Susanna Cooke investigates translocations and their role in cancer

The DNA of solid tumours, such as breast, colorectal and lung cancers, undergoes many alterations compared to that of normal cells. One example of this is the rearrangement of DNA (translocation), rather than changes to the DNA code (mutation). DNA in healthy human cells is arranged into 23 pairs of chromosomes, whilst the DNA in cancer cells can undergo chromosomal rearrangement as a result of translocations. These chromosomal translocations join sequences from two different chromosomes. Historically, the importance of this particular type of rearrangement in solid tumours has been disregarded since translocations usually result in loss of material from the chromosomes involved and it was this loss, rather than the junction where the two chromosomes fuse, that was assumed to be important.

Chromosomal translocations in solid tumours are often considered to be 'unbalanced'. This means that there is loss of chromosomal material in the process of breaking and fusing with another chromosome. Previously, it was thought that the resulting loss of DNA causes the effects of chromosomal translocations in cancer development. Genes that would normally be present on the chromosomes are lost during translocations thereby changing the cell's genetic identity. However, it has recently emerged that many more translocations than expected are actually 'balanced'. Balanced translocations can occur without any associated loss of DNA when two chromosomes break and each piece of one chromosome fuses to a piece of the other. When these types of translocations occur the only change that could be contributing to cancer development is the point of fusion. Since all the genetic material is still present, the point of fusion is the only affected region where some change would have happened.

The importance of chromosomal translocation, including balanced translocation, in liquid tumours such as leukaemias and lymphomas, is well established. This was first observed in chronic myeloid leukaemia (CML), where 90% of cases have a balanced translocation of chromosomes 9 and 22. Chromosomal translocations are traditionally expected to be products of a fusion between the broken ends of two different chromosomes. However, they can be more complex and this can correlate with poor prognosis.

Given the prevalence of this 9-22 fusion in CML, one would predict that this fusion were crucial for disease development. Studies have revealed that the translocation fuses the front end of one gene, BCR, to the tail end of another gene, ABL. The ABL gene encodes an enzyme (tyrosine kinase) that has a role in cell division and differentiation. The translocation results in its constitutive activation. This means that, instead of becoming functional white blood cells, cells with the translocation divide continuously, never developing enough to carry out their specialised function. This defines them as tumour cells.

The ubiquity of this translocation in CML, and its importance to malignancy, make it an ideal therapeutic target. The drug imatinib mesylate (known commercially as Glivec) was designed to inhibit the activity of this fusion protein and has proved to be one of the most successful anti-cancer drugs ever developed. This highlights the main advantage of using fusion genes as therapeutic targets: they are unique to the cancer cells and therefore allow more selective targeting of culprit cells than the standard chemotherapy agents.

Recent research has begun to show that chromosomal translocations may be just as important in the development of solid tumours as they are in leukaemias and lymphomas. In 2005, scientists at the University of Michigan showed that around 80% of prostate cancers have a fusion of TMPRSS2, a gene which is highly expressed in the prostate, to either the ERG or ETV1 genes, which act to control the expression of dozens of other genes. This results in high production of the ERG and ETV proteins in the prostate cells, where they are not usually found, thus contributing to malignant changes. This study clearly demonstrated the existence of genes commonly affected by fusion and recurrent chromosomal rearrangements in solid tumours.

The general aims of cancer research are three-fold. The ultimate aim is to identify new therapeutic targets and develop new therapies that will allow successful treatment of the disease. However, at this stage in our battle against cancer, it is also important to identify new diagnostic and prognostic markers. Early diagnosis dramatically increases the chances of successful treatment. The accurate prediction of disease course and outcome increases the treatment options available to the patient. Patients with a naturally less aggressive form of cancer can be treated more conservatively, thus avoiding the side effects of intensive treatment. Patients with the most aggressive forms of disease can be given more informed decisions about whether to pursue treatment, with serious side effects, when it is unlikely to have any significant impact on survival. The recent discovery of chromosome translocations that contribute to the development of solid tumours has the potential to impact both cancer therapy and prognostics. The resulting fusions provide unique targets for therapy. The presence and structure of a translocation can correlate with disease course and outcome. This furthers our understanding of the causes and potential treatments of cancer.

Suzanne Cooke is a PhD student in the Department of Pathology