REPORT: The cancer epigenome – a new frontier in cancer research
Author: Professor Constanze Bonifer, Head of Experimental Haematology at LIMM (pictured below fifth from the left, front)
Candlelighters funds two projects at St James’s Hospital that use state-of-the-art technology to establish new ways of looking at cancer cells to work out why they are cancerous. This involves the collaboration of the group of Professor Constanze Bonifer, Head of Experimental Haematology at the Leeds Institute of Molecular Medicine (LIMM), and Professor David Westhead, Chair of Bioinformatics, Faculty of Biological Sciences. (See 
pictured Professor Bonifer's Molecular Haemopoiesis and Epigenetics Group at the Section of Experimental Haematology at LIMM. Two of these posts are funded by Candlelighters.)
Cancerous cells all have the same essential problem: they don’t stop growing when the body’s normal systems tell them to. Research in the last few years has led to a new understanding of how cancer cells develop and why these cells do not respond to the signals that control their growth. We are now able to perform new tests that try and lift the veil of why these cells have gone astray. The reason for this, as it turns out, lies in the command centre of all cells: the nucleus, which holds genes coded in strands of DNA.
Genes control how the different types of cells develop. All cells in our body contain the same DNA and genes, since we all develop from one fertilized egg. This egg cell divides very rapidly and then different cell types develop, making the various parts of our bodies. Cells that can go on to grow into many different sorts of cells, for example white blood cells or platelet producing cells, are called ‘stem cells’. (They can be thought of as the stem from which the ‘leaves’ of different types of cells emerge.) The different types of cells switch on vastly different genetic programs. This makes a liver cell that makes enzymes that allow us to drink alcohol very different from a brain cell that allows us to think. It is therefore clear that in addition to the DNA-sequence that contains the genes, there has to be another layer of control that tells which cells to switch which genes on and off. This additional control layer is called the “epigenetic” (‘above the genetic’) layer.
In the last year great progress has been made in our understanding of which molecules in the nucleus form the epigenetic layer or the “epigenome” and tell genes what to do. The core of the matter is how the genes are ‘packed’ into the nucleus by molecules called chromatin proteins. Inactive genes are held tightly compacted by these proteins, and their DNA is hidden, whereas active genes have areas that are ‘unpacked’, and can ‘go to work’. If this process is in any way disturbed, this may lead to serious developmental defects or cancer. This is precisely what has happened in leukaemic cells.
Cancer arises when stem cells, for example in the blood-forming bone marrow, are hit by a mutation (change) in their DNA. Such mutations can come about from anything that can damage DNA, such as X-rays, radioactivity or cigarette smoke, or can just happen by chance, like a spelling mistake when copying out. Often the mutation has no effect at all, but in some cases the cell nucleus contains a gene that is normally not active, or a gene that makes a protein that is normally not made. If this protein switches other genes on or off, the consequences can be devastating. The finely balanced order in which genes are switched on or off is now disturbed. What happens then can be described like a domino effect. First, some genes are regulated the wrong way. This can lead to cells that grow a bit more than they should, but are otherwise quite normal. The body does not notice them, and many perfectly healthy people have cells in their blood that contain a ‘leukaemic’ mutation. However, over time and many generations of blood cells, additional mutations occur that tip the balance from a cell that grows a bit too much, to a cell where normal development grinds to a halt. The cells are then trapped in their immature stage and become malignant, forming leukaemic cells that keep growing and growing, faster and faster, and finally take over the body. The very same process that I have described for leukaemia occurs also in other forms of cancers. However, studies of leukaemias have significantly enhanced our understanding of that process, particularly because the malignant cells of leukaemia are very easy to study by simply taking blood.
In recent years it has been shown that disturbances in the chromatin that ‘packs’ the genes in the cell nucleus accompany these different stages of cancer development. It is now clear that in leukaemia and also in other cancers many genes that should be in an unpacked chromatin structure are suddenly compacted, or vice versa. Therefore new drugs have been developed, so called “epigenetic drugs” that are aimed at reversing these changes. Some people respond to such drugs, others do not, and the scientific basis for this difference is unknown. In addition, we do not know how a small initial mutation that turns a normal blood cell into a pre-cancer cell can over time have such devastating consequences. Up to now we have simply lacked the technology to study the order of events that turn a normal cell over time into a cancer cell.
We now have such a technology and our Candlelighters-supported labs are going to use it to study precisely the questions outlined above. Methods have been developed to determine the entire DNA sequence of one person in a very short time, and this technology has been modified to study changes in the chromatin in all genes of one individual person. This can be used to identify many different “epigenetic” alterations. We recently acquired one of these new machines at St James’s Hospital which is operated by Professor Graham Taylor. Several groups at the Section of Experimental Haematology are now comparing normal and mutated cells and examine what is wrong with them. One feature of such experiments is that they produce enormous amounts of data and it takes specialist knowledge to make sense of them. This is done by bioinformaticians, 
such as Professor David Westhead (see pictured below) and his group who develop new computer programs to interpret the information that the laboratory workers have produced.
The results of these experiments may be extremely important for how we diagnose patients in the future. DNA-sequencing technology is becoming cheaper every day and there will come a time when we will be able to perform such studies with each patient that is diagnosed as a carrier of a mutation or who has developed the disease. We hope that ‘personalized medicine’ will then allow us to tailor therapies targeted precisely at the problem identified in that individual. This is currently many years away: first we will have to develop and rigorously test such new technologies. These initial steps are what we are currently doing and our early results are very promising.
