William's Fund

2003

Childhood Cancer Research Fund
John Radcliffe Hospital, Oxford
(Reg. charity no. 1057295)

September 2003 Update from Christopher Mitchell PhD FRCP, Consultant Paediatric Oncologist (formerly William's consultant)

Sophie Hill who started working with us in Since March 2001, has been working part time in the laboratory since the birth of her son. We have now been joined by Elizabeth Rapa, who started work for us in March 2002. Elizabeth has a lot of previous experience in the molecular biology of cancer and has been a great addition to the team. We hope that Elizabeth's work will be suitable for her to complete a PhD thesis during her time with us.We have also recently had a medical student, Emily Carpenter, join us on a temporary contract, but we hope Emily will be able to continue at least some of her work in the lab as she carries on with her medical studies. These three appointments have been possible only as a result of the generosity of the friends and family of William Dodd. We are grateful to Peter and Johanna Dodd for this opportunity to thank all of you who have given so generously to support this research, and to explain a little of what it is we are trying to find out.

First, we need to explain a bit about genetics. Everything about us is encoded in the chemical known as DNA. The DNA in our cells is organised into genes and the genes in turn are organised in chromosomes. The genes provide the blueprint for producing all the proteins that cells need to function. A human cell contains about 100,000 genes, organised into 23 pairs of chromosomes. In any one cell though, only a few genes relevant to that cell's function are turned on or "expressed". Obviously, it is important that the DNA is kept in proper condition while the cells do the work required of them or when they divide, so there are intricate mechanisms within the cell to make sure that any damage is properly repaired and that the chromosomes replicate themselves properly. These mechanisms are also encoded in the genes, so it is rather like having a car that can repair itself if it stops working properly, or can make itself a new one when the old one wears out!

Occasionally, however, when a cell is damaged or divides, the processes do not work properly and the chromosomes can get jumbled up - a process called chromosome translocation. For example, a bit of chromosome 2 can break off and get stuck onto a broken bit of chromosome 13. When this happens part of a gene on one chromosome adjacent to the break can find itself in the company of part of another gene adjacent to the break on the other chromosome. The two genes can then get spliced together to make a completely new gene with all sorts of unusual properties.

Many malignant tumours have within their cells recognisable and specific rearrangements of their chromosomes, and often it is possible to demonstrate that the affected genes have combined to make either a new protein or one that expressed when it shouldn't be. We are particularly interested in a translocation between chromosomes 2 and 13 seen in a type of tumour called a rhabdomyosarcoma, which is a tumour of muscle. We think that the translocation results in one of the involved genes being turned on in a cell type where it ought to be turned off. We are trying to understand how it is that such a thing can happen, in the hope that we might in due course discover a way of turning it off again. Such a discovery might in due course provide us with a completely new way of treating this type of tumour, and might also give us hints for dealing with other types of tumours.

Over the past couple of years we have worked to get our experimental methods established and working smoothly. The techniques we use are difficult to master and are prone to not working - usually for no very obvious or good reason! We have completed a series of experiments showing how the genes involved in the translocation are no longer regulated properly as the cells go through the process of division. We hope that this work will shortly be published in a cancer research journal; when it is, we will of course be acknowledging the support from William's Fund, and I will also supply a link so that any of you who want to read the whole article can easily have access to it.

We are now working on the next set of experiments in which we are trying to disentangle the series of events that follow on from the abnormal regulation e demonstrated previously. To do this work we are using a new method in which we can compare the cells at different points in the process of division and identify any genes that are inappropriately turned on or off. We are also comparing using the same method cancer cells with normal cells. Once the genes have been identified we can determine the code within the gene to see if it is one that has previously been described, and potentially of further interest, or whether it is a completely new gene, and therefore potentially of even more interest. In this process the resources of the Human Genome Project help us hugely, and make the research go much more quickly than would have been the case even five years ago.

Gradually we are building up a complete picture of all the events that are going wrong in the cancer cell. We still have a long way to go and every set of new results tends to create even more questions than it answers. We were very fortunate recently to get a small grant from the University of Oxford to help with our running and salary costs and we are awaiting the outcome of a number of other grant applications. We hope that the publication of some of our results will help in achieving longer term funding from one of the major cancer charities, but these grants are relatively small in number and extremely competitive. We are very grateful to all of the supporters of William's Fund for giving us the opportunity to pursue our research and to allow us to establish ourselves as making useful contributions to the scientific understanding of childhood cancer.

Christopher Mitchell PhD FRCP, Consultant Paediatric Oncologist (formerly William's consultant)
Sophie Hill PhD, Post-postdoctoral Research Assistant

Elizabeth Rapa MSc, Research Assistant
The Oxford Radcliffe Hospital -A National Health Service Trust

The Childhood Cancer Research Fund is part of the Oxford Radcliffe Hospitals Charitable Fund.

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