is one of the key features of myeloma. Another important area being studied is how variation in the capacity of the body to repair such damage can affect the risk of developing myeloma."
A question of interest to both patients and doctors alike is why, if a group of people encounter a toxic exposure, only a limited number of them develop disease. ?Is it just bad luck?? is a frequently asked question. While there is undoubtedly a contribution of chance, it is not the whole story. Doctors are just beginning to address this question using the information coming from our new understandings of human genome. It is clear to everyone that people differ in size, eye and skin colour and nobody would be surprised to be told that people with dark skin are less susceptible to developing sunburn if they lie on the beach in the summer. The same is true for all the systems of the body where a range of functional activity between people can be identified. These variations are governed by minor genetic changes and can affect the risk of developing a variety of different diseases including cancer and myeloma. The trouble has been that until now we have not been able to recognise these differences.

What has changed recently is that we can now recognise some of the changes in the genetic code, which makes up DNA that governs these differences. The commonest of these changes are known as SNPs (single nucleotide polymorphisms) and there could be as many as 60,000 of these which exert effects on disease. The changes alter either the amount of a protein or its function and, therefore, they can affect the chance of developing myeloma, its time of onset or its severity, and what is more, it is now being suggested that, these changes can affect the outcome of treatment. These changes can now be easily detected using modern diagnostic tests, which means for the first time their clinical significance can be fully explored.

Over the next years, it is expected that we will be able to detect a complete genetic profile for an individual and so predict their likelihood of developing a disease and their outcome after treatment.

Now that we can detect these changes, we need to apply them in the clinical environment with the aim of solving issues important for myeloma patients. One common question that causes major concern is whether they have an inherited disease, which means their children are at increased risk of developing myeloma. Certain rare families with an apparent increased risk of myeloma have been identified, but in the overwhelming majority of cases it is not considered to be familial and does not pose any increased risk for the children or families of patient. So it can cause confusion if doctors say that inherited genetic variation can contribute to the risk of developing myeloma. It is, therefore, important to point out the major differences between a familial disease and a genetic predisposition. The most important differential features of these two distinct states is the number and type of genes involved. In a familial disease it is usually a single gene, which causes very obvious effects and inevitably gives rise to disease usually at a young age. For the genetic predisposition we describe here, it is not a single abnormality that is important but the combined effects of variation within a number of different body systems together with a significant impact from life style and environmental exposures. Consequently, in order to study this question, scientists need to combine expertise in genetics with exposure assessment and epidemiology rather than looking within families. The studies often have to be large, well designed, and combine an assessment of exposure with tests for genetic variation.

One of the important features of these genetic variants is that they can modify the effects of toxic exposures, which can cause myeloma encountered in everyday life. This type of effect is referred to as a ?gene/environment interaction?. This concept is well illustrated by considering the consequences of exposing a group of individuals to a large amount of a toxin known to cause myeloma. In this case the majority of exposed individuals would be expected to develop disease. However, in the normal environment, exposure levels are low and only susceptible individuals would be expected to develop disease. The susceptible individuals could be identified by their genetic make up but would be at no increased risk in the absence of the toxic exposure.

A number of distinct body systems have been identified which can affect the damage occurring as a consequence of environmental exposures.

These include the Glutathione S Transferase (GST) family of proteins, which protect against a number of toxic environmental exposures, and the cytochrome P450 (CYP450) family of proteins, which can act to increase the damaging effects of a toxin before it is removed from the body. Underactivity at GST may therefore be a risk factor as may over-activity at CYP450. DNA damage is one of the key features of myeloma. Another important area being studied is how variation in the capacity of the body to repair such damage can affect the risk of developing myeloma. Genetic variation in the cytokine control of the immune system could also affect the risk of developing myeloma. IL6 is a key cytokine and a number of studies have looked at inherited variation within this gene. No associations have been found as yet but there has been a suggestion that variation affecting the pro-inflammatory cytokine TNFa has been suggested to affect the risk of developing myeloma.

Using these new tests in this fashion is designed to help us understand what exposures cause myeloma and also to identify individuals who are at increased risk. While this type of observation will in time lead us to understand, and possibly prevent, exposure to factors which cause myeloma, there is another use to which this information can be put. In many ways, the current treatments used for myeloma can be considered as toxic exposure where the benefits of exposure far outweigh the toxic effects. However, in some individuals the risks of side effects may be greater, and where alternate treatment options are available it may be preferable to use these. Genetic testing is beginning to help in this area. The GST P1 subtype of glutathione S transferase is important in the metabolism of some of the most effective chemotherapy agents used for the treatment of myeloma (alkylating agents like melphalan and cyclophosphamide). It has a number of different genetic variants, which can decrease its activity. Individuals who have inherited the under-active variants seem to have an increased risk of side effects but seem to have a better outcome after treatment. This approach is not fully developed and could not be used to direct treatment at present, but if this sort of testing is integrated into future trials it will allow us to use our treatments better. Genetic testing can also be used to help in the development of new treatments. Many pharmaceutical companies discard active therapeutic agents because the rare individual develops side effects. These individuals often have a defined genetic make up, and if this can be recognised, the drug can be reserved for people who do not get side effects and will benefit from treatment. The study of this area is called pharmacogenomics. These tests have to be distinguished from tests on the myeloma tumour DNA. Tests on this material using the new genetic approaches are designed with the aim of predicting how the tumour cells will respond to treatment.

Access to genetic information is one of the key developments that has given doctors a new tool to develop more effective prevention and treatment strategies for myeloma. It is important to use this new approach in the correct clinical settings: clinical trials and case control studies. This means that patients will be asked to give their permission for their blood samples to be taken, stored, and tested. If we are going to make effective progress in eradicating the clinical consequences of myeloma, it is important that patients take part in these studies. These studies have to be large, and consequently doctors and scientists will have to come together in large groupings with the common goal of understanding and treating this disease.

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